is legal and common. In fact, one in five prescriptions
written today are for off
–
label use.
—
Agency for Healthcare Research and Quality
Psychotropic drugs are commonly used for children and adolescents to treat mental health
disorders, yet many of these drugs are not FDA approved for use in these populations. Thus,
their use is consi
dered “off
–
label,” and it is often up to the best judgment of the prescribing
clinician. As a PMHNP, you will need to apply the best available information and research on
pharmacological treatments for children in order to safely and effectively treat chil
d and
adolescent patients. Sometimes this will come in the form of formal studies and approvals for
drugs in children. Other times you may need to extrapolate from research or treatment
guidelines on drugs in adults. Each individual patient case will need
to be considered
independently and each treatment considered from a risk assessment standpoint. What
psychotherapeutic approach might be indicated as an initial treatment? What are the potential
side effects of a particular drug?
NOTE
:
For this Ass
ignment, you consider these questions and others as you explore FDA
–
approved (“on
label”)
pharmacological treatments, non
-FDA-
approved (“off
-label”)
pharmacological treatments, and nonpharmacological treatments for disorders in children and
adolescents.
REFERENCE
https://www.ahrq.gov/patients
–
consumers/patient
–
involvement/off
-label-drug-
usage.html
TO PREPARE
·
Your Instructor will assign a specific disorder for you to research for this Assignment.
·
Use the
SCH
OOL
library to research evidence
–
based treatments for your assigned
disorder in
children and adolescents.
You will need to recommend one FDA
-approved
drug, one off
–
label drug, and one nonpharmacological intervention for treating this
disorder in children and adolescents.
The Assignment (1
–
2 pages)
Recommend one FDA-approved drug, one off-label drug, and one nonpharmacological intervention for treating your assigned disorder in children and adolescents.
Explain the risk assessment you would use to inform your treatment decision making. What are the risks and benefits of the FDA-approved medicine? What are the risks and benefits of the off-label drug?
Explain whether clinical practice guidelines exist for this disorder and, if so, use them to justify your recommendations. If not, explain what information you would need to take into consideration.
Support your reasoning with at least three scholarly resources, one each on the FDA-approved drug, the off-label, and a non-medication intervention for the disorder. Attach the PDFs of your sources.
THE SPEICIFIC DISORDER: ADHD in child or adolescent.
ASSIGNMENT 1
:
Prescribing for Children and Adolescents
Off
–
label prescribing is when a physician gives you a drug that the U.S. Food and
Drug Administration (FDA) has approved to treat a condition different than your
condition. This practice
is legal and common. In fact, one in five prescriptions
written today are for off
–
label use.
—
Agency for Healthcare Research and Quality
Psychotropic drugs are commonly used for children and adolescents to treat mental health
disorders, yet many of these drugs are not FDA approved for use in these populations. Thus,
their use is consi
dered “off
–
label,” and it is often up to the best judgment of the prescribing
clinician. As a PMHNP, you will need to apply the best available information and research on
pharmacological treatments for children in order to safely and effectively treat chil
d and
adolescent patients. Sometimes this will come in the form of formal studies and approvals for
drugs in children. Other times you may need to extrapolate from research or treatment
guidelines on drugs in adults. Each individual patient case will need
to be considered
independently and each treatment considered from a risk assessment standpoint. What
psychotherapeutic approach might be indicated as an initial treatment? What are the potential
side effects of a particular drug?
NOTE
:
For this Ass
ignment, you consider these questions and others as you explore FDA
–
approved (“on label”) pharmacological treatments, non
–
FDA
–
approved (“off
–
label”)
pharmacological treatments, and nonpharmacological treatments for disorders in children and
adolescents.
Psychotropic drugs are commonly used for children and adolescents to treat mental health
disorders, yet many of these drugs are not FDA approved for use in these populations. Thus,
their use is considered “off-label,” and it is often up to the best judgment of the prescribing
clinician. As a PMHNP, you will need to apply the best available information and research on
pharmacological treatments for children in order to safely and effectively treat child and
adolescent patients. Sometimes this will come in the form of formal studies and approvals for
drugs in children. Other times you may need to extrapolate from research or treatment
guidelines on drugs in adults. Each individual patient case will need to be considered
independently and each treatment considered from a risk assessment standpoint. What
psychotherapeutic approach might be indicated as an initial treatment? What are the potential
side effects of a particular drug?
NOTE: For this Assignment, you consider these questions and others as you explore FDA-
Zakhari, R. (2020). The psychiatric-mental health nurse practitioner certification review manual. Springer.
Chapter 5, “Psychopharmacology”
REQUIRED MEDIA
RUBR
IC
TO FFL FOR ASSIGNMENT 1 DIDATIC
Ex
c
ellent
Good
Fair
Poor
In 1
–
2 pages, address th
e
f
ollowing:
• Recommend one
FDA
–
appro
ved
drug, one
of
f
–
label drug,
and one
non
ph
arm
acological
intervention for
treating your assigned disorder in
children and
adolescents.
23
(23%)
–
25
(25%)
The response accurate
ly
and concise
ly
explains one FDA
–
approved drug, one
off-
label drug, and
one
nonpharmacologic
al intervention
that
would be appropriate for treating the
assigned
disorder in children
and
adolescents.
2
0
(
20
%)
–
22
(22%)
The response accurately explains one
FDA-
approved drug, one off
-label drug,
and one nonpharm
acological
intervention that would be appropriate
for treating the assigned disorder in
children and adolescents.
1
8
(18%)
–
1
9
(19%)
The response somewhat vaguely or
inaccurately explains one FDA
–
approved drug, one off-label drug, and
one nonpharmacologic
al intervention
that would be appropriate for treating
the
assigned disorder in children and
adolescents.
0
(0%)
–
1
7
(17%)
The response vaguely or inaccurately
explains interventions that would be
appropriate for treating the assigned
disorder in children
and
adolescents.
Interventions may not represent the
three types of interventions required,
or response may be
missing.
• Explain the risk assessment you
would use to inform your treatment
decision making. What are the risks
and benefits of
the FDA
-approved
medicine? What are the risks and
benefits of the off
–
label drug?
23 (23%) – 25 (25%)
The response accurately and concisely
explains the risk assessment you would
use to
inform your treatment decision
making. A concise and accurate
explanation of the ri
sks and benefits of
each ph
armacological
intervention is
provided.
20
(20%)
– 22 (22%)
The response accurately explains the
risk assessment you would use to
inform your treatment decision
making. An adequate explanation of
the risks and benefits of each
pharmacological intervention is
provided.
18 (18%) – 19 (19%)
The response somewhat vaguely or
inaccurately explains the risk
assessment you would use to inform
your treatment decision making. The
explanation of the risks and benefits of
each pharmacological
intervention is
somewhat vague or inaccurate.
0 (0%) – 17 (17%)
The response vaguely or inaccurately explains the risk assessment you would
use to inform your treatment decision
making. The risks and benefits of each
pharmacological intervention is vague
or inaccurate. Or, the response is
missing.
• Explain whether clinical practice
guidelines exist for this disorder and, if
so, use them to justify your
recommendations.
If not, explain what
information you would need to take
into considerat
ion.
23 (23%) – 25 (25%)
The response accurately and concisely
uses either clinical guidelines (if
available) or other information from
the lit
erature to
justify intervention
recommendations.
20 (20%) – 22 (22%)
The response accurately uses either
clinical
guidelines (if available) or other
information from the lit
erature to
justify
intervention recommendations.
18 (18%) – 19 (19%)
The response somewhat vaguely or
inaccurately uses either clinical
guidelines (if available) or other
information from the literature to
justify intervention recommendations.
0 (0%) – 17 (17%)
The response vaguely or inaccurately uses either
clinical guidelines (if available) or other
information from
the literature to justify intervention
recommendations.
Or, the response is
missing.
• Support your reasoning with at least
three scholarly
resources, one each on
the FDA-
approved drug, the off
–
label,
and a non
–
medication intervention for
the disorder. Be sure they are current
(no more than 5 years old). Attach the
PDFs of your sources.
9
(9%)
–
10
(10%)
The response provides at least thre
e
c
urrent, evidence
–
based resources
from the literature to support the
intervention recommendations.
The
resources reflect the latest clinical
guidelines and provide strong justification for decision making.
8
(8%)
– 8 (8%)
The response provides at least three
current, evidence
-based resources from the literature
to support the intervention
recommendations.
7
(7%)
– 7 (7%)
Three evidence
–
based resources are
provided to support the intervention
recommendations, but they may only
provide vague or weak justificat
ion.
0 (0%) –
6
(6%)
Two or fewer resources are provided
to support the intervention
recommendations. The resources may
not be current or evidence based.
Written Expression and Formatting – Paragraph Development and Organization:
Paragraphs make clear points that support well-developed ideas, flow logically, and demonstrate continuity of ideas. Sentences are carefully focused—neither long and rambling nor short and lacking substance. A clear and comprehensive purpose statement and introduction are provided that delineate all required criteria.
5 (5%) – 5 (5%)
Paragraphs and sentences follow writing standards for flow, continuity, and clarity.
A clear and comprehensive purpose statement, introduction, and conclusion are provided that delineate all required criteria.
4 (4%) – 4 (4%)
Paragraphs and sentences follow writing standards for flow, continuity, and clarity 80% of the time. Purpose, introduction, and conclusion of the assignment are stated, yet are brief and not descriptive.
3.5 (3.5%) – 3.5 (3.5%)
Paragraphs and sentences follow writing standards for flow, continuity, and clarity 60%–79% of the time.
Purpose, introduction, and conclusion of the assignment are vague or off topic.
0 (0%) – 3 (3%)
Paragraphs and sentences follow writing standards for flow, continuity, and clarity <60% of the time.
No purpose statement, introduction, or conclusion were provided.
Written Expression and Formatting – English Writing Standards:
Correct grammar, mechanics, and proper punctuation
5 (5%) – 5 (5%)
Uses correct grammar, spelling, and punctuation with no errors
4 (4%) – 4 (4%)
Contains one or two grammar, spelling, and punctuation errors
3.5 (3.5%) – 3.5 (3.5%)
Contains several (three or four) grammar, spelling, and punctuation errors
0 (0%) – 3 (3%)
Contains many (five or more) grammar, spelling, and punctuation errors that interfere with the reader’s understanding
Written Expression and Formatting – The paper follows correct APA format for title page, headings, font, spacing, margins, indentations, page numbers, parenthetical/narrative in-text citations, and reference list.
5 (5%) – 5 (5%)
Uses correct APA format with no errors
4 (4%) – 4 (4%)
Contains one or two APA format errors
3.5 (3.5%) – 3.5 (3.5%)
Contains several (three or four) APA format errors
0 (0%) – 3 (3%)
Contains many (five or more) APA format errors
Total Points:
RUBR
IC TO FFL FOR ASSIGNMENT 1 DIDATIC
Excellent
Good
Fair
Poor
In 1
–
2 pages, address the following:
• Recommend one FDA
–
approved
drug, one off
–
label drug, and one
nonpharmacological intervention for
treating your assigned disorder in
children and adolescents.
23
(23%)
–
25
(25%)
The response accurately and concisely
explains one FDA
–
approved drug, one
of
f
–
label drug, and one
nonpharmacological intervention that
would be appropriate for treating the
assigned disorder in children and
adolescents.
20
(20%)
–
22
(22%)
The response accurately explains one
FDA
–
approved drug, one off
–
label drug,
and one nonpharm
acological
intervention that would be appropriate
for treating the assigned disorder in
children and adolescents.
18
(18%)
–
19
(19%)
The response somewhat vaguely or
inaccurately explains one FDA
–
approved drug, one off
–
label drug, and
one nonpharmacologic
al intervention
that would be appropriate for treating
the assigned disorder in children and
adolescents.
0
(0%)
–
17
(17%)
The response vaguely or inaccurately
explains interventions that would be
appropriate for treating the assigned
disorder in children
and adolescents.
Interventions may not represent the
three types of interventions required,
or response may be missing.
• Explain the risk assessment you
would use to inform your treatment
decision making. What are the risks
and benefits of the FDA
–
appro
ved
medicine? What are the risks and
benefits of the off
–
label drug?
23
(23%)
–
25
(25%)
The response accurately and concisely
explains the risk assessment you would
use to inform your treatment decision
making. A concise and accurate
explanation of the ri
sks and benefits of
each pharmacological intervention is
provided.
20
(20%)
–
22
(22%)
The response accurately explains the
risk assessment you would use to
inform your treatment decision
making. An adequate explanation of
the risks and benefits of each
ph
armacological intervention is
provided.
18
(18%)
–
19
(19%)
The response somewhat vaguely or
inaccurately explains the risk
assessment you would use to inform
your treatment decision making. The
explanation of the risks and benefits of
each pharmacological
intervention is
somewhat vague or inaccurate.
0
(0%)
–
17
(17%)
The response vaguely or inaccurately
explains the risk assessment you would
use to inform your treatment decision
making. The risks and benefits of each
pharmacological intervention is vague
or inaccurate. Or, the response is
missing.
• Explain whether clinical practice
guidelines exist for this disorder and, if
so, use them to justify your
recommendations. If not, explain what
information you would need to take
into consideration.
23
(23%)
–
25
(25%)
The response accurately and concise
ly
uses either clinical guidelines (if
available) or other information from
the literature to justify intervention
recommendations.
20
(20%)
–
22
(22%)
The response accurately uses either
clinical guidelines (if available) or other
information from the lit
erature to
justify intervention recommendations.
18
(18%)
–
19
(19%)
The response somewhat vaguely or
inaccurately uses either clinical
guidelines (if available) or other
information from the literature to
justify intervention recommendations.
0
(0%)
–
17
(17%)
The response vaguely or inaccurately
uses either clinical guidelines (if
available) or other information from
the literature to justify intervention
recommendations. Or, the response is
missing.
• Support your reasoning with at least
three scholarly
resources, one each on
the FDA
–
approved drug, the off
–
label,
and a non
–
medication intervention for
the disorder. Be sure they are current
(no more than 5 years old). Attach the
PDFs of your sources.
9
(9%)
–
10
(10%)
The response provides at least three
c
urrent, evidence
–
based resources
from the literature to support the
intervention recommendations. The
resources reflect the latest clinical
8
(8%)
–
8
(8%)
The response provides at least thre
e
current, evidence
–
based resources
from the literature to support the
intervention recommendations.
7
(7%)
–
7
(7%)
Three evidence
–
based resources are
provided to support the intervention
recommendations, but they may only
provide vague or weak justificat
ion.
0
(0%)
–
6
(6%)
Two or fewer resources are provided
to support the intervention
recommendations. The resources may
not be current or evidence based.
RUBRIC TO FFL FOR ASSIGNMENT 1 DIDATIC
Excellent Good Fair Poor
In 1–2 pages, address the following:
• Recommend one FDA-approved
drug, one
off-label drug, and one
nonpharmacological intervention for
treating your assigned disorder in
children and adolescents.
23 (23%) – 25 (25%)
The response accurately and concisely
explains one FDA-approved drug, one
off-label drug, and one
nonpharmacological intervention that
would be appropriate for treating the
assigned disorder in children and
adolescents.
20 (20%) – 22 (22%)
The response accurately explains one
FDA-approved drug, one off-label drug,
and one nonpharmacological
intervention that would be appropriate
for treating the assigned disorder in
children and adolescents.
18 (18%) – 19 (19%)
The response somewhat vaguely or
inaccurately explains one FDA-
approved drug, one off-label drug, and
one nonpharmacological intervention
that would be appropriate for treating
the assigned disorder in children and
adolescents.
0 (0%) – 17 (17%)
The response vaguely or inaccurately
explains interventions that would be
appropriate for treating the assigned
disorder in children and adolescents.
Interventions may not represent the
three types of interventions required,
or response may be
missing.
• Explain the risk assessment you
would use to inform your treatment
decision making. What are the risks
and benefits of the FDA-approved
medicine? What are the risks and
benefits of the off-label drug?
23 (23%) – 25 (25%)
The response accurately and concisely
explains the risk assessment you would
use to inform your treatment decision
making. A concise and accurate
explanation of the risks and benefits of
each pharmacological intervention is
provided.
20 (20%) – 22 (22%)
The response accurately explains the
risk assessment you would use to
inform your treatment decision
making. An adequate explanation of
the risks and benefits of each
pharmacological intervention is
provided.
18 (18%) – 19 (19%)
The response somewhat vaguely or
inaccurately explains the risk
assessment you would use to inform
your treatment decision making. The
explanation of the risks and benefits of
each pharmacological intervention is
somewhat vague or inaccurate.
0 (0%) – 17 (17%)
The response vaguely or inaccurately
explains the risk assessment you would
use to inform your treatment decision
making. The risks and benefits of each
pharmacological intervention is vague
or inaccurate. Or, the response is
missing.
• Explain whether clinical practice
guidelines exist for this disorder and, if
so, use them to justify your
recommendations. If not, explain what
information you would need to take
into consideration.
23 (23%) – 25 (25%)
The response accurately and concisely
uses either clinical guidelines (if
available) or other information from
the literature to justify intervention
recommendations.
20 (20%) – 22 (22%)
The response accurately uses either
clinical guidelines (if available) or other
information from the literature to
justify intervention recommendations.
18 (18%) – 19 (19%)
The response somewhat vaguely or
inaccurately uses either clinical
guidelines (if available) or other
information from the literature to
justify intervention recommendations.
0 (0%) – 17 (17%)
The response vaguely or inaccurately
uses either clinical guidelines (if
available) or other information from
the literature to justify intervention
recommendations. Or, the response is
missing.
• Support your reasoning with at least
three scholarly resources, one each on
the FDA-approved drug, the off-label,
and a non-medication intervention for
the disorder. Be sure they are current
(no more than 5 years old). Attach the
PDFs of your sources.
9 (9%) – 10 (10%)
The response provides at least three
current, evidence-based resources
from the literature to support the
intervention recommendations. The
resources reflect the latest clinical
8 (8%) – 8 (8%)
The response provides at least three
current, evidence-based resources
from the literature to support the
intervention recommendations.
7 (7%) – 7 (7%)
Three evidence-based resources are
provided to support the intervention
recommendations, but they may only
provide vague or weak justification.
0 (0%) – 6 (6%)
Two or fewer resources are provided
to support the intervention
recommendations. The resources may
not be current or evidence based.
Psychopharmacology Algorithms
Clinical Guidance from the Psychopharmacology Algorithm
Project at the Harvard South Shore Psychiatry Residency Progra
m
Psychopharmacology Algorithms
Clinical Guidance from the Psychopharmacology Algorithm
Project at the Harvard South Shore Psychiatry Residency
Program
David
N
. Osser, MD
Associate Professor of Psychiatry
Harvard Medical School at the VA Boston Healthcare System
Brockton, Massachusetts
Acquisitions Editor: Chris Teja
Product Development Editor: Ariel S. Winter
Marketing Manager: Phyllis Hitner
Production Project Manager: Kirstin Johnson
Design Coordinator: Holly McLaughlin
Manufacturing Coordinator: Beth Welsh
Editorial Coordinator: Dave Murphy
Prepress Vendor: S4Carlisle Publishing Services
All rights reserved. This book is protected by copyright. No part of this book may be reproduced or
transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies,
or utilized by any information storage and retrieval system without written permission from the copyright
owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this
book prepared by individuals as part of their official duties as U.S. government employees are not covered
by the above-mentioned copyright. To request permission, please contact Wolters Kluwer at Two
Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at permissions@lww.com , or
via our website at
shop.lww.com
(products and services).
9 8 7 6 5 4 3 2 1
Printed in China
Library of Congress Cataloging-in-Publication Data
Names: Osser, David N. (David Neal), editor.
Title: Psychopharmacology algorithms: clinical guidance from the Psychopharmacology Algorithm Project
at the Harvard South Shore Psychiatry Residency Program / [edited by] David N. Osser.
Description: Philadelphia: Wolters Kluwer Health, [2021] |
I
ncludes bibliographical references and index. |
Summary: “Algorithms are useful in the field of psychopharmacology as they can serve as guidelines for
avoiding the biases and cognitive lapses that are common when treating conditions that rely on uncertain
data. In spite of this, evidence-based practices in psychopharmacology often require years to become
widely adopted. The Psychopharmacology Algorithm Project at Harvard’s South Shore Medical Program
is an effort to speed up the adoption of evidence-based research into the day-to-day treatment of
patients”— Provided by publisher.
Identifiers: LCCN 2020018487 | ISBN 9781975151195 (paperback)
Subjects: MESH: Psychopharmacology Algorithm Project at the Harvard South Shore Psychiatry Residency
Program. | Mental Disorders—drug therapy | Psychotropic Drugs—administration & dosage | Algorithms
| Practice Guidelines as Topic | Evidence-Based Medicine
Classification: LCC RC483 | NLM WM 402 | DDC 616.89/18—dc23
LC record available at https://lccn.loc.gov/2020018487
This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied,
including any warranties as to accuracy, comprehensiveness, or currency of the content of this work.
This work is no substitute for individual patient assessment based upon healthcare professionals’
examination of each patient and consideration of, among other things, age, weight, gender, current or prior
medical conditions, medication history, laboratory data and other factors unique to the patient. The
publisher does not provide medical advice or guidance and this work is merely a reference tool. Healthcare
professionals, and not the publisher, are solely responsible for the use of this work including all medical
judgments and for any resulting diagnosis and treatments.
Given continuous, rapid advances in medical science and health information, independent professional
verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and
treatment options should be made and healthcare professionals should consult a variety of sources. When
mailto:permissions@lww.com
http://www.shop.lww.com
treatment options should be made and healthcare professionals should consult a variety of sources. When
prescribing medication, healthcare professionals are advised to consult the product information sheet (the
manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of use,
warnings and side effects and identify any changes in dosage schedule or contraindications, particularly if
the medication to be administered is new, infrequently used or has a narrow therapeutic range. To the
maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any
injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise,
or from any reference to or use by any person of this work.
shop.lww.com
http://www.shop.lww.com
CONTRIBUTORS
Harmony Raylen Abejuela, MD
Clinical Fellow in Psychiatry
Harvard Medical School
Boston Children’s Hospital
Boston, Massachusetts
Arash Ansari, MD
Instructor in Psychiatry
Department of Psychiatry
Harvard Medical School
Attending Psychiatrist
Faulkner Hospital
Boston, Massachusetts
Laura A. Bajor, DO
Clinical Fellow in Psychiatry
Harvard Medical School
Harvard South Shore Psychiatry
Residency Training Program
Brockton, Massachusetts
Ashley M. Beaulieu, DO
Clinical Fellow in Psychiatry
Department of Psychiatry
Harvard Medical School
VA Boston Healthcare System
Brockton, Massachusetts
Lance R. Dunlop, MD
Acting Medical Director
Cambria County Mental Health/Mental Retardation Clinic
Johnstown, Pennsylvania
Christoforos Iraklis Giakoumatos, MD
Christoforos Iraklis Giakoumatos, MD
Clinical Fellow in Psychiatry
Harvard Medical School
VA Boston Healthcare System
Brockton, Massachusetts
Leonard S. Lai, MD
Clinical Instructor
Department of Psychiatry
Harvard Medical School
Attending Psychiatrist
Faulkner Hospital
Boston, Massachusetts
James J. Levitt, MD
Assistant Professor of Psychiatry
Harvard Medical School
VA Boston Healthcare System
Brockton, Massachusetts
Theo Manschreck, MD
Clinical Professor of Psychiatry
Harvard Medical School at the VA Boston
Healthcare System
Brockton, Massachusetts
Corrigan Mental Health Center
Fall River, Massachusetts
Harvard Commonwealth Center of Excellence in Clinical Neuroscience and
Psychopharmacological Research
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Othman Mohammad, MD
Clinical Fellow in Psychiatry
Harvard Medical School
Boston Children’s Hospital
Boston, Massachusetts
David N. Osser, MD
Associate Professor of Psychiatry
Associate Professor of Psychiatry
Harvard Medical School at the VA Boston Healthcare System
Brockton, Massachusetts
Robert D. Patterson, MD
Lecturer in Psychiatry
Harvard Medical School
McLean Hospital
Belmont, Massachusetts
Kenneth C. Potts, MD
Assistant Professor of Psychiatry
Harvard Medical School
Associate Chief of Psychiatry
Faulkner Hospital
Boston, Massachusetts
Mohsen Jalali Roudsari, MD
Laboratory for Clinical and Experimental Psychopathology
Corrigan Mental Health Center
Fall River, Massachusetts
Harvard Commonwealth Center of Excellence in Clinical Neuroscience and
Psychopharmacological Research
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Paul M. Schoenfeld, MD
Instructor in Psychiatry
Department of Psychiatry
Harvard Medical School
Attending Psychiatrist
Faulkner Hospital
Boston, Massachusetts
Dana Wang, MD
Rivia Medical PLLC
New York, NY
Edward Tabasky, MD
Department of Psychiatry
NYS Psychiatric Institute
NYS Psychiatric Institute
Columbia University College of Physicians and Surgeons
New York, New York
Michael Tang, DO
Clinical Fellow in Psychiatry
Harvard Medical School
VA Boston Healthcare System
Brockton, Massachusetts
Ana Nectara Ticlea, MD
Clinical Fellow in Psychiatry
Harvard Medical School
Harvard South Shore Psychiatry
Residency Training Program
Brockton, Massachusetts
T
INTRODUCTION AND HOW TO USE
THIS BOOK *
his book contains reprints of nine peer-reviewed algorithms that were
published between 2010 and 2020. I have carefully re-read each one. In a
very few instances, sentences were found that did not convey the authors’
intended point correctly. With permission of the publishers, these sentences were
improved. Each paper is followed by a freshly-written Update which includes
any changes from the original algorithm recommendations and a review of new
information that adds or modifies the level of support for previous
recommendations.
I am not sure if you should read the article first, and then the Update or vice-
versa. You may want to try both sequences with different chapters. Maybe by
reading the Update first you will be prepared for what has changed when you
encounter it in the original paper. However, there are relatively few changes in
most algorithms, and the main discussions and arguments supporting the
reasoning for the recommendations are in the main paper. In either case, after
reading both, the reader should be clear on how the algorithm should be
sequenced (and the supporting evidence) as of the time of completion of the
writing which was January, 2020.
The first chapter is a reprint of a paper giving a perspective on why we need
psychopharmacology algorithms and the evidence-base for their utility.
The last two chapters are reprints of other papers (of which I was a co-author)
that provide supplementary information and add support to the users of the
algorithms. There is a long book chapter on Inpatient Psychopharmacology
which reviews many issues pertinent to inpatient work with medications but also
is applicable in outpatient settings as well. Though published in 2009, it seems
surprisingly current and very few corrections were needed even though this was
not a peer-reviewed publication. The final chapter describes a teaching program
in psychopharmacology for the residents at the Harvard South Shore Psychiatry
Residency Training Program (HSSRTP) that utilizes algorithms as one of the
methods of teaching the subject. The algorithms in this book could be used in a
similar manner by teachers. The courses that we give now at HSSRTP have
changed somewhat in the 15-20 years since this publication. However, we still
teach basic psychopharmacology (medications, their pharmacology, their uses,
their side effects) in the early years of residency and use the algorithms in this
book in the teaching with more advanced residents. Each of the algorithm
teaching sessions includes a study of an important paper that helped influence
some part of the algorithm, looking critically at methodology, statistics used,
biases that could have affected the results, and the relationship with other studies
of the same issues.
PATIENT ASSESSMENT PRIOR TO CONSULTIN
G
ALGORITHMS
The first step before prescribing psychiatric medication for a patient is to
undertake a thorough psychiatric assessment. This involves reviewing past
treatments and their effectiveness, considering the medical problems of the
patient and noting the treatments for them that they are currently receiving (or
perhaps should be receiving, as the case may be), conducting a psychiatric
interview that considers the chief complaint(s), history of present illnesses, past
and developmental histories, psychosocial and relationship histories, and mental
status examination. It concludes with a formulation of the apparent causes of the
person’s problems and a diagnostic impression based on the criteria in the
Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). One
must evaluate the whole patient in order to understand the context of the specific
disorders that might be targets for pharmacotherapy. 1 Anything less than this
adds to the risks of errors in the choice of medications. This evaluation may need
to be spread over several meetings before reaching final (but still tentative)
initial conclusions. Ninety minutes is a time frame frequently required to
evaluate a new patient in this manner, including the time for reviewing the
previous record and writing the assessment. It might require longer or shorter
times. Often, in the current managed care environment or in public sector care,
clinicians are not allowed this much time (if employed) or may elect to take less
time (in private practice) because of financial pressures. Clinical experience may
convince practitioners that they can do an adequate psychiatric assessment in
less time than just indicated and chose the correct medication for the correct
diagnoses. Patients are usually not fooled, however: they very often can
recognize when someone has taken a very short time to evaluate problems that
the patient knows to be quite complex. They may be dubious when they are
quickly sent home with a prescription. Subsequent very brief visits may
strengthen the patient’s impression of receiving “fast food” style care. This kind
of practice is undermining the public’s confidence in our profession. 2
Use of the DSM-5 criteria for diagnosis is required in order to use these
algorithms. This in not because we believe it is a perfect system for diagnosis
but because the studies on which these algorithms rely are all based on evidence
derived from psychopharmacology treatment studies of patients who met these
criteria. Any use of these algorithms in patients diagnosed idiosyncratically or by
some improvisational method that attempts to shortcut the DSM-5 diagnostic
process may produce suboptimal results and may not be worthy of being called
evidence-supported practice.
In many of the earlier studies cited, the patients met criteria for DSM-IV or
DSM-III diagnoses. When there have been important differences between the
older and newer DSM criteria the authors have done their best to help determine
the relevance of these studies to current criteria. Some diagnostic criteria have
changed relatively little and the current criteria are still largely adequate for
applying the findings from studies using previous criteria. Schizophrenia is an
example of this situation. However, generalized anxiety disorder (GAD) criteria,
for example, have changed considerably and the algorithm for GAD takes this
into account.
Many patients fall short of meeting DSM-5 criteria for one or more diagnoses
which otherwise seem appropriate. These are difficult situations, but it may be
reasonable to consider the algorithm’s recommendations though with less
confidence because the patients on which the recommendations are based are not
fully comparable.
You may notice that there is no algorithm for schizoaffective disorder, though
we have one for schizophrenia and for mania with psychosis. This is because
there is no adequate or significant quantity of evidence out there from which an
algorithm can be derived. See the algorithm for schizophrenia for a full
discussion of that issue with appropriate references and suggestions for how to
treat patients who meet the DSM-5 criteria for schizoaffective disorder.
HOW TO HANDLE COMORBIDITY
Some have said: “All my patients are complex and have lots of comorbidity, so
the algorithms are useless to me.” Sometimes, this is an excuse to not be
informed about the best evidence for treating each diagnosis separately. In
response, I suggest the following: when there is comorbidity, delineate the
various diagnoses that are present. Then, determine (in collaboration with the
patient) the one that seems to be contributing the most to the patient’s distress or
dysfunction, and treat that first with evidence-derived treatments as in these
algorithms. For example, if the patient has rapid cycling bipolar disorder plus
other problems, getting the bipolar disorder under control may be the top
priority, and if that is accomplished some or all of the other problems may
become milder or subclinical in severity. Another example would be a patient
actively using substances. Getting the patient into remission from their use
disorders will, in many cases, deserve priority. Even cannabis use disorder,
which can exacerbate bipolar disorder and post-traumatic stress disorder, 3 may
need to be addressed before one can expect medications normally effective for
those comorbidities to have the usual benefit.
There is some information about management of important comorbidities in
each algorithm paper, showing how the presence of these comorbidities modifies
the basic algorithm for that diagnosis. When there is no useful evidence on how
to manage the primary disorder with comorbidities that may be present, it seems
reasonable to treat the primary diagnosis in accordance with the algorithm unless
a good reason to not do so is apparent. Then, if there is some success in
managing the primary problem, address the next most important diagnosis that is
still causing distress or disability. If there is a lack of success with the first
diagnosis, reassess the differential diagnoses again and perhaps on this
reconsideration it will appear that there is another diagnosis that is most
important. Continue with one diagnosis at a time, and usually one change of
treatment at a time, until all the major diagnoses are managed optimally. With
complex patients, this can be a project that can take many months of fairly
intensive care, but it can be gratifying for the clinician and patient to see a
process of gradual improvement of one diagnosis after another that is affecting
their quality of life.
Other factors may affect the order of treatment of the different diagnoses,
including the patient’s willingness to accept the risks of side effects of the
medications for the diagnosis, patient willingness to accept the diagnosis itself
(due to stigma or other considerations), and drug interactions or other medical
considerations that may require certain diagnoses to be managed first.
Remember that a change in treatment can include addition or subtraction of a
medication – both can have significant positive and adverse effects, so it is best
not to do two changes at once if possible. Even discontinuation of nicotine can
have major adverse neuropsychiatric effects. 4
WHAT ABOUT PSYCHOTHERAPY AND OTHER NON-
MEDICATION TREATMENTS?
These algorithms are designed to help choose the most evidence-supported
medication if the practitioner decides to use medication. They do not generally
offer guidance for when to select medication as a first-line treatment over
psychotherapy, or when to add medication to psychotherapy if psychotherapy is
chosen first-line. The focus of the algorithms is to provide help with deciding
which medication should be chosen first, second and third.
WHAT DETERMINES THE ORDER OF RECOMMENDED
MEDICATIONS IN THE ALGORITHMS?
The order of selection of medications in the algorithms is derived from
consideration of efficacy (results in randomized, placebo-controlled trials),
effectiveness (outcome in less-well-controlled or observational studies, case
series, and other reports), ability to maintain initial efficacy or effectiveness, and
side effect burden that is acceptable to patients over the short term and
(importantly) long term. These are important considerations, with greater or
lesser importance depending on the level of treatment-resistance of the target
problem. For example, a medication that is very well tolerated but does not have
the largest effect size might be chosen for the first treatment for a disorder
instead of one that has a large effect size but more side effects. Patients who
have already failed several trials might need to try a medication which has more
severe side effects but greater evidence of effectiveness. Whenever possible,
algorithms in this book offer a selection of medications at each node that are
judged by the authors to be of approximately equal efficacy and tolerability. The
specifics vary and the choice will be made by the prescriber and patient agreeing
on the medication that seems the best fit for their needs given what side effects
they would be most willing to risk. Sometimes there will be first-line options at a
particular node but also some second line options that are reasonable to consider
if the side effects of the first-line choices are all unacceptable to the patient or
clinician.
Occasionally cost is a consideration, but only if deciding between two or more
choices of approximately equal efficacy and safety. In that case we suggest
choosing the less expensive option.
THE WEBSITE FOR THESE ALGORITHMS
The recommendations in the algorithms in this book may also be accessed online
at the website www.psychopharm.mobi . There one can find flowcharts of each
algorithm, and each node has a box that is linked to a short text which is an
http://www.psychopharm.mobi
abbreviated version of the texts in the algorithm papers. There are a few
references in each box, and these are linked to PubMed so if you click on them,
the article abstract will appear. The website is best employed to quickly obtain a
reminder of the recommendations with which the reader is already familiar from
having read the full text with the nuanced analysis of the evidence base leading
to the recommendations. Sometimes there will be only subtle preferences for
some options over others and this can only be appreciated by having read the full
texts: the web version can seem unduly rigid or be misleading without having
read the full explanation. An advantage of the versions on the web is that they
are updated when there are important new developments, so they are always the
latest versions. Also, as new algorithms are developed they will appear on the
website.
EVIDENCE-BASED MEDICINE: AN ART
The practice of evidence-based medicine is an art – because it requires making
decisions based on voluminous, uncertain and very hard-to-quantify data. 5
These algorithms help provide users with the important evidence and what it
might mean for practice. However, the art involves the ability to determine how
well the evidence applies to any given patient. Competent practitioners may
“deviate” from the what the evidence suggests when that evidence does not seem
generalizable to their patient because of comorbidities or complexities not
addressed by the evidence. The algorithms in this book endeavor to address
many of these complexities so as to make them as useful as possible to the
largest number of patients, but there will be many gaps. Patients may not be
willing to take the most effective treatments. Some of the art of medicine is in
the ability to persuade patients to take the most evidence-based treatment. Part of
this persuasiveness comes from the patient having confidence that the prescriber
has listened well, understands the total patient and appears ready to be available
in a timely manner with practical solutions to side effects that might occur. 6
Clinicians who are also academicians and specialize in certain diagnoses may
not find these algorithms that useful. They already know the evidence as well or
better than the authors of these papers. They see in consultation or treat directly
many treatment-resistant patients and apply their knowledge to the best of their
considerable ability. However, the generalist practitioner who treats many kinds
of patients may not be able to devote the huge amount of time required to
critically evaluate the evidence base for all the diagnoses they encounter. For
them, it may seem reasonable to have one place to go where they can find
thoughtful analyses of the evidence distilled into algorithmic heuristics.
However, there does have to be some trust involved that the experts writing
these algorithms (and the peer reviewers who contributed) have produced
reliable and actionable advice.
Clinical experience is also important in decision making, but there will be
more to say about that in the next chapter.
WHAT ALGORITHMS ARE NEXT?
We have published one new algorithm in 2020 since this book went to
production, so it could not be included in the book: An Algorithm for Core
Symptoms of Autism Spectrum Disorder in Adults. 7 There are two new
algorithms that are being drafted and hopefully are coming soon:
Psychopharmacology for Behavioral Symptoms in Dementia., and Adults with
Attention-Deficit Hyperactivity Disorder. A revision of the 2011 Posttraumatic
Stress Disorder algorithm also has a manuscript in draft form.
It is the author’s intention to update this book with future editions.
DISCLOSURE OF COMPETING INTERESTS
The author of this book has received no compensation from drug companies.
Royalties are earned from another book: Ansari A and Osser DN.
Psychopharmacology: A concise Overview for Students and Clinicians, 2nd
Edition 2015, published by CreateSpace. A third edition will appear in 2020 with
Oxford University Press. These books do not contain algorithms.
IMPORTANT NOTE
The information presented in this book is meant to be a summary or overview of
prescribing suggestions for different diagnostic situations. The content should be
used by prescribing clinicians as a consultation, but the recommendations should
not be followed rigidly. There should be thoughtful and thorough evaluation of
the appropriateness of the suggestions herein before prescribing. The author is
not rendering professional services through this book. Although every effort has
been made to present the material accurately, no representations are made as to
the accuracy or completeness of the contents. There may be typographical or
other errors including misinterpretations of the evidence base or failure to take
into account uncited studies. Before prescribing anything, the package insert of
the medication should be reviewed and the medication should be administered in
accordance with the relevant information. Patients should not make any changes
in their treatment based on the contents of this book without consulting with
their prescribing provider.
REFERENCES
1. Baldessarini RJ. Status and prospects for psychopharmacology. In: Chemotherapy in Psychiatry 3ed.
New York: Springer; 2013:251-63.
2. Zulman DM, Haverfield MC, Shaw JG, et al. Practices to Foster Physician Presence and Connection
With Patients in the Clinical Encounter. JAMA 2020;323:70-81.
3. Mammen G, Rueda S, Roerecke M, Bonato S, Lev-Ran S, Rehm J. Association of Cannabis With
Long-Term Clinical Symptoms in Anxiety and Mood Disorders: A Systematic Review of Prospective
Studies. J Clin Psychiatry 2018;79.
4. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline,
bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-
blind, randomised, placebo-controlled clinical trial. Lancet 2016;387:2507-20.
5. Worsham C, Jena AB. Decision making: The art of evidence-based medicine. In: Harvard Business
Review . Cambridge, MA: Harvard Business School; 2019.
6. Salzman C, Glick I, Keshavan MS. The 7 sins of psychopharmacology. J Clin Psychopharmacol
2010;30:653-5.
7. Gannon S, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore Program:
An algorithm for core symptoms of autism spectrum disorder in adults. Psychiatry Res
2020;287:112900.
* I thank Robert D. Patterson, M.D. for his contributions to this introductory chapter.
T
ACKNOWLEDGMENTS
he author wishes to thank his many collaborators that contributed to the
development and publication of these algorithms, those who provided
support and encouragement in these endeavors, and those who aided in
bringing them to the awareness of clinicians and others who have found them
useful.
First of all, there are the coauthors of the articles, who are also listed on the
title page of each algorithm reprint. These 20 authors (many of them were
residents in training at the Harvard South Shore Psychiatry Residency Training
Program) spent, in many cases, hundreds of hours on nights and weekends
searching for articles, reading them, communicating with coauthors in
discussions of their importance, and preparing draft after draft of the algorithm
articles before submission and in response to reviewers’ critiques. Without their
hard work and energy, these articles would never have been written.
I also thank the blinded reviewers of each article. Though I do not know who
they were, these individuals were clearly experts on the subject matter of the
articles and made substantive and sophisticated criticisms that required
resolution and achievement of consensus before the articles could be accepted
for publication. These reviews added significant validity to the final versions of
each algorithm in that they reduced any initial biases detected and broadened the
number of persons in agreement with the interpretations of the literature in the
final published version.
My supporters over the years deserve heartfelt thanks. Algorithms are
controversial, and some physicians do not welcome the appearance of
medication treatment algorithms in psychiatry no matter how evidence-
supported and peer-reviewed they may be. I have more to say about this in the
introductory chapter. The following mentors and supporters from the United
States and in corners of the world have offered strong moral and practical
support at different points (or continuously) over the years: (listed
alphabetically) Ross Baldessarini, MD; Mark Bauer, MD; Rogelio Bayog, MD;
Mesut Çetin, MD (Turkey); B. Eliot Cole, MD; Joseph Coyle, MD; Anne
Dantzler, MD; John Davis, MD; Lynn DeLisi, MD; Serdar Dursun, MD
(Canada); Jan Fawcett, MD; Eugene Fierman, MD; Ira Glick, MD; Shelly
Greenfield, MD; Susan Gulesian, MD; Flavio Guzman, MD (Argentina); Philip
Janicak, MD; Kenneth Jobson, MD; Gary Kaplan, MD; Xiang-Yang Li, MD;
Steven Locke, MD; Mansfield Mela, MD (Canada); Herbert Meltzer, MD; Dean
Najarian, RPh, BCPP; Jessica Oesterheld, MD; Jonathan Osser (my brother);
Chester Pearlman, MD; Ronald Pies, MD; John Renner, MD; Raluca Savu, MD;
Richard I. Shader, MD (my first and perhaps most significant mentor in
psychopharmacology); Miles Shore, MD; Tian-Mei Si, MD (China); Robert
Sigadel, MD; Stephen Soreff, MD; Dan Stein, MD (South Africa); Cheng-Hua
Tien, MD (China); Ming Tsuang, MD; Xin Yu, MD (China); and Carlos Zarate,
MD.
Next, there is perhaps my most significant supporter, collaborator, overall
mentor, friend, and the psychiatrist who did the most by far to encourage me to
keep producing these algorithms and who made extraordinary efforts (that
I
never could have done on my own) over decades to circulate the algorithms in
computerized versions and over the Internet using progressively improved
interfaces: Robert D. Patterson, MD. Surely, without his input, these academic
products would never have been completed much less achieved the level of
recognition, such as it is, that they may have achieved. He is the director of the
Information Technology component of this work and is the creator of our
website www.psychopharm.mobi .
And finally, I want to thank from the bottom of my heart my beloved and
beautiful wife of 38 years, Stephanie, and our children Roselin and Daniel, who
put up with my many, many hours devoted to this calling when I could have
been spending more quality time with them.
I hope I have not left out anyone that should be on this list and if so please
accept my apology.
David N. Osser, MD
Needham, Massachusetts
January 2020
http://www.psychopharm.mobi
CONTENTS
1) On the Value of Evidence-Based Psychopharmacology Algorithms
David N. Osser, MD and Robert D. Patterson, MD
2) The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: An Update on Bipolar Depression
Dana Wang, MD and David N. Osser, MD
3) The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: An Algorithm for Acute Mania
Othman Mohammad, MD and David N. Osser, MD
4) The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: An Update on Unipolar Nonpsychotic Depression
Christoforos Iraklis Giakoumatos, MD and David Osser, MD
5) The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: 2012 Update on Psychotic Depression
Michael Tang, DO and David N. Osser, MD
6) The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: An Update on Schizophrenia
David N. Osser, MD, Mohsen Jalali Roudsari, MD, and Theo Manschreck,
MD
7) The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: An Algorithm for Generalized Anxiety Disorder
Harmony Raylen Abejuela, MD and David N. Osser, MD
8) The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: An Update on Generalized Social Anxiety Disorder
David N. Osser, MD and Lance R. Dunlop, MD
9) The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: An Update on Posttraumatic Stress Disorder
Laura A. Bajor, DO, Ana Nectara Ticlea, MD, and David N. Osser, MD
10) The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: An Algorithm for Adults with
Obsessive-Compulsive Disorder
Ashley M. Beaulieu, DO, Edward Tabasky, MD, and David N. Osser, MD
11) Pharmacologic Approach to the Psychiatric Inpatient
Arash Ansari, MD, David N. Osser, MD, Leonard S. Lai, MD, Paul M.
Schoenfeld, MD, and Kenneth C. Potts, MD
12) Guidelines, Algorithms, and Evidence-Based Psychopharmacology
Training for Psychiatric Residents
David N. Osser, MD, Robert D. Patterson, MD, and James J. Levitt, MD
Index
L
On the Value of Evidence-Based
Psychopharmacology Algorithms
David N. Osser , MD 1 and Robert D. Patterson, MD 2
ucian Leape raised awareness of the high error rate in medicine ( 1
). These errors may be due to “slips” (unintentional mistakes) or
may result from not obtaining key facts about the patient’s history
or from not knowing or applying the best evidence for optimal care of
the patient. The remedy for the latter is said to be the practice of
Evidence-Based Medicine (EBM) – which has been defined by
Sackett and colleagues as “…integrating clinical expertise with the
best available external clinical evidence from systematic research” ( 2
).
However, EBM is easier said than done. For psychopharmacology,
it requires a laborious process of activity and thinking. First one must
make a criteria-based Diagnostic and Statistical Manual diagnosis,
identifying subtypes, specifiers, and comorbidity that may affect what
treatment will be preferred. This is necessary because almost all of the
psychopharmacology evidence is derived from studies of patients that
are carefully diagnosed by these criteria. The treatment history must
then be explored in detail for adequacy and outcomes of trials in order
to avoid repeating ineffective or harmful approaches used in the past.
Finally, it is necessary to search for, find, read, and interpret the
pertinent literature. This idealized approach to clinical practice is
impractical because it takes far too much time and requires use of
cognitive processes that may be unfamiliar to some clinicians.
These barriers have limited the usefulness of EBM in the day-to-day
practice of medicine and psychopharmacology.
Instead of using EBM, clinicians often resort to quicker but more
error-prone processes of decision-making ( 3 ). Reflexive decisions are
decisions made without consciously considering any alternative,
usually because you are in a hurry. Under this heading there are bias-
driven judgments, which are decisions motivated by overconfidence
based on some bias. Also there is the availability heuristic, which is
grabbing the first idea that comes to mind ( 4 , 5 ). Another cause of
errors is the affective heuristic which is the tendency of affect-laden
practice experiences (either positive or negative) to be far more
influential than considerations based on the scientific evidence. For
example, if you once had a patient who had a Stevens-Johnson
syndrome from lamotrigine, you may be reluctant to prescribe that
medication again even if it is a preferred option for preventing
recurrence of bipolar depression. If statistics are presented on the low
frequency of this syndrome, you will not believe them.
These quick, intuitive decisions are sometimes excused (or praised)
as being part of the art of medicine. Faith in this art is part of the
culture of medicine, with deep historical roots. For thousands of years,
the apprentice model dominated training in medical practice. The art is
initially conveyed by more experienced mentors, and then augmented
by personal experience as the emerging practitioner makes his/her own
mistakes. As Groopman has noted, we do not want airline pilots to
learn from their mistakes – we want them to make the right decisions
every time. However, the healthcare system continues to be built on a
foundation of mistakes followed by “corrective action plans” (3 ).
Busy physicians typically do a limited review of the patient’s
history and mental status, focusing on certain symptoms or historical
details that seem likely to explain the patient’s chief complaint, after
which the treatment plan just “falls into place” ( 6 ). Practice is
centered on faith in a collection of “rules of thumb” that can be
applied rapidly and confidently. However, Michael O’Donnell, M.D.,
former editor of the British Medical Journal, quipped that this kind of
clinical experience ran result in “… making the same mistakes over
and over with increasing confidence over an impressive number of
years” ( 7 ).
There is a neurobiology of how people react to information and
experience. Risk-taking tendency, for example, is a strongly heritable
personality trait (0.58 heritability in twins ( 8 )). Thus, while some
psychiatrists will rarely use clozapine even when clearly indicated
because of fear of its risks, others may have minimal fear and even
overlook necessary monitoring. This is not the only reason that
clozapine is under-prescribed, however: it has been found that when
scientifically validated, well-evidenced treatment approaches take
more time than what physicians do now and believe works well, they
will not provide the time-consuming treatment ( 9 ).
Other problems with using clinical experience as the primary basis
for practice are the generally small Ns of the experience, and sampling
differences: i.e., the patient to be treated now may not in fact be at all
similar to the dimly-recollected previous patients.
Drug companies are also shaping decision-making, sometimes
against EBM, taking advantage of “novelty preference bias,”
“familiarity effect” and “overoptimism bias” ( 10 ). Their
representatives provide education that may be neither objective nor
comprehensive but is quick, easy, and often accompanied by free
samples. The pharmaceutical firms (usually in collaboration with
academic psychiatry) produce most of the psychopharmacological
studies and influence their design, interpretation, and publication in
ways that tend to encourage excessive valuation of new expensive
products ( 11 , 12 ). These studies are typically done for short lengths
of time in otherwise healthy and uncomplicated patients who are not
representative of the more difficult patients seen in typical practice
who may be suicidal, use substances, and have much medical
comorbidity. This has undermined confidence in the applicability of
much of the evidence-base ( 13 ), and at the least requires that EBM
practitioners become sophisticated in their ability to detect the flaws
and biases of studies so that they will not draw false conclusions from
them.
This brings us to the proposed solution to these problems in
teaching and learning psychopharmacology: psychopharmacology
algorithms that are informed by the evidence and that distill and
synthesize the available research and organize it into a coherent
blueprint for practice. The algorithms should be developed and
updated frequently by consensus among respected EBM experts who
have distanced themselves from drug-company support. They should
clearly indicate best or preferred practice for cases of progressive
complexity, and from initial treatment through very treatment-resistant
scenarios. They should provide a scaffolding structure for organizing
the data relevant to specific kinds of patients. Thus, if a new study is
published, or a new medication becomes available, information about
these developments can be combined with and compared with the
other knowledge on the shelf for that decision point. The clinician can
decide if the new information should change practice for a typical
patient at that node of the algorithm – or wait for the expert consensus
update. Experts have argued that healthcare desperately needs such
syntheses, and the production of them needs to be recognized as a
methodology and field in its own right ( 14 , 15 ).
What are some of the qualities of these algorithms/guidelines that
would indicate that they are valid enough for clinical use? The
Institute of Medicine has proposed a comprehensive set of standards (
16 ). Few existing guidelines meet all the criteria, which include
authors (a) having few to no conflicts of interest, (b) providing
explanations of the reasoning behind each recommendation, (c)
obtaining rigorous external review before publication, and (d)
updating frequently. To these it there should be added that evidence of
short and long term safety are considerations that are just as important
as efficacy evidence in motivating the sequencing of medication
recommendations ( 17 ). Further, there should be acknowledgement of
other published algorithms with different conclusion and an analysis
of the basis for the differences with attempts to resolve them (17 ). The
impact of comorbidity, medical and psychiatric, including the effect if
the patient is a woman of child-bearing potential, should be assessed
and recommendations offered.
Finally, it should be emphasized that algorithms, no matter how
well-constructed, should not be followed rigidly as if they represent
absolute truth. They are aids to judgment, and practitioners should be
free to determine whether or not they are suitable for application to an
individual patient. Despite this caveat, it is worth noting that evidence
from other fields (e.g. – engineering) suggests that when algorithm-
based decisions and individual expert judgment have been compared,
the results have favored algorithm adherence ( 18 , 19 ). Occasionally,
the expert makes a “brilliant” judgment when deviating from the
algorithm that proves correct, but more often when the expert deviates,
the result is an error. A good algorithm or guideline will offer and
discuss some of the alternatives that could be considered at each node
and why they are not favored first-line but could be reasonable under
some circumstances.
What is the evidence that following psychopharmacology
algorithms improves outcome? While standardized care driven by
evidence-supported algorithms is a model that has produced good
outcomes with other illnesses such as diabetes, pneumonia, and heart
disease ( 20 ), there have not been very many studies in psychiatry and
the results have been modest. Bauer examined tests of guidelines up to
the year 2000 and found that 6 of 13 studies reported improved
outcomes associated with guideline adherence ( 21 ). More recent
psychopharmacology algorithm studies in depression were reviewed
by Adli and colleagues ( 22 ) who found that patients treated with the
algorithm initially benefitted more than the control group but further
separation from “treatment as usual” did not necessarily occur over
time ( 23 ). The early benefits could have been due to more intensive
patient involvement with the project coordinator in the algorithm
group. Studies in schizophrenia have found small advantages from
following an algorithms (Texas Algorithm Project and German
Society for Psychiatry guideline), including reduced side effects and
less polypharmacy with antipsychotics ( 24 , 25 ). The differences
were not robust perhaps because all controlled studies to date have
compared use of an entire algorithm versus treatment as usual. In an
algorithm there are multiple recommendations. Clinicians in the
treatment-as-usual arms also usually do most of them. Of the
recommendations that clinicians do not follow so often, the
alternatives chosen will sometimes produce a significant difference in
outcome and some may not. In the schizophrenia studies, physicians
rarely complied with the algorithm recommendation to use clozapine
after two adequate trials of antipsychotics. The control groups also did
not use much clozapine. This may account for the lack of strong
outcome differences: the algorithm-following physicians did not
choose to follow the recommendation with the greatest likelihood of
producing a better overall outcome for their patients!
The Texas and German algorithm groups did find that regular
intensive educational discussions about the guidelines (which requires
support by hospital and clinic leadership) can overcome some of these
barriers. Discussions with patients to convince them of the value of the
algorithm recommendations may be another critical factor.
A recent objection to EBM in general and the algorithms/guidelines
derived from the evidence has come from the new emphasis on the
potential for “personalized medicine (PM)” ( 26 ). Since evidence is
gathered from studies of heterogeneous patient populations (e.g. –
major depression) it can only give an average or typical response rate
in such a group. However, this conflict between EBM and PM appears
to be based on a false dichotomy. When specific biological markers or
other tests enable the delineation of subgroups with specific treatment,
this will be added to the diagnostic process that precedes the
application of the algorithm, and the personalized treatment will be
applied to those eligible for it. Then, the others in the population will
be appropriate candidates for the general recommendations.
An unsolved problem with the clinical use of even the best
algorithms is that some clinicians may feel pressed to make hasty
consultations with the algorithm’s summary flowchart rather than
reading the full text and appreciating all the nuances of the reasoning.
The result can be grossly inaccurate appreciation of what is
recommended and significant patient care errors. On the other hand,
caveat emptor (let the buyer beware) is an appropriate aphorism to
warn those too eager to utilize algorithms. Some of the algorithms that
have been presented in a variety of publications are oversimplified,
subject to significant biases, or may give bad advice due to reasoning
errors.
The Psychopharmacology Algorithm Project at the Harvard South
Shore Program based at the VA Boston Healthcare System, Brockton
Division, has been publishing and revising psychopharmacology
algorithms for over 20 years. The more recent ones seem to meet
many but not all of the IOM guidelines for quality ( 27 – 33 ). Most are
available on the project’s web site www.psychopharm.mobi . Their
strongest feature is that the facts cited, analysis of the literature, and
reasoning are examined in a blinded peer review process by up to 5
content experts selected by the journal editors. If the reasoning, based
on the evidence interpretations provided, was plausible to all
reviewers, then it was retained. When there were differences of
opinion, adjustments were made or further exploration of pertinent
evidence was done until consensus was achieved or a stronger
argument in support of the authors’ interpretation was composed.
Algorithms will be of more practical value when their most
important advice – advice that differs from usual practice and may
give better results – can be provided to the prescribing clinician at the
point of care as part of a computerized medical record and order-entry
system. Computerized expert systems are not yet common in
psychiatric practice, though they are in many other complex endeavors
such as flying airplanes, piloting boats, driving cars to reach a specific
destination, complying with tax laws, and analyzing case law to come
up with the best legal arguments. Patient outcomes could improve if
algorithm-based computer applications to aid the practice of
psychopharmacology were to be developed and then utilized by
clinicians.
http://www.psychopharm.mobi
REFERENCES
1. Leape LL. Error in medicine. JAMA. 1994;272(23):1851-7.
2. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine:
what it is and what it isn’t. BMJ. 1996;312(7023):71-2.
3. Groopman J. How Doctors Think. Boston: Houghton Mifflin Company;
2007.
4. Tversky A, Kahneman D. Judgment under Uncertainty: Heuristics and Biases. Science.
1974;185(4157):1124-31.
5. Kassirer JP, Kopelman RI. Derailed by the availability heuristic. Hosp Pract (Off Ed).
1987;22(6):59-60, 5-9.
6. Patel VL, Arocha JF, Kaufman DR. A primer on aspects of cognition for medical informatics. J
Am Med Inform Assoc. 2001;8(4):324-43.
7. O’Donnell M. A Sceptic’s Medical Dictionary. London: BMJ Publishing Group; 1997.
8. Ebstein RP, Zohar AH, Benjamin J, Belmaker RH. An update on molecular genetic studies of
human personality traits. Appl Bioinformatics. 2002;1(2):57-68.
9. Buchman TG, Patel VL, Dushoff J, Ehrlich PR, Feldman M, Feldman M, et al. Enhancing the
use of clinical guidelines: a social norms perspective. J Am Coll Surg. 2006;202(5):826-36.
10. Makhinson M. Biases in medication prescribing: the case of second-generation antipsychotics.
J Psychiatr Pract. 2010;16(1):15-21.
11. Osser DN. Cleaning up evidence-based psychopharmacology. Psychopharm Review.
2008;43(3):19-26.
12. Sen S, Prabhu M. Reporting bias in industry-supported medication trials presented at the
American Psychiatric Association meeting. J Clin Psychopharmacol. 2012;32(3):435.
13. Levine R, Fink M. The case against evidence-based principles in psychiatry. Med Hypotheses.
2006;67(2):401-10.
14. Dickersin K. Health-care policy. To reform U.S. health care, start with systematic reviews.
Science. 2010;329(5991):516-7.
15. Davidoff F, Miglus J. Delivering clinical evidence where it’s needed: building an information
system worthy of the profession. JAMA. 2011;305(18):1906-7.
16. Ransohoff DF, Pignone M, Sox HC. How to decide whether a clinical practice guideline is
trustworthy. JAMA. 2013;309(2):139-40.
17. Osser DN, Patterson RD. Algorithms for psychopharmacology. In: Shader RI, ed. Manual of
Psychiatric Therapeutics, Third Edition. Boston: Little, Brown and Co.; 2003:479-84 .
18. Dawes RM. The robust beauty of improper linear models in decision making. In: Kahneman
D, Slovic P, Tversky A, eds. Judgment Under Uncertainty: Heuristics and Biases. New York:
Cambridge University Press; 1983:391-407.
22. Adli M, Bauer M, Rush AJ. Algorithms and collaborative-care systems for depression: are they
effective and why? A systematic review. Biol Psychiatry. 2006;59(11):1029-38.
23. Trivedi MH, Rush AJ, Crismon ML, Kashner TM, Toprac MG, Carmody TJ, et al. Clinical
results for patients with major depressive disorder in the Texas Medication Algorithm Project.
Arch Gen Psychiatry. 2004;61(7):669-80.
24. Miller AL, Crismon ML, Rush AJ, Chiles J, Kashner TM, Toprac M, et al. The Texas
medication algorithm project: clinical results for schizophrenia. Schizophr Bull.
2004;30(3):627-47.
25. Weinmann S, Hoerger S, Erath M, Kilian R, Gaebel W, Becker T. Implementation of a
schizophrenia practice guideline: clinical results. J Clin Psychiatry. 2008;69(8):1299-306.
26. de Leon J. Evidence-based medicine versus personalized medicine: are they enemies? J Clin
Psychopharmacol. 2012;32(2):153-64.
27. Ansari A, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore
Program: an update on bipolar depression. Harv Rev Psychiatry. 2010;18(1):36-55.
28. Bajor LA, Ticlea AN, Osser DN. The Psychopharmacology Algorithm Project at the Harvard
South Shore Program: an update on posttraumatic stress disorder. Harv Rev Psychiatry.
2011;19(5):240-58.
29. Hamoda HM, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South
Shore Program: an update on psychotic depression. Harv Rev Psychiatry. 2008;16(4):235-47.
30. Osser DN, Dunlop LR. The Psychopharmacology Algorithm Project at the Harvard South
Shore Program: an update on generalized social anxiety disorder. Psychopharm Review.
2010;45(12):91-8.
31. Tang M, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: 2012 update on psychotic depression. Journal of Mood Disorders. 2012;2(4):167-79.
32. Osser DN, Jalali-Roudsari M, Manschreck T. The Psychopharmacology Algorithm Project at
the Harvard South Shore Program: an update on schizopnrenia. Harv Rev Psychiatry.
2013;21(1):18-41.
33. Mohammad OM, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South
Shore Program: an algorithm for acute mania. 2013:Submitted.
1 Associate Professor of Psychiatry, Harvard Medical School at the VA Boston Healthcare
System, Brockton Division, 940 Belmont Street, Brockton, MA 02301, US
A
E-mail: david.osser@va.gov
2 Lecturer in Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street,
Belmont, MA 02478, USA,
E-mail: bpatterson5961@gmail.com
Bulletin of Clinical Psychopharmacology 2013;23(1):XX-X
mailto:david.osser@va.gov
mailto:bpatterson5961@gmail.com
The Psychopharmacology Algorithm Project at
the Harvard South Shore Program: An Update
on Bipolar Depression
Dana Wang , MD 1 and David N. Osser, MD 2
Abstract
Background: The Psychopharmacology Algorithm Project at the Harvard South Shore
Program (PAPHSS) published algorithms for bipolar depression in 1999 and 2010.
Developments over the past 9 years suggest that another update is needed.
Methods: The 2010 algorithm and associated references were reevaluated. A literature
search was conducted on PubMed for recent studies and review articles to see what
changes in the recommendations were justified. Exceptions to the main algorithm for
special patient populations, including those with attention-deficit hyperactivity disorder
(ADHD), posttraumatic stress disorder (PTSD), substance use disorders, anxiety
disorders, and women of childbearing potential, and those with common medical
comorbidities were considered.
Results: Electroconvulsive therapy (ECT) is still the first-line option for patients in
need of urgent treatment. Five medications are recommended for early usage in acute
bipolar depression, singly or in combinations when monotherapy fails, the order to be
determined by considerations such as side effect vulnerability and patient preference.
The five are lamotrigine, lurasidone, lithium, quetiapine, and cariprazine. After trials
of these, possible options include antidepressants (bupropion and selective serotonin
reuptake inhibitors are preferred) or valproate (very small evidence-base). In bipolar II
depression, the support for antidepressants is a little stronger but depression with
mixed features and rapid cycling would usually lead to further postponement of
antidepressants. Olanzapine+fluoxetine, though Food and Drug Administration (FDA)
approved for bipolar depression, is not considered until beyond this point, due to
metabolic side effects. The algorithm concludes with a table of other possible
treatments that have some evidence.
Conclusions: This revision incorporates the latest FDA-approved treatments
(lurasidone and cariprazine) and important new studies and organizes the evidence
systematically.
INTRODUCTION
Bipolar depression (BP-DEP) is the predominant mood state for
patients with bipolar disorder and is associated with significantly more
long-term impairment in psychosocial functioning and quality-of-life
compared with unipolar depression. 1 Unipolar depression and bipolar
depression differ in response to pharmacotherapeutic agents. 2 BP-
DEP can present in bipolar I or bipolar II disorders, with mixed
features or rapid cycling. There is a lifetime prevalence of up to 20%
for comorbidity with posttraumatic stress disorder (PTSD), 47% for
substance use disorders, 3 , 4 and 75% for anxiety disorders. 5 These
comorbidities complicate diagnosis and selection of pharmacotherapy.
There is a paucity of evidence-supported treatment choices.Only
four medications have received United States Food and Drug
Administration (FDA) approval for acute BP-DEP. The olanzapine-
fluoxetine combination (OFC) was the first approved, in 2003.
Quetiapine was approved in 2006. In 2013, lurasidone was approved
as a monotherapy and as an adjunct to ongoing lithium or valproate for
bipolar I depression. The fourth, cariprazine, was approved in 2019.
Lamotrigine is approved for prevention of relapse in bipolar I disorder
(mainly against BP-DEP), though studies did not provide sufficient
support for approval for acute episodes. Lithium has FDA approval for
acute mania and for prevention of bipolar mood episodes, but not for
acute BP-DEP. There is a variety of options without solid evidence of
efficacy or FDA-labeling for BP-DEP, including traditional
antidepressants. Clinical experience and other heuristics contribute to
decisions to prefer less-evidenced strategies. 6 In this paper, a
treatment approach is presented that considers the most up-to-date
evidence and shows how to best apply it in a variety of clinical
scenarios ranging from initial treatment to the most treatment-resistant
cases while taking into account some of the comorbidities frequently
encountered.
This is an update of the 2010 algorithm of the Psychopharmacology
Algorithm Project at the Harvard South Shore Program (PAPHSS). 7 It
includes new recommendations for bipolar depression with comorbid
attention-deficit hyperactivity disorder (ADHD), PTSD, substance use
disorders, anxiety disorders, and women of childbearing potential or
pregnant, and some medical conditions.
MATERIALS AND
METHODS
The methods used in developing new and revised PAPHSS algorithms
have been described previously.7 – 11 In brief, the authors reviewed the
2010 BP-DEP algorithm, conducted literature searches using PubMed
with keywords pertaining to available psychopharmacological agents
with a focus on new randomized controlled trials (RCTs), and
consulted recent guidelines, reviews, and meta-analyses. The authors
consider short- and long-term efficacy, effectiveness, tolerability, and
safety of the different treatment options, and then formulate an
opinion-based qualitative distillation of this literature focused on what
changes seem appropriate to make in the previous peer-reviewed and
published version. Basic principles include a preference for using the
fewest medications whenever possible and emphasizing acute
effectiveness but also with particularly strong focus on long-term
safety and tolerability, given that bipolar disorder may be life-long.
The evidence that a regimen can prevent future illness episodes is also
important.
After informal review by other experts, PAPHSS algorithm drafts
are submitted for publication in peer-reviewed journals. The review
process provides additional validation of the appropriateness and
plausibility of the authors’ interpretation of the literature.
The algorithm is meant as a heuristic to aid judgment but should not
be applied rigidly: practitioners must be free to determine whether the
recommendations seem reasonable taking into account the unique
aspects of each patient.
DIAGNOSIS OF BIPOLAR DEPRESSION
By definition, patients diagnosed with BP-DEP meet criteria for a
major depressive episode and have a history of manic or hypomanic
episodes. Hypomania is difficult to diagnose retrospectively and
vigorous pursuit of the diagnosis may be required. A “pre-bipolar”
depression 12 should be suspected in patients with: a family history of
bipolar disorder or suicide, a relatively young age at onset, a history of
quick remissions and frequent recurrences, current or past postpartum
psychosis or major mood disturbance, past poor response to
antidepressants, and history of antidepressant-emergent agitation,
irritability, or suicidality. In addition, depression with “atypical”
features (hypersomnia, hyperphagia with weight gain, leaden
paralysis, and rejection sensitivity) also warrants close monitoring for
emergence of hypomania or mania. 13 Those with a seasonal pattern of
mood fluctuation can also be at risk for bipolar disorder. 14
THE ALGORITHM
The flowchart
A summary and overview of the algorithm appears in Figure 1 . The
questions, evidence analysis, and reasoning that support the
recommendations at each node are presented below. The following
discussion focuses on a sequence of options most pertinent to BP-DEP
patients that are relatively uncomplicated by comorbidities. Later,
exceptions to these recommendations in special patient populations
will be considered in Table 2 .
Figure 1. Flowchart for the algorithm for pharmacotherapy of bipolar depression
Abbreviations: ECT, electroconvulsive therapy; IV, intravenous; OFC, olanzapine and
fluoxetine combined; SSRI, selective serotonin reuptake inhibitor
Node 1: Is electroconvulsive therapy urgently indicated?
Node 1: Is electroconvulsive therapy urgently indicated?
Electroconvulsive therapy (ECT) is a highly effective treatment for
BP-DEP. 15 ECT can be urgently indicated in patients with severe
suicidality, catatonia, insufficient oral intake, and medical conditions
that limit the use of psychotropic medications. In BP-DEP, ECT
produced a 65%-80% short-term response rate (≥50% symptomatic
improvement) and 53% remission rate. 16 – 18 An RCT of ECT in
treatment-resistant BP-DEP, defined as two trials with adequate dose
and duration of antidepressants or lithium, quetiapine, lamotrigine, or
olanzapine, found a 74% response rate compared with 35% with an
algorithm-based pharmacological approach. 19 Medication treatment
failure is not a reliable predictor for ECT response, coadministration
of psychotropic medication does not alter efficacy, and patients with
longer depressive episodes may be more likely to respond. 20 BP-DEP
may need fewer treatments to respond to ECT than those with unipolar
depression.16 , 21 ECT may be viewed as a treatment of “first resort”
given the morbidity associated with prolonging depressive illness with
medication trials with a low probability of effectiveness. Use of ECT
as a maintenance treatment of BP-DEP, however, remains poorly
evaluated.
The N-methyl-D-aspartate antagonist ketamine has been tested in
treatment-resistant BP-DEP with single intravenous infusions (0.5
mg/kg over 40 minutes) added to a mood stabilizer, with positive
response in 50%-80% of subjects that lasted 7-10 days, with a
decrease in suicidality. 22 – 24 Repeated dosing on 6 of the following 12
days was well tolerated except for transient dissociative symptoms, but
eight of nine subjects relapsed into depression within 19 days after the
last dose of ketamine. 25
A role for ketamine is possible for hospitalized, treatment-resistant
patients who refuse or do not tolerate ECT. 26 , 27 It can produce rapid
improvement and patients may then accept other treatments for
maintenance. Little is known about the effectiveness or safety of
ketamine given repeatedly over prolonged periods. Nasal spray
preparations of ketamine (esketamine) and similar agents 28 have so far
received little evaluation in bipolar depression.
Node 2: The patient is not currently on a mood stabilizer
If ECT is refused, not available, or not indicated, there are five
algorithm pathways (Nodes 2-6) depending on which medicines a
patient is taking at the time of evaluation. Node 2 is the pathway if the
patient is currently not taking any mood-stabilizing medication. Five
treatment options are recommended for priority consideration here, all
of which have some proven effectiveness in BP-DEP: lithium,
quetiapine, lamotrigine, lurasidone, and cariprazine. Each is discussed
below, with information about their effectiveness and adverse effect
risks. It seems reasonable to select any of these as a first choice in
Node 2, depending on clinician and patient preferences and
considering expected vulnerability to harmful effects. OFC is also
discussed although it is not among the first-line choices in this
algorithm.
Node 2 is a core node in the algorithm and has the longest text.
Other node discussions may refer the reader back to analyses
presented in Node 2.
Lithium
Lithium has not been demonstrated to have efficacy in acute BP-DEP
and it does not have FDA approval for this indication. Early studies
provided positive data, mostly from long-term observational studies.
29
, 30 However, the only large rigorously controlled study was Astra-
Zeneca’s EMBOLDEN I, which was a randomized, double-blind
comparison of quetiapine, lithium, and placebo in 802 BP-DEP
patients (62.5% bipolar I). 31 Lithium was not better than placebo (P =
.13) but quetiapine was significantly better (P < .001). The mean
serum lithium concentration was only 0.61 mEq/L, which is rather
low. In post-hoc analysis, however, even a subgroup of 34 patients
with lithium levels >0.8 mEq/L, while doing slightly better than the
lower lithium level group, had a non-significant improvement.
A placebo-controlled study in 117 outpatients by Nemeroff et al is
often cited as evidence supporting lithium as a monotherapy for BP-
DEP. 32 In this trial, BP-DEP patients treated with lithium were
collected into two groups, one with serum lithium levels ≤0.8 mEq/L
vs >0.8. Lithium was then augmented for 10 weeks with placebo,
imipramine, or paroxetine. There was no difference in efficacy among
the three groups regardless of lithium level, but the high lithium level
group (plus placebo) did quite well. It would have been informative if
the authors had provided a direct comparison of the results with high
vs low levels of lithium (with suitable controls) but this secondary
analysis was not included in the paper. Higher levels of lithium ≥0.6
mEq/L were associated with better prevention of BP-DEP recurrences
than lower levels in a comparison study with quetiapine. 33
Comprehensive reviews of lithium treatment have consistently
shown lithium to have a significant antisuicidal effect and to decrease
long-term mortality. 34 – 37 This is important due to the high rate of
suicide attempts of up to 32.4% in bipolar I and 36.3% in bipolar II. 38 ,
39 Even though its antisuicidal property is not rapidly apparent, the
benefits accrue over time. 40 Stopping lithium increases the risk of
suicide by ninefold. 41
Another benefit of lithium is its proposed unique neuroprotective
effects. 42 – 46 Bipolar disorder patients on long-term lithium have
better-preserved white matter structural integrity. 47 Lithium treated
bipolar patients were spared the loss of cortical thickness and
hippocampal volume that occurred in non-lithium-treated bipolar
patients, and brain preservation was similar to matched healthy
controls. 45 , 48 , 49 Aside from possibly improving the clinical course of
bipolar disorder, the neuroprotective effect seems to confer additional
benefits in delaying the onset of Alzheimer’s disease, and it may
favorably alter the course of Parkinson’s disease. 50
Lithium is also associated with reduced risk of stroke in bipolar
patients compared to other treatments, perhaps because of reduction in
atherosclerosis. 51
The benefits of lithium treatment seem to exist for patients across
the life span, 52 , 53 but recent data suggest that the long-term benefit is
greatest when started early in the course of the illness. Lithium
monotherapy prevents both mania (risk ratio 0.52) and depression
relapses (risk ratio 0.78), 54 and is also more likely than the other
treatments used for bipolar disorder to be maintained as a
monotherapy over time. 55 – 57 In an RCT comparing quetiapine vs
lithium for 1 year of maintenance effects, lithium was superior,
especially in the second half of the year. 58 Finally, a new “real-world
effectiveness” nationwide Finnish cohort study found lithium to be
associated with the lowest rate of psychiatric and medical
hospitalizations in bipolar disorder patients. 59 Lithium works less well
in rapid cyclers but so do all other mood-stabilizing medications. 60 – 62
Lithium has many adverse effects, both common and infrequent,
that contribute to its avoidance by many clinicians and refusal by some
patients. Many patients do not tolerate even relatively minor side
effects such as tremor, nausea, loose stools, hair loss, and blunted high
moods. 63 Training, clinical experience, tenacious effort in patient
education, and consulting the literature on side effect management 64 ,
65 can all assist the prescriber in overcoming some of these problems.
Weight gain with lithium is a common concern, but it is significantly
less than with quetiapine, valproate, and olanzapine. 66 Another area of
significant concern with the use of lithium is the possibility that abrupt
lithium discontinuation may worsen the natural course of bipolar
disorder, leading to increased or earlier manic and depressive relapses.
67 In a group of patients who were stable for years, 50% relapsed
within 8 months after abrupt lithium discontinuation, vs within 37
months with gradual discontinuation. 68 Consequently, if lithium
treatment is initiated, it should be done with the expectation that it
would be continued as a long-term maintenance agent and that it
would be tapered off gradually if and when it needed to be
discontinued. 35 , 69 Initial and ongoing discussions with the patient
about this issue are important.
Regarding lithium’s risk for end-stage kidney disease, the number
needed to harm (NNH) has been estimated to be 300, but this may be
an overestimate because of biases in the study design. 70 A recent large
observation study actually found no increase in end-stage kidney
disease on lithium compared with controls and no difference from
patients on valproate. 71 However, chronic kidney disease (not end-
stage) was more frequent with over 20 years of lithium use.71 , 72
Lithium patients should have regular kidney function monitoring. 73
Thyroid function should be monitored routinely as well, using
thyroid-stimulating hormone (TSH) for initial screening. Lithium
interferes with thyroid function by several possible mechanisms, and if
untreated up to 50% of patients may develop goiters, especially
women. 74 Some vulnerable patients may develop rapid cycling as a
consequence. 75
Quetiapine
Quetiapine is an FDA-approved medicine for acute BP-DEP, based on
evidence from two large manufacturer-supported studies BOLDEN I
(the BipOLar DEpressioN study group) and II. Both trials showed
clear, but not dose-dependent, separation from placebo for patients
being treated daily with either 300 or 600 mg of quetiapine. 76 , 77 In
BOLDEN I, 58% of patients treated with quetiapine responded (>50%
reduction of initial depression ratings) compared to 36% with placebo,
and separation was apparent by 1 week. The bipolar II subjects did not
respond as well as bipolar I patients, but rapid cyclers in both groups
responded to quetiapine more than placebo.76 In the BOLDEN II
replication study, bipolar II subjects may have responded better than in
the preceding trial. Clinical improvement was also greater with
quetiapine than placebo in both bipolar I and II disorder subjects in
ratings of quality-of-life 78 and anxiety. 79
The EMBOLDEN (Efficacy of Monotherapy Seroquel in BipOLar
DEpressioN) I (mentioned earlier) and II trials are placebo-controlled
studies that compared quetiapine vs lithium (level 0.6-1.2 mEq/L) and
quetiapine vs paroxetine (20 mg/d). Both trials found that quetiapine
produced greater response than placebo or the active comparators.31 , 80
Treatment-emergent mania/hypomania was infrequent with quetiapine
and somewhat more prevalent in the paroxetine group than with
placebo.80
Several adverse effects were associated with quetiapine treatment in
these studies. Serum triglyceride levels increased with quetiapine but
decreased with placebo and lithium. Subjects with clinically important
weight changes were ≥7% with quetiapine vs 2% with lithium.31 , 66
Unpublished trials of quetiapine in the 1990s found high rates of
clinically significant weight gain. 81 , 82 Quetiapine has also been
reported to reduce insulin sensitivity in youths aged 9-18, more than
risperidone or placebo. 83
Quetiapine can also prolong the electrocardiographic QTc
repolarization interval. In 2011, the FDA added a warning about this
to the quetiapine package insert, similar to the one for citalopram.
There is one placebo-controlled maintenance trial of quetiapine as a
monotherapy for bipolar disorder, based on an enrichment and
discontinuation design. 84 BP-DEP subjects improved with open-label
quetiapine were then randomized to continue quetiapine or switch,
over 2 weeks, to lithium or placebo for up to 2 years. Both lithium and
quetiapine were similarly superior to placebo. The study has been
criticized for using a sample that was enriched with quetiapine
responders and for a possible negative impact of quetiapine
discontinuation. Nevertheless, lithium showed similar increased time
to new episodes of both depression and mania, and thus performed
better than might have been expected.84 , 85 The FDA did not approve
quetiapine monotherapy as a maintenance treatment for bipolar
disorder.
Lamotrigine
Lamotrigine monotherapy has emerged as a possible first choice
medication for BP-DEP because of its lower risk of adverse effects
(other than rashes) compared with alternatives including lithium and
quetiapine. It is not associated with weight gain and may actually
decrease weight. 86 It is also less likely to cause unwanted
neurocognitive effects and sedation. 87 Most of the rashes associated
with lamotrigine are benign, but dermatologic and mucosal necrosis
(Stevens-Johnson syndrome) have been associated with early use of
lamotrigine in about 1/1000 cases, especially with rapidly escalating
doses and in association with valproate co-treatment. 88 , 89
The evidence supporting lamotrigine efficacy for acute BP-DEP,
however, appears to be mixed, at best. One double-blind, placebo-
controlled study of lamotrigine (at 50 or 200 mg/d) in bipolar I
depression (n = 195) found favorable results. 90 At 50 mg, 41% of
patients improved compared to 26% with placebo; at 200 mg, 51%of
patients showed improvement. A small, placebo-controlled, crossover
study of patients with refractory (mostly rapid cycling) BP-DEP also
found a similar response rate with lamotrigine. 91 Results from
multiple open-label or less well-controlled studies also suggest that
lamotrigine may be effective for acute BP-DEP in both bipolar I and II
disorders, though benefits are delayed by the need for slow increases
of dosing to effective levels (typically 200-300 mg/d). 92 – 96
These positive findings have been countered by four large, negative,
placebo-controlled RCTs supported and designed by the manufacturer
for the treatment of acutely depressed bipolar I and II patients. 97 None
of the four studies found a statistical difference between lamotrigine
and placebo. Lamotrigine did not receive FDA approval for acute BP-
DEP. Nevertheless, a meta-analysis 98 of these five studies found a
modest overall benefit with a 27% drug-placebo difference in effect
size. In the more severely ill patients (initial 17-item Hamilton Rating
Scale for Depression score of 24 or more), however, lamotrigine had a
greater separation from placebo (47%) because placebo effect was
lower in these subjects. Lamotrigine was not better than placebo if the
baseline Hamilton was lower than 24 (7% difference).
A case series of 40 consecutive subjects with bipolar I disorder
found that the optimal plasma level of lamotrigine for the maintenance
treatment for BP-DEP was about 4 μg/mL. 99
The efficacy of lamotrigine as maintenance treatment in delaying
recurrences of BP-DEP (but not [hypo]manic episodes) is fairly
robust. Two large, 18-month trials 100 , 101 showed efficacy, enabling
lamotrigine to obtain FDA approval for maintenance use. It had no
efficacy for preventing mania, but at least did not increase the risk of
mania compared with placebo. Another study101 compared lithium and
lamotrigine for maintenance against depressive relapse. It favored
lamotrigine, but may have been influenced by enrichment with
patients who initially responded to lamotrigine for acute BP-DEP and
were then randomized to continue lamotrigine or switch to lithium.
Lamotrigine has shown no efficacy in treating acute mania,15 which
makes it less desirable than lithium, quetiapine, or cariprazine for
many patients with acute BP-DEP in that there may be no coverage for
[hypo]manic phases of the illness. Thus, for any patient whose
hypomanias have been more than mild and others who have had full
mania, a second medication to address mania will be needed. On the
other hand, the relatively benign adverse effect profile of lamotrigine
might make it a first choice for some patients, especially if previous
hypomanias have been mild or infrequent and not necessarily in urgent
need of coverage, as in type II bipolar disorder.
Lurasidone
In the only trials of lurasidone monotherapy vs placebo to date, 102
patients were randomized to 20-60 or 80-120 mg/d. After 6 weeks,
similar improvement was found in the low and high dosage groups,
with the number needed to treat (NNT) being 6 and 7, respectively, but
adverse reactions of nausea, vomiting, sedation, and extrapyramidal
symptoms (EPS) were greater with the higher doses though there was
no difference in the rate of discontinuation. Lurasidone appears to
have fewer problems with weight gain than lithium and QTc
prolongation compared with quetiapine. 103 , 104 Akathisia and nausea
105 are the most distressing side effects for patients taking lurasidone.
The efficacy of lurasidone and quetiapine in BP-DEP appears to be
similar with different outcome measures. 106 , 107 However, the
lurasidone monotherapy study mentions the use of a “quality control
process” for some of the data that are not described. The cited
“Concordant Rater Systems” has a website that cites a reference 108
describing procedures to enhance rater assessment stability including
eliminating raters with the 15% highest or lowest ratings of patient
symptoms. With different approaches to optimizing signal
enhancement from the rater data, one may wonder whether the
reported efficacy of lurasidone is as similar to quetiapine as it appears.
Lurasidone trials conducted so far have included bipolar I patients
with BP-DEP. Post-hoc analysis found efficacy for treating BP-DEP
with mixed features. 109
Lurasidone has not been studied as a treatment for acute mania nor
as a long-term treatment to prevent recurrences of [hypo]mania.
Contrary to expectation (most antipsychotics are also antimanic), case
reports have suggested that lurasidone may precipitate [hypo]mania,
perhaps especially in relatively low doses used in BP-DEP (eg, 40
mg). 110
Cariprazine
Cariprazine is a new second-generation antipsychotics (SGA) that
received FDA approval for bipolar mania with and without mixed
features 111 – 113 in 2015. In June 2019, cariprazine received FDA
approval for acute bipolar depression in doses of 1.5 or 3 mg daily.
There are three published studies and a fourth one will be published
soon. 114 All but the first reported positive results. In the most recent
published report, there was a comparison of 1.5 and 3 mg with placebo
in bipolar I depressed (but not suicidal) patients without psychosis
who had not failed on other bipolar depression medications. 115 Both
doses produced improvement vs placebo by the primary outcome
measure of rating scale score change, but the secondary measure of
global impression of improvement only found efficacy on 3 mg and
the NNT was 8.3 (12 for the 1.5 mg dose).
Citrome performed a data synthesis of all four studies and, usefully,
compared the cariprazine results with the results with other
medications approved for acute bipolar depression.114 The overall
NNT for improvement (50% reduction in rating scale scores) was 10
for cariprazine. This may be compared to an NNT of 5 for the
lurasidone studies and 6 for the quetiapine studies. The NNH for
weight gain was 16 with quetiapine, 58 for lurasidone, and 50 for
cariprazine. Weight gain could be greater over the long term: these
were all 6-week studies. There were also no significant lipid or
glucose changes with cariprazine. The major side effects of cariprazine
were nausea, akathisia, restlessness, and EPS, and these were dose
related. Considering the evidence on benefits and these harms, the
lower approved dose (1.5 mg) seemed best for most patients. In the
2019 study, patients were begun on 1.5 mg and increased to 3 mg after
2 weeks if there was no response.
Cariprazine joins quetiapine as the second SGA that is FDA-
approved for both mania and depression, but it has significant
advantages in metabolic side effects over quetiapine. However, it may
be less effective for depression, and the approved doses for mania (3
to 6 mg) are significantly higher than the optimal dose for depression.
Thus, at the optimal dose of 1.5 mg for depression, there may not be
protection against mania. However, the same may be said for
quetiapine, which is effective for depression at 300 mg, but doses for
mania are usually higher.
Other SGAs for bipolar depression
Some other atypical antipsychotics tested in BP-DEP have not shown
efficacy. Examples include adjunctive use of ziprasidone 116 and
aripiprazole monotherapy in two large RCTs. 117 In the 8-week
aripiprazole studies, there was separation from placebo in some of the
earlier weeks, but by week 8, there was no difference (NNT = 44).
Dosage at endpoint reached a mean of 16.5 mg. Some have speculated
that lower doses (eg, starting at 2-5 mg and titrating up to 5-10 mg)
might have produced a comparable and more sustained antidepressant
effect (perhaps due to less akathisia), and this deserves study. In the
only maintenance study of aripiprazole in bipolar disorder (following
successful treatment of acute mania at higher doses), there was no
difference from placebo in preventing depressions or mixed states with
depressive symptoms over 6 months follow-up. 118 It seems that BP-
DEP treatment priority should be given to the SGAs with stronger
supporting evidence.
Olanzapine-fluoxetine combination and olanzapine
monotherapy
Another FDA-approved treatment for acute BP-DEP is OFC. A large
(n = 788) RCT comparing placebo, olanzapine monotherapy, and OFC
in depressed patients with bipolar I disorder demonstrated a
statistically significant and clinically meaningful response with OFC.
Olanzapine alone was statistically better than placebo, but the
difference did not appear clinically significant and seemed to be due
mostly to improvement in sleep and appetite, rather than in the core
symptoms of depression. 119 Another study compared OFC to
lamotrigine with no placebo arm. 120 It found similar remission rates
with both active treatments, with somewhat more rapid improvement
in BP-DEP with OFC, whereas lamotrigine was better tolerated overall
and did not worsen parameters of metabolic syndrome.
Olanzapine monotherapy was tested in another trial in Japan. 121
Again, the benefits for BP-DEP were statistically significant, but the
effect size appeared clinically insignificant with most improvement in
appetite and sleep. Long-term follow-up in two East Asian samples
found reduced risk of recurrences of both depression and [hypo]mania
but with an increased risk of weight gain. 122 , 123
Despite its effectiveness in acute BP-DEP, OFC is not
recommended in the early nodes of this algorithm. The severe
metabolic effects of olanzapine contribute to long-term risk for
morbidity and mortality. 124 Even a single dose of olanzapine was
found to alter glucose and lipid metabolism and increase insulin
resistance. 125 Olanzapine monotherapy is not recommended at all in
this algorithm.
The effectiveness of OFC does not seem to generalize to other
combinations of SGAs and antidepressants. In a recent meta-analysis
of six controlled studies of other combinations, no clinically
significant benefit was found. Over 1-year follow-up, there was an
increased risk of [hypo]manic mood switching with antidepressants vs
placebo combined with SGAs. 1
26
Are there any other options for early use in bipolar
depression?
Valproate might be effective in BP-DEP, but this impression is based
on four small studies with a total of only 142 subjects and some
significant problems (eg, one had a drop-out rate of 53% on
valproate). 127 , 128 As a maintenance treatment to prevent BP-DEP
episodes, according to a 2014 meta-analysis of 33 RCTs, valproate did
not demonstrate efficacy, whereas lithium and lamotrigine did have
significant preventative effect. 129 The large 2010 BALANCE study
contributed to the evidence-base for valproate’s inferiority as a
treatment for bipolar disorder, compared with lithium, and the
combination was only slightly more effective than lithium alone. 130 –
132 Valproate also has important adverse effects especially weight gain
and is a severe teratogen. 133 Therefore, valproate might be considered
later as an option for BP-DEP, but is not recommended among first-
line treatments.
Neither carbamazepine (CBZ) nor oxcarbazepine have sufficient
evidence to support efficacy in BP-DEP. 134
No antidepressant is FDA-approved explicitly for the treatment of
BP-DEP except for fluoxetine when combined with olanzapine, as
discussed. Antidepressant monotherapy in bipolar I disorder is
discouraged in expert consensus evaluations of the literature,
especially when mixed features are present, and even when added to a
mood stabilizer.2 , 135 More recently, data from the Systematic
Treatment Enhancement Program for Bipolar Disorder (STEP-BD)
study confirmed that rapid cyclers continued on antidepressants
(despite concurrent mood stabilizer treatment) had much worse
maintenance outcomes. 136 They had triple the rate of depressive
episodes per year compared with subjects whose antidepressants were
discontinued. These were patients who seemed initially to have a good
response to the added antidepressant. The STEP-BD study also found
that antidepressants seem to cause a unique syndrome of dysphoria,
irritability, and insomnia that is not part of the natural course of most
bipolar patients. 137 Patients treated with an antidepressant for acute
depression were 10 times more likely to develop this “antidepressant-
associated chronic irritable dysphoria” (ACID) syndrome.
Their efficacy with bipolar II depression is less clear, though risks
of dangerous mood switching are lower than with bipolar I depression.
Evidence is accumulating that antidepressants including sertraline and
venlafaxine may be effective and relatively safe (with respect to
cycling) from short-term studies without placebo controls in patients
with non-mixed bipolar II depressions. 138 , 139 Sertraline was recently
compared to lithium alone or sertraline plus lithium in 142 subjects in
a 16-week randomized study of the acute treatment of bipolar II
depression. 140 The response and mood switch rates did not differ, but
more patients dropped out on the combination treatment, and it did not
work faster than the others. However, the switchers on lithium had a
mean serum lithium level of only 0.41 mEq/L compared to non-
switchers who had a mean level of 0.62 mEq/L.
There is a long-term (1 year), controlled study of maintenance
treatment with fluoxetine in patients with bipolar II depression who
had responded acutely to open-label fluoxetine monotherapy. 141
Eighty-one patients were randomized to fluoxetine, lithium, or
placebo. The time to relapse was significantly longer with fluoxetine.
An editorial pointed out that the study suffered from 75% attrition
over the course of the protocol, and the sample was 100% enriched
with responders to fluoxetine. 142 Also, patients on fluoxetine were
three times more likely to present with some hypomanic symptoms at
follow-up visits. As noted earlier, STEP-BD found no improvement
from adding antidepressants to ongoing mood stabilizers compared
with avoiding doing so. 143
In summary, more study is required before there can be a firm
recommendation that antidepressants should be among early options
for managing bipolar II depression. Antidepressants do have generally
milder side effects compared with SGAs, lithium, and lamotrigine
(considering the rash risk). If antidepressants are considered, clinicians
should be careful to diagnose bipolar II strictly according to the DSM-
IV or -5 criteria, 144 as was done in these studies. A key criterion
differentiating bipolar I mania from the hypomania in bipolar II that
clinicians may overlook is that manic episodes are associated with
“marked impairment in social or occupational functioning.” Often,
impairment from the [hypo]mania that on superficial evaluation did
not appear “marked” may later be recognized as such, and the
diagnosis will become bipolar I and antidepressants will drop from
early consideration.
In summary for Node 2
Lithium, quetiapine, lamotrigine, lurasidone, and cariprazine are the
five preferred options for acute BP-DEP. Clinicians should choose a
suitable first choice medication from among these, depending on the
patient’s tolerance of particular adverse effects, need for an agent that
will prevent switching to mania, and other factors.
Nodes 3-6: Overview
Nodes 3-6 start algorithm branches for depressed patients currently
taking some medication for BP-DEP and address whether to optimize
dose, add or change treatment for the next step (See Figure 1 ).
Node 3: Is the patient currently on lithium?
As discussed in Node 2, lithium monotherapy may have limited
effectiveness for acute BP-DEP especially if the trough level is <0.8
mEq/L. Therefore, clinicians should consider increasing the dose, if
tolerated, to reach a serum lithium level >0.8 mEq/L.32 If the patient
already has a level above 0.8, go to Node 7 where quetiapine,
lamotrigine, lurasidone, and cariprazine are considered for the next
step.
Node 4: Is the patient taking carbamazepine, lamotrigine,
or valproate?
One should first optimize the dose of these anticonvulsants:
lamotrigine to 200-400 mg/d (optimal level may be about 4 μg/mL, as
noted earlier99 ); valproate or CBZ to usually employed levels (for
mania, 50-125 or 4-12 μg/mL, respectively). 8 If doses are already
optimized, then add or change to lithium, quetiapine, lurasidone,
lamotrigine, or cariprazine considering the factors discussed in Node
2. Depending on the medication chosen, adding or switching will
depend on whether the patient needs coverage for mania, as discussed
in Node 2.
Some clinicians like to add an antidepressant to depressed patients
on valproate, but in the STEP-BD study, as noted earlier, this was not
better than adding placebo.143 If CBZ is retained, addition of
lurasidone is contraindicated according to the package insert due to
particularly strong induction of the metabolism of lurasidone by CBZ,
which can result in 85% reduction in serum concentrations of
lurasidone. Cariprazine is also a P450 3A4 substrate and metabolism
would be induced by CBZ.
Node 5: Is the patient taking quetiapine, lurasidone, or
cariprazine monotherapy?
The daily dose of quetiapine used in the BP-DEP registration trials
was 300-600 mg and for lurasidone it was 40-120 mg. This dose
should be continued for up to 6 weeks especially if partial response
occurs and improvement is continuing. If response remains
unsatisfactory, then evidence supports adding lithium to lurasidone.107
There are no studies, however, combining lithium and quetiapine for
acute BP-DEP. A maintenance study, however, found quetiapine
better than placebo when combined with lithium or valproate. 145
Therefore, addition of lithium to quetiapine is a reasonable choice.
Based on this one study, valproate addition might be reasonable as
well, but it is not one of the top choices for reasons explained earlier at
Node 2.
Another option would be to combine lamotrigine and quetiapine. In
the CEQUEL (Comparative Evaluation of Quetiapine Plus
Lamotrigine) double-blind study, 202 patients receiving quetiapine
were randomized to addition of lamotrigine up to 200 mg/d, 500 μg/d
of folic acid, or placebo. 146 With quetiapine plus lamotrigine, there
was improvement in depressive symptoms at 12 and 52 weeks and
fewer recurrences of depression. Surprisingly, folate yielded a
somewhat less favorable response than with quetiapine alone.
There are no studies as yet combining cariprazine with other
medications for BP-DEP.
Alternatively, if the patient has not had an adequate trial of
monotherapy with any of the other four recommended options, then
one could switch to one of them, as discussed in Node 2.
Node 6: Is the patient taking an antidepressant, or
olanzapine alone or with fluoxetine?
These are treatments that are not favored for early use in BP-DEP for
the reasons discussed in Node 2. The STEP-BD results showing the
harms of continuing patients on antidepressants, including more
frequent cycling into depressions and switches into ACID (irritable
dysphoric states), argue against this common practice.136 , 137
Therefore, if the patient is on one of them now and is depressed, the
recommendation is the same as in Node 2. One may discontinue the
existing medication with gradual dose reduction over at least 2 weeks
to limit any risk of mood destabilization. At the same time, start
lithium, quetiapine, lamotrigine, lurasidone, or cariprazine depending
on the patient’s expected side effect tolerance and the other
considerations discussed in Node 2.
Node 7: Is the patient still depressed after an adequate
trial of the first treatment selected at Node 2 or after
changes recommended in Nodes 3-6?
Options to consider for this second medication trial are any of the five
drugs discussed that are first-line but not yet tried. As shown in Figure
1 , the algorithm recommends staying at Node 7 in the event of
unsatisfactory response, continuing to try up to all five of the
recommended first-line treatments (if acceptable to clinician and
patient) before continuing to Node 8. Adding or changing treatments
are possibilities. The next medication could be added even if it is
ineffective for [hypo]mania (eg, lamotrigine), provided that the first
medication has a mania-preventing effect (eg, lithium). One could
switch to the next medication if the choice is likely to be effective for
mania (eg, lithium, quetiapine, or cariprazine) but probably not
lurasidone which is unstudied in mania.
Quetiapine is effective as an acute monotherapy for BP-DEP, and it
has maintenance efficacy as an adjunct to another mood stabilizer, 147 ,
148 but it adds metabolic and other adverse effect risks that can be a
problem over the long term. Lamotrigine has one (n=124) positive
study as an add-on to lithium in bipolar I and II depression 149 : 52% of
subjects met criteria for response, compared to 32% with placebo
(NNT=5), but 8% switched to [hypo]mania with lamotrigine as did 3%
of those given placebo. As noted at Node 2, maintenance efficacy in
BP-DEP is reasonably well established for lamotrigine and it is well
tolerated by most patients. Lurasidone was found effective and well
tolerated as monotherapy and as an adjunct to lithium and other mood
stabilizers.107
What about adding an antidepressant to the first-line BP-
DEP medication?
Antidepressants are a popular choice at Node 7 and earlier, for many
clinicians. However, they have inconsistent evidence for efficacy in
BP-DEP and they induce recurrent depressions and other negative
states as discussed earlier.143 Also, in a meta-analysis of six placebo-
controlled RCTs of adding an antidepressant (selective serotonin
reuptake inhibitors [SSRIs], bupropion, or agomelatine) to lithium or
other mood stabilizers (mentioned earlier), there was little additional
improvement (standardized mean difference 0.165) and no differences
in response or remission rates.126 Furthermore, there was a
significantly increased risk of switch to [hypo]mania within a year of
follow-up (OR 1.8) suggesting a destabilizing effect on the course of
some bipolar disorder patients. See Node 8 for further discussion of
the benefits and risks of antidepressants. We still do not recommend
OFC here, because of the long-term metabolic side effects of the
olanzapine component.
Node 8: Consider an antidepressant in non-rapid cycling
BP-DEP or possibly valproate
One arrives at Node 8 after the patient has been tried on up to five BP-
DEP medicines (and combinations) without a history of rapid cycling
(four or more mood episodes per year) or mixed episodes. Also, there
should be no history of [hypo]mania after receiving an antidepressant.
For rapid cyclers or patients with BP-DEP with mixed features, go to
Node 9.
Use of an antidepressant
The International Society for Bipolar Disorders (ISBP) Task Force of
68 experts reviewed the literature and prepared a report on the use of
antidepressants in bipolar disorder in 2013.2 Twelve recommendations
were made, based on consensus of at least 80% of the experts.
Three recommendations pertinent to this step in the algorithm arose
from their report. Our comments are in italics:
Avoid antidepressants in all patients with current or past mixed
states. Discontinue any antidepressants in use during a mixed
state. [There are no new studies offering further evidence on this
topic .]
In bipolar II depression, antidepressant monotherapy can be used
but not if there are mixed features (defined as two or more
hypomanic symptoms). Observe closely for any manic/mixed
symptoms developing. [There are no studies since 2013
evaluating bipolar II mixed cases treated with antidepressants, so
this recommendation seems still pertinent .]
Avoid antidepressants in all patients with recent or past rapid
cycling. [Two recent studies evaluated bipolar II depressed
patients with rapid cycling and found no greater mood switching
and no reduction in effectiveness compared with non-rapid
cyclers. 140 , 150 However, these studies did not have placebo
controls so it is not known if the antidepressants were effective.
As noted, rapid cyclers had much worse outcomes with
depression in the STEP-BD study. 136 ]
Thus, it might be reasonable to consider adding an antidepressant to a
mood stabilizer at Node 8, and even to consider antidepressant
monotherapy for a bipolar II depressed patient—but not for patients
with previous or current mixed features. For rapid cycling bipolar II
patients, cautious antidepressant monotherapy can be considered but
clinicians should stay alert for depression recurrences. In choosing an
antidepressant, safety may be the primary consideration: bupropion
and SSRIs seem to have less risk of inducing cycling than venlafaxine
in bipolar I patients. 151 In bipolar II patients, however, venlafaxine
monotherapy was not a problem in one study.150 Fluoxetine is best
avoided because of the long half-life of its active metabolite,
norfluoxetine, which might prolong an emerging manic episode.
Valproate
Despite having very limited evidence of efficacy in acute BP-DEP as
discussed in Node 2, valproate can be considered as an option here. Its
dosage should be adjusted to the higher end of the usual serum level,
70-90 μg/mL, according to some expert opinion. 131
Node 9: Continuing to avoid antidepressant in high-risk
patients
Patients who reached this point of the algorithm have been tried on
lithium, quetiapine, lurasidone, lamotrigine, and cariprazine unless one
or more were deemed unacceptable due to intolerability or side effect
risks. In addition, they have risk factors for the use of an
antidepressant including mixed features, rapid cycling, and history of
[hypo]mania or a mixed state after receiving an antidepressant.
Options include, trying valproate (also offered in Node 8) or
combinations of the five recommended BP-DEP medicines not yet
tried. This may also be the point to consider OFC.
Node 10: Highly refractory bipolar depression
Many evidence-supported treatments have been tried by this point and
yet the patient’s response remains unsatisfactory. The diagnosis of BP-
DEP should be reviewed again, as it also should after each previous
trial that produced an unsatisfactory response. Table 1 lists several
more options and cites pertinent evidence. ECT is discussed first
because of its strong effectiveness, and the others are in no particular
order. This is not meant to be an exhaustive list.
Table 1 | Options to consider for treatment-resistant bipolar
depression
Treatment Comments
Reconsider ECT ECT may produce a 50% response rate at this point and thus may be by
far the best option. 153 , 154 See Node 1
Other device-based
interventions
Transcutaneous magnetic stimulation, vagus nerve stimulation, and
deep brain stimulation have possible value but have not been
adequately studied in BP-DEP. Transcranial direct stimulation is a
promising new option with efficacy. 155 Adjunctive bright light therapy
for an hour given at Noon was much more effective than dim red light
for BP-DEP in a recent small study. 156 Patients were on antimanic
agents, and rapid cyclers and mixed syndrome patients were excluded
Stimulants, modafinil, or
armodafinil
Methylphenidate has many case reports and may be mildly effective
based on uncontrolled data. Lisdexamfetamine in a recent RCT in 25
subjects had no efficacy on the total depression scores but depressed
mood and fatigue/sleepiness were improved. 157
Modafinil was tested in a placebo-controlled RCT (n = 85) with overall
positive effect on depression though primarily due to improvement in
energy symptoms. There were no manic switches. 158 Armodafinil has
had three large placebo-controlled RCTs as an adjunct. One was
positive (NNT = 9) and two were negative. The manufacturer decided
not to file for an FDA indication. 159
Pramipexole Pramipexole, a D3 agonist, has had two small positive short-term
placebo-controlled trials as an adjunct (n = 21, n = 22). 160 , 161 Note
that, rapid cyclers were excluded, and it was poorly tolerated. However,
it can have persisting benefit. 162 , 163
Clozapine There are no controlled studies in BP-DEP, but open-label reports show
possible benefit in some cases. 164 , 165 One report documented 4 years
of stable improvement in a patient with refractory psychotic bipolar
disorder treated with clozapine 166 and another suggested reduced rates
of hospitalization for BP-DEP episodes with addition of clozapine.
Add omega-3 fatty acids
(O3FAs)
In six RCTs, O3FAs were not effective in BP-DEP. 168 However,
another (n = 75) found improvement in mildly to moderately depressed
patients. 169 A meta-analysis of adjunctive O3FAs (n=291) found
evidence of efficacy in acute BP-DEP with a low-moderate effect size
of 0.34. 170 O3FAs may be particularly well tolerated.
Add aripiprazole This SGA, which is FDA-approved as an adjunct for non-bipolar
depression, has had multiple open-label and uncontrolled studies
showing some effectiveness in bipolar depressed patients. 171 – 177
However, unlike quetiapine and lurasidone, it has failed to show
efficacy as monotherapy in two large controlled studies,117 although
post-hoc analysis showed some improvement in severely depressed
patients. 178 It has been suggested that the average doses (15-18 mg/d)
might have been too high in these negative studies.117 In the most
recent positive report, doses up to 5 mg were used. 173
Add sleep deprivation
combined with light therapy
A group in Italy has reported two consecutive large prospective open
trials of 24-h sleep deprivation with light therapy added to lithium in
inpatients with BP-DEP, 83% of whom had histories of medication
resistance. 179 There were significant benefits for depression and
suicidality. The findings were replicated by other investigators in an
open-label controlled trial comparing with medication alone, and the
results were sustained over 7 wk. 180 This “chronotherapy” approach
deserves more investigation
Add triiodothyronine (T3) A retrospective chart review of 125 treatment-resistant, depressed
patients with bipolar II and 34 with bipolar NOS disorders found that
they had failed trials of an average of 14 previous treatments. 181 With
addition of “supraphysiological” doses of T3 averaging 90 μg daily,
33% remitted and 84% improved. There may be investigator bias in
addition to other problems with chart review studies
EXCEPTIONS: COMORBIDITY AND
OTHER FEATURES IN BP-DEP AND HOW
THEY AFFECT THE ALGORITHM
Table 2 lists common comorbidities and other circumstances with
suggestions on how the algorithm might change for these patients
based on evidence considerations.
Table 2 | Comorbidity and other features in bipolar depression:
How they affect the algorithm
Comorbid Conditions Evidence
Considerations Recommendations
Posttraumatic Stress Disorder
(PTSD)
Co-occurring BP-DEP and
PTSD are associated with
increased suicide risk, rapid
cycling, substance use disorder,
and greater depressive
symptoms. 182 , 183
PTSD has a higher prevalence
in BP-DEP compared with
general population, with overall
20% lifetime prevalence rate.3
Common symptoms require
differentiation (irritability,
insomnia, decreased
concentration).
PTSD-related insomnia and
anxiety could be treated with
prazosin. 185 Quetiapine could
be reasonable (be aware of
weight gain).
Lamotrigine has some efficacy
Lithium might reduce
vulnerability to PTSD. 184
Lamotrigine has some efficacy
in PTSD. 186
Attention-Deficit/Hyperactivity
Disorder (ADHD)
Stimulants added for ADHD
symptoms with effective
ongoing mood stabilizer seem
safe, but use without a mood
stabilizer is associated with 6-7
fold increased risk of inducing
[hypo]mania. 187
Atomoxetine and armodafinil
have been insufficiently studied
in this comorbidity. 188 , 189
Patients should be on a mood
stabilizer before adding any
stimulant to address ADHD
symptoms or excessive day time
fatigue
DSM 5 Anxiety Disorders Up to 75% of bipolar disorder
patients have at least one
comorbid anxiety disorder at
some point. These are
associated with more frequent
mood episodes and poorer
treatment outcome.5
Anxiolytic agents such as
buspirone, gabapentin, and
benzodiazepines may be
helpful. Valproate sometimes is
helpful in treatment-resistant
panic disorder. However,
quetiapine had no efficacy for
BP-DEP nor comorbid
generalized anxiety disorder in
one RCT. 190
Women of childbearing
potential and pregnant women
Valproate is by far the most
teratogenic agent used for
bipolar disorder. 191 Valproate
(but not lamotrigine) may also
lower intelligence scores in
young children exposed to it in
utero. 192
Carbamazepine is associated
with increased spina bifida,
cardiac anomalies, and vitamin
K deficiencies late in
pregnancy.191
Avoid valproate in any woman
with the potential to become
pregnant: should the patient
become pregnant it may already
be too late to remove it before
harm is done. High dose folate
(4-5 mg daily) has been
recommended 201 but probably
has no protective effect.133
Carbamazepine is almost as
harmful and should be avoided.
Lithium is preferred over
valproate and carbamazepine.
Data on lamotrigine suggest low
risk of fetal harm as
monotherapy, but cleft palate is
a concern. 193 – 197
Lithium has lower
For some patients, lithium
should be the first choice 203
The SGAs with efficacy in BP-
DEP are generally first choice,
though data are very limited in
Lithium has lower
malformation risks than
valproate and carbamazepine.
Cardiac malformations occurred
in 2.4% of infants exposed to
lithium (0.6% for ventricular
outflow obstruction) vs 1.2% of
unexposed babies (0.2%
ventricular outflow), an
adjusted risk ratio of 1.65. The
risk rises with higher doses, but
is still lower than previously
thought. 198
ECT treatment during
pregnancy causes fetal heart
rate reduction, uterine
contraction, and premature
labor in up to 1/3 of the
subjects. ECT was found to
have an overall fetal mortality
rate of 7%. 199
Although the safety of
antipsychotics in pregnancy has
not been clearly established
(due to many limitations in the
studies), they seem to be
relatively safe. 200
The SGAs that cause weight
gain appear to increase risk of
gestational metabolic
complications including
diabetes and babies large for
gestational age. Olanzapine may
be associated with low and high
birth weight and a small risk of
malformation including hip
dysplasia, meningocoele,
ankyloblepharon, and neural
tube defects.201
Patients stopping medication
during pregnancy had a relapse
rate of 80% for depression, 16%
for mania relapse, and 3.9% for
mixed episode in postpartum.
202
though data are very limited in
pregnancy. 204
Lamotrigine may be considered.
ECT treatment during
pregnancy warrants more
caution than previously thought.
It can be used for severe
depression, catatonia,
medication resistant illness,
extremely high risk for suicide,
psychotic agitation, severe
physical decline due to
malnutrition, dehydration, or
other life threatening
conditions.199
Prescribe as few drugs as
possible—ideally, one. But,
when pregnancy occurs during
treatment, it is usually best to
continue the previous regimen
to avoid exposure to even more
agents, except if the patient was
on valproate or carbamazepine
(probably switch).
Adjust doses as pregnancy
progresses. Blood volume
expands 30% in third trimester.
Plasma level monitoring is
helpful.
Anticholinergic drugs should
not be prescribed to pregnant
women except for acute, short-
term need.
Depot antipsychotics should not
be routinely used in pregnancy:
infants may show
extrapyramidal symptoms for
several months
Substance Use Disorders
(SUDs)
Reported lifetime prevalence of
BP-DEP and any substance use
disorder is as high as 47%,
especially in bipolar I disorder
(60%). Active SUDs are
associated with poorer outcome
with medication treatments but
there are very limited data in
this patient population due to
exclusion criteria.4
Valproate in one small study
showed significant reduction in
alcohol drinking in patients with
BP-DEP. 205
Citicoline added to standard
treatment of comorbid cocaine
dependence in manic patients
showed improvement in
substance abuse. 206
Naltrexone and acamprosate
have been shown to have
modest ability to reduce alcohol
drinking behaviors. 207 , 208
Remission of SUDs is a high
treatment priority
Cardiac disease or use of QTc-
prolonging drugs
Quetiapine has had 5 studies
measuring QTc prolongation
but the manufacturer has
refused to release the QTc data.
209 However, in 2011 the FDA
mandated a new QTc warning
in the quetiapine package insert
with requirements for
monitoring.
Based on clinical trials thus far,
lurasidone has been shown to
have minimal alteration of
QTc.104
If risk of QTc prolongation is a
significant concern, quetiapine
would be relatively undesirable.
Consider lurasidone.
Review the patient’s
medications for other QTc-
prolonging agents and monitor
for risk factors for Torsade’s,
such as bradycardia and
electrolyte abnormalities
Other medical comorbidities Medical comorbidities are
common
Hepatitis and liver cirrhosis:
avoid valproate and
carbamazepine when possible.
Among SGAs, quetiapine and
olanzapine have higher risk of
transaminase elevations
transaminase elevations
Renal filtration impairment:
avoid lithium. Lamotrigine is
also renally excreted.
Obesity, hyperlipidemia,
metabolic syndrome: consider
lamotrigine, carbamazepine, or
lurasidone
COMPARISON WITH OTHER BP-DEP
GUIDELINES AND ALGORITHMS
A “meta-consensus” of other guidelines found significant
disagreements. 152 Though the recommendations herein are generally
in accord with most recently published guidelines, there are some
differences, in part because the current algorithm places such strong
emphasis on long-term side effect considerations. For example, other
guidelines propose OFC as a first-line treatment, but in this algorithm
it is not recommended until after most other evidenced options. Table
3 summarizes key recommendations in other guidelines published
since 2013.
Table 3 | Other guidelines and algorithms for the treatment of
acute bipolar depression
Guideline/Algorithm Year Key Points
The psychopharmacology algorithm project
at the Harvard South Shore Program: an
update on bipolar depression7
2010 Last version of the present algorithm.
Lithium, quetiapine, and lamotrigine were
first-line options, with a slight preference for
lithium.
Adding an antidepressant could be
considered after above options in low-risk
patients
Canadian Network for Mood and Anxiety
Treatments (CANMAT) and International
2013 Bipolar I: first-line lithium, lamotrigine,
quetiapine monotherapy, olanzapine plus
SSRI, or combinations with lithium,
Society for Bipolar Disorders (ISBP)
collaborative update of CANMAT
guidelines for the management of patients
with bipolar disorder: update 2013135
SSRI, or combinations with lithium,
valproate plus antidepressant.
Bipolar II: first-line quetiapine only; second-
line lithium, lamotrigine, atypical
antipsychotic plus antidepressants, and
others
National Institute for Health and Care
Excellence: Clinical Guidelines 210
2014 First-line medications were quetiapine,
olanzapine, OFC, lamotrigine, valproate, and
lithium
Royal Australian and New Zealand College
of Psychiatrists clinical practice guidelines
for mood disorders. 211
2015 Quetiapine, lurasidone, olanzapine were
first-line monotherapy options, followed by
lithium, valproate, and lamotrigine as
second-line monotherapy choices.
Evidence-based guidelines for treating
bipolar disorder: Revised third edition
recommendations from the British
Association for Psychopharmacology 212
2016 Firstline medications included quetiapine,
lurasidone, olanzapine, and OFC.
Lamotrigine was second line.
Escitalopram, fluoxetine, lithium, and
paroxetine were third-line recommendations
The international College of Neuro-
Psychopharmacology (CINP) Treatment
Guidelines for Bipolar Disorder in Adults
(CINP-BD-2017) 213
2016 Lurasidone and quetiapine were
recommended as first line.
Escitalopram, fluoxetine, olanzapine, and
OFC were the second-line
recommendations.
Lithium was fourth line given the level of
evidence.
CONCLUDING COMMENT
Notwithstanding the development of this and other algorithms and
guidelines, the treatment of BP-DEP remains a challenge for both
clinicians and patients. A considerable degree of uncertainty remains
about which of the treatments constitute first-, second-, or third-line
therapies. Practitioners will need to remain ever alert to emerging
evidence and evolving changes in practice in order to provide safe and
effective management of their BP-DEP patients.
ACKNOWLEDGMENT
The authors thank Ross J. Baldessarini, MD for his thorough and
thoughtful review of a draft of this paper.
CONFLIC T OF INTERESTS
This manuscript represents original material, has not been previously
published, and is not under consideration for publication elsewhere.
All authors have read and approved the final submitted version of this
manuscript. All authors do not have any financial conflict of interest to
declare.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were
created or analyzed in this study.
ORCID
https://orcid.org/0000-0002-9477-241X
REFERENCES
1. Judd LL, Schettler PJ, Solomon DA, et al. Psychosocial disability and work role function
compared across the long-term course of bipolar I, bipolar II and unipolar major depressive
disorders. J Affect Disord . 2008;108:49-58.
2. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders
(ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry .
2013;170:1249-1262.
3. Hernandez JM, Cordova MJ, Ruzek J, et al. Presentation and prevalence of PTSD in a bipolar
disorder population: a STEP-BD examination. J Affect Disord . 2013;150:450-455.
4. Pettinati HM, O’Brien CP, Dundon WD. Current status of co-occurring mood and substance use
disorders: a new therapeutic target. Am J Psychiatry . 2013;170:23-30.
5. Provencher MD, Guimond AJ, Hawke LD. Comorbid anxiety in bipolar spectrum disorders: a
neglected research and treatment issue? J Affect Disord . 2012;137:161-164.
6. Osser DN, Patterson RD. On the value of evidence-based psychopharmacology algorithms.
Bulletin of Clinical Psychopharmacology . 2013;23:1-5 .
https://orcid.org/0000-0002-9477-241X
7. Ansari A, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore
Program: an update on bipolar depression. Harv Rev Psychiatry . 2010;18:36-55.
8. Mohammad O, Osser DN. The psychopharmacology algorithm project at the Harvard South
Shore Program: an algorithm for acute mania. Harv Rev Psychiatry . 2014;22:274-294.
9. Osser DN, Roudsari MJ, Manschreck T. The psychopharmacology algorithm project at the
Harvard South Shore Program: an update on schizophrenia. Harv Rev Psychiatry . 2013;21:18-
40.
10. Abejuela HR, Osser DN. The psychopharmacology algorithm project at the Harvard South
Shore Program: an algorithm for generalized anxiety disorder. Harv Rev Psychiatry .
2016;24:243-256.
11. Giakoumatos CI, Osser D. The psychopharmacology algorithm project at the Harvard South
Shore Program: an update on unipolar nonpsychotic depression. Harv Rev Psychiatry .
2019;27:33-52.
12. O’Donovan C, Garnham JS, Hajek T, Alda M. Antidepressant monotherapy in pre-bipolar
depression; predictive value and inherent risk. J Affect Disord . 2008;107:293-298.
13. Bowden CL. Strategies to reduce misdiagnosis of bipolar depression. Psychiatr Serv .
2001;52:51-55.
14. Byrne EM, Raheja UK, Stephens SH, et al. Seasonality shows evidence for polygenic
architecture and genetic correlation with schizophrenia and bipolar disorder. J Clin Psychiatry
. 2015;76(02):128–134.
15. Goodwin FK, Jamison KR. Manic-depressive illness, bipolar disorders and recurrent
depression (2nd edn). New York: Oxford University Press;2007.
16. Daly JJ, Prudic J, Devanand DP,et al. ECT in bipolar and unipolar depression: differences in
speed of response. Bipolar Disord . 2001;3:95-104.
17. Medda P, Perugi G, Zanello S, Ciuffa M, Cassano GB. Response to ECT in bipolar I, bipolar II
and unipolar depression. J Affect Disord . 2009;118:55-59.
18. Dierckx B, Heijnen WT, van den Broek WW, Birkenhager TK. Efficacy of electroconvulsive
therapy in bipolar versus unipolar major depression: a meta-analysis. Bipolar Disord .
2012;14:146-150.
19. Schoeyen HK, Kessler U, Andreassen OA, et al. Treatment-resistant bipolar depression: a
randomized controlled trial of electroconvulsive therapy versus algorithm-based
pharmacological treatment. Am J Psychiatry . 2015;172:41-51.
20. Kho KH, Zwinderman AH, Blansjaar BA. Predictors for the efficacy of electroconvulsive
therapy: chart review of a naturalistic study. J Clin Psychiatry . 2005;66:894-899.
21. Loo CK, Mahon M, Katalinic N, Lyndon B, Hadzi-Pavlovic D. Predictors of response to
ultrabrief right unilateral electroconvulsive therapy. J Affect Disord . 2011;130:192-197.
22. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add- on trial of an N-methyl-D-
aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry .
2010;67:793-802.
23. Zarate CA, Brutsche NE, Ibrahim L, et al. Replication of ketamine’s antidepressant efficacy in
bipolar depression: a randomized controlled add-on trial. Biol Psychiatry . 2012;71:939-946.
24. Ballard ED, Ionescu DF, Vande Voort JL, et al. Improvement in suicidal ideation after
ketamine infusion: relationship to reductions in depression and anxiety. J Psychiatr Res .
2014;58:161-166.
25. aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose
intravenous ketamine for treatment-resistant depression. Biol Psychiatry . 2010;67:139-145.
26. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in
the treatment of mood disorders. JAMA Psychiatry . 2017;74:399-405.
27. Zorumski CF, Conway CR. Use of ketamine in clinical practice: a time for optimism and
caution. JAMA Psychiatry . 2017;74:405-406.
28. Lara DR, Bisol LW, Munari LR. Antide pressant, mood stabilizing and procognitive effects of
very low dose sublingual ketamine in refractory unipolar and bipolar depression. Int J
Neuropsychopharmacol . 2013;16:2111-2117.
29. Baldessarini RJ, Tondo L. Does lithium treatment still work? Evidence of stable responses
over three decades. Arch Gen Psychiatry . 2000;57:187-190.
30. Frances AJ, Kahn DA, Carpenter D, Docherty JP, Donovan SL. The expert consensus
guidelines for treating depression in bipolar disorder. J Clin Psychiatry . 1998;59(Suppl4):73-
79 .
31. Young AH, McElroy SL, Bauer M, et al. A double-blind, placebo-hcontrolled study of
quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression
(EMBOLDEN I). J Clin Psychiatry . 2010;71:150-162.
32. Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of
imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry .
2001;158:906-912.
33. Nolen WA, Weisler RH. The association of the effect of lithiumin the maintenance treatment
of bipolar disorder with lithium plasma levels: a post hoc analysis of a double-blind study
comparing switching to lithium or placebo in patients who responded to quetiapine (Trial 144).
Bipolar Disord . 2013;15:100-109.
34. Baldessarini RJ, Tondo L, Faedda GL, Suppes TR, Floris G, Rudas N. Effects of the rate of
discontinuing lithium maintenance treatment in bipolar disorders. J Clin Psychiatry .
1996;57:441-448.
35. Baldessarini RJ, Tondo L, Hennen J. Effects of lithium treatment and its discontinuation on
suicidal behavior in bipolar manic-depressive disorders. J Clin Psychiatry . 1999;60(Suppl
2):77-84; discussion 111–6.
36. Cipriani A, Pretty H, Hawton K, Geddes JR. Lithium in the prevention of suicidal behavior
and all-cause mortality in patients with mood disorders: a systematic review of randomized
trials. Am J Psychiatry . 2005;162:1805-1819.
37. Smith KA, Cipriani A. Lithium and suicide in mood disorders: updated meta-review of the
scientific literature. Bipolar Disord . 2017;19:575-586.
38. Novick DM, Swartz HA, Frank E. Suicide attempts in bipolar I and bipolar II disorder: a
review and meta-analysis of the evidence. Bipolar Disord . 2010;12:1-9.
39. Tondo L, Pompili M, Forte A, Baldessarini RJ. Suicide attempts in bipolar disorders:
comprehensive review of 101 reports. Acta Psychiatr Scand . 2016;133:174-186.
40. Young AH. Review: lithium reduces the risk of suicide compared with placebo in people with
depression and bipolar disorder. Evid Based Ment Health . 2013;16:112.
41. Tondo L, Hennen J, Baldessarini RJ. Lower suicide risk with long-term lithium treatment in
major affective illness: a meta-analysis. Acta Psychiatr Scand . 2001;104:163-172.
42. Bearden CE, Thompson PM, Dalwani M, et al. Greater cortical gray matter density in lithium-
treated patients with bipolar disorder. Biol Psychiatry . 2007;62:7-16.
43. Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer’s disease in elderly
patients with bipolar disorder. Br J Psychiatry . 2007;190:359-360.
44. Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral
sclerosis. Proc Natl Acad Sci USA . 2008;105:2052-2057.
45. Giakoumatos CI, Nanda P, Mathew IT, et al. Effects of lithium on cortical thickness and
hippocampal subfield volumes in psychotic bipolar disorder. J Psychiatr Res . 2015;61:180-
187.
47. Gildengers AG, Butters MA, Aizenstein HJ, et al. Longer lithium exposure is associated with
better white matter integrity in older adults with bipolar disorder. Bipolar Disord .
2015;17(3):248–256.
48. Moore GJ, Cortese BM, Glitz DA, et al. A longitudinal study of the effects of lithium
treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive
bipolar disorder patients. J Clin Psychiatry . 2009;70:699-705.
49. Lyoo IK, Dager SR, Kim JE, et al. Lithium-induced gray matter volume increase as a neural
correlate of treatment response in bipolar disorder: a longitudinal brain imaging study.
Neuropsychopharmacology . 2010;35:1743-1750.
50. Forlenza OV, De-Paula VJ, Diniz BS. Neuroprotective effects of lithium: implications for the
treatment of Alzheimer’s disease and related neurodegenerative disorders. ACS Chem Neurosci
. 2014;5:443-450.
51. Lan C-C, Liu C-C, Lin C-H, et al. A reduced risk of stroke with lithium exposure in bipolar
disorder: a population-based retrospective cohort study. Bipolar Disord . 2015;17:705-714 .
52. Lepkifker E, Iancu I, Horesh N, Strous RD, Kotler M. Lithium therapy for unipolar and bipolar
depression among the middle-aged and older adult patient subpopulation. Depress Anxiety .
2007;24(8):571-576.
53. Patel NC, Delbello MP, Bryan HS, et al. Open-label lithium for the treatment of adolescents
with bipolar depression. J Am Acad Child Adolesc Psychiatry . 2006;45:289-297.
54. Severus E, Taylor MJ, Sauer C, et al. Lithium for prevention of mood episodes in bipolar
disorders: systematic review and meta- analysis. Int J Bipolar Disord . 2014;2:15.
55. Baldessarini RJ, Leahy L, Arcona S, Gause D, Zhang W, Hennen J. Patterns of psychotropic
drug prescription for U.S. patients with diagnoses of bipolar disorders. Psychiatr Serv .
2007;58:85-91.
56. Kessing LV, Hellmund G, Geddes JR, Goodwin GM, Andersen PK. Valproate v. lithium in the
treatment of bipolar disorder in clinical practice: observational nationwide register-based
cohort study. Br J Psychiatry . 2011;199:57-63.
57. Hayes JF, Marston L, Walters K, Geddes JR, King M, Osborn DP. Lithium vs. valproate vs.
olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder: a population-
based UK cohort study using electronic health records. World Psychiatry . 2016;15:53-58.
58. Berk M, Daglas R, Dandash O, et al. Quetiapine v. lithium in the maintenance phase following
a first episode of mania: randomised controlled trial. Br J Psychiatry . 2017;210:413-421.
59. Lähteenvuo M, Tanskanen A, Taipale H, et al. Real-world effectiveness of pharmacologic
treatments for the prevention of rehospitalization in a finnish nationwide cohort of patients
with bipolar disorder. JAMA Psychiatry . 2018;75:347-355.
60. Kessing LV, Vradi E, Andersen PK. Starting lithium prophylaxis early v. late in bipolar
disorder. Br J Psychiatry . 2014;205:214-220.
61. Kemp DE, Gao K, Fein EB, et al. Lamotrigine as add-on treatment to lithium and divalproex:
lessons learned from a double-blind, placebo-controlled trial in rapid-cycling bipolar disorder.
Bipolar Disord . 2012;14:780-789.
63. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic
drugs in acute mania: a multiple-treatments meta-analysis. Lancet . 2011;378:1306-1315.
64. Jefferson JW, Greist AH, Ackerman DL. Lithium encyclopaedia for clinical Practice.
Washington, DC: APA Press;1987.
65. Goldberg JF, Ernst CL. Managing the side effects of psychotropic medications (2nd edn)
Washington, DC: American Psychiatric Publishing; 2019.
66. Hayes JF, Marston L, Walters K, Geddes JR, King M, Osborn DP. Adverse renal, endocrine,
hepatic, and metabolic events during maintenance mood stabilizer treatment for bipolar
disorder: a population-based cohort study. PLoS Medicine . 2016;13:e1002058.
67. Cavanagh J, Smyth R, Goodwin GM. Relapse into mania or depression following lithium
discontinuation: a 7-year follow-up. Acta Psychiatr Scand . 2004;109:91-95.
68. Suppes T, Baldessarini RJ, Faedda GL, Tondo L, Tohen M. Discontinuation of maintenance
treatment in bipolar disorder: risks and implications. Harv Rev Psychiatry .1993;1:131-144.
69. Goodwin GM. Recurrence of mania after lithium withdrawal. Implications for the use of
lithium in the treatment of bipolar affective disorder. Br J Psychiatry . 1994;164:149-152.
70. Aiff H, Attman P-O, Aurell M, et al. Effects of 10 to 30 years of lithium treatment on kidney
function. J Psychopharmacol . 2015;29(5):608-614.
71. Kessing LV, Gerds TA, Feldt-Rasmussen B, Andersen PK, Licht RW. Use of lithium and
anticonvulsants and the rate of chronic kidney disease: a nationwide population-based study.
JAMA Psychiatry . 2015;72:1182-1191.
72. Tondo L, Abramowicz M, Alda M, et al. Long-term lithium treatment in bipolar disorder:
effects on glomerular filtration rate and other metabolic parameters. Int J Bipolar Disord .
2017;5:27 .
73. Aiff H, Attman PO, Aurell M, Bendz H, Schon S, Svedlund J. End-stage renal disease
associated with prophylactic lithium treatment. Eur Neuropsychopharmacol . 2014;24:540-
544.
74. Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med . 1995;333:1688-1694.
75. Kupka RW, Luckenbaugh DA, Post RM, Leverich GS, Nolen WA. Rapid and non-rapid
cycling bipolar disorder: a meta-analysis of clinical studies. J Clin Psychiatry . 2003;64:1483-
1494.
76. Calabrese JR, Keck PE, Macfadden W, et al. A randomized, double-blind, placebo-controlled
trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry .
2005;162:1351-1360.
77. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I
and II depression: a double-blind, placebo- controlled study (the BOLDER II study). J Clin
Psychopharmacol . 2006;26:600-609.
78. Endicott J, Rajagopalan K, Minkwitz M, Macfadden W. A randomized, double-blind, placebo-
controlled study of quetiapine in the treatment of bipolar I and II depression: improvements in
quality of life. Int Clin Psychopharmacol . 2007;22:29-37.
79. Hirschfeld RM, Weisler RH, Raines SR, Macfadden W. Quetiapine in the treatment of anxiety
in patients with bipolar I or II depression: a secondary analysis from a randomized, double-
blind, placebo-controlled study. J Clin Psychiatry . 2006;67:355-362.
80. McElroy SL, Weisler RH, Chang W, et al. A double-blind, placebo- controlled study of
quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II).
J Clin Psychiatry . 2010;71:163-174.
81. Vedantam S. A silenced drug study creates an uproar. Washington Post. 2009.
82. Wilson D. Drug maker’s email released in Seroquel lawsuit. NY Times. 2009.
83. Ngai YF, Sabatini P, Nguyen D, et al. Quetiapine treatment in youth is associated with
decreased insulin secretion. J Clin Psychopharmacol . 2014;34:359-364.
84. Weisler RH, Nolen WA, Neijber A, Hellqvist A, Paulsson B. Continuation of quetiapine
versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial
144: a randomized controlled study). J Clin Psychiatry . 2011;72:1452-1464.
85. Goodwin FK, Whitham EA, Ghaemi SN. Maintenance treatment study designs in bipolar
disorder: do they demonstrate that atypical neuroleptics (antipsychotics) are mood stabilizers?
CNS Drugs . 2011;25:819-827.
86. Bowden CL, Calabrese JR, Ketter TA, Sachs GS, White RL, Thompson TR. Impact of
lamotrigine and lithium on weight in obese and nonobese patients with bipolar I disorder. Am J
Psychiatry . 2006;163:1199-1201.
87. Gualtieri CT, Johnson LG. Comparative neurocognitive effects of 5 psychotropic
anticonvulsants and lithium. MedGenMed. 2006;8:46.
88. Calabrese JR, Sullivan JR, Bowden CL, et al. Rash in multicenter trials of lamotrigine in mood
disorders: clinical relevance and management. J Clin Psychiatry . 2002;63:1012-1019.
89. Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J. Risk of Stevens-Johnson
syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology .
2005;64:1134-1138.
90. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind
placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I
depression.Lamictal 602 Study Group. J Clin Psychiatry . 1999;60:79-88.
91. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and
92. Kusumakar V, Yatham LN. An open study of lamotrigine in refractory bipolar depression.
Psychiatry Res . 1997;72:145-148.
93. Calabrese JR, Bowden CL, McElroy SL, et al. Spectrum of activity of lamotrigine in
treatment-refractory bipolar disorder. Am J Psychiatry . 1999;156:1019-1023.
94. Robillard M, Conn DK. Lamotrigine use in geriatric patients with bipolar depression. Can J
Psychiatry . 2002;47:767-770.
95. Chang K, Saxena K, Howe M. An open-label study of lamotrigine adjunct or monotherapy for
the treatment of adolescents with bipolar depression. J Am Acad Child Adolesc Psychiatry .
2006;45:298-304 .
96. Savas HA, Selek S, Bulbul F, Kaya MC, Savas E. Successful treatment with lamotrigine in
bipolar depression: a study from Turkey. Aust N Z J Psychiatry . 2006;40:498-500.
97. Calabrese JR, Huffman RF, White RL, et al. Lamotrigine in the acute treatment of bipolar
depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord .
2008;10:323-333.
98. Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM. Long- term lithium therapy for
bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J
Psychiatry . 2004;161:217-222.
99. Kesebir S, Akdeniz F, Demir A, Bilici M. A comparison before and after lamotrigine use in
long term continuation treatment: effect of blood level. Journal of Mood Disorders .
2013;3:47-51.
100. Bowden CL, Calabrese JR, Sachs G, et al. A placebo-controlled 18- month trial of
lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with
bipolar I disorder. Arch Gen Psychiatry . 2003;60:392-400.
101. Calabrese JR, Bowden CL, Sachs G, et al. A placebo-controlled 18-month trial of
lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I
disorder. J Clin Psychiatry . 2003;64:1013-1024.
102. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I
depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry .
2014;171:160-168.
103. Belmaker RH. Lurasidone and bipolar disorder. Am J Psychiatry . 2014;171:131-133.
104. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15
antipsychotic drugs in schizophrenia: a multiple- treatments meta-analysis. Lancet .
2013;382:951-962.
105. Ketter TA, Miller S, Dell’Osso B, Calabrese JR, Frye MA, Citrome L. Balancing benefits
and harms of treatments for acute bipolar depression. J Affect Disord . 2014;169(Suppl
1):S24-S33.
106. De Fruyt J, Deschepper E, Audenaert K, et al. Second generation antipsychotics in the
treatment of bipolar depression: a systematic review and meta-analysis. J Psychopharmacol
.2012;26:603-617.
107. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or
valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-
controlled study. Am J Psychiatry . 2014;171:169-177.
108. Sachs GS. Use of quality metrics as eligibility criteria to improve signal detection. Biol
Psychiatry . 2014;75(9S):S31.
109. McIntyre RS, Cucchiaro J, Pikalov A, Kroger H, Loebel A. Lurasidone in the treatment of
bipolar depression with mixed (sub-syndromal hypomanic) features: post hoc analysis of a
randomized placebo-controlled trial. J Clin Psychiatry . 2015;76(04):398–405.
110. Doan LA, Williams SR, Takayesu A, Lu B. Case series reports on lurasidone-associated
mania. J Clin Psychopharmacol . 2017;37:264-266.
111. Calabrese JR, Keck, Jr PE, Starace A, et al. Efficacy and safety of low- and high-dose
cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind,
placebo-controlled study. J Clin Psychiatry . 2015;76:284-292.
112. Sachs GS, Greenberg WM, Starace A, et al. Cariprazine in the treatment of acute mania in
bipolar I disorder: a double-blind, placebo-controlled, phase III trial. J Affect Disord
.2015;174:296-302.
113. Durgam S, Starace A, Li D, et al. The efficacy and tolerability of cariprazine in acute mania
associated with bipolar I disorder: a phase II trial. Bipolar Disord .2015;17:63-75.
114. Citrome L. Cariprazine for bipolar depression: What is the number needed to treat, number
needed to harm and likelihood to be helped or harmed? Int J Clin Pract . 2019;73:e13397.
115. Earley W, Burgess MV, Rekeda L, et al. Cariprazine treatment of bipolar depression: a
randomized double-blind placebo-controlled phase 3 study. Am J Psychiatry . 2019;176:439-
448.
116. Sachs GS, Ice KS, Chappell PB, et al. Efficacy and safety of adjunctive oral ziprasidone for
acute treatment of depression in patients with bipolar I disorder: a randomized, double-blind,
placebo-controlled trial. J Clin Psychiatry . 2011;72:1413-1422.
117. Thase ME, Jonas A, Khan A, et al. Aripiprazole monotherapy in nonpsychotic bipolar I
depression: results of 2 randomized, placebo-controlled studies. J Clin Psychopharmacol .
2008;28:13-20 .
118. Keck PE, Calabrese JR, McQuade RD, et al. A randomized, double-blind, placebo-controlled
26-week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin
Psychiatry . 2006;67:626-637.
119. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine
combination in the treatment of bipolar I depression. Arch Gen Psychiatry . 2003;60:1079-
1088.
120. Brown EB, McElroy SL, Keck PE, et al. A 7-week, randomized, double-blind trial of
olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I
depression. J Clin Psychiatry . 2006;67:1025-1033.
121. Tohen M, McDonnell DP, Case M, et al. Randomised, double-blind, placebo-controlled
study of olanzapine in patients with bipolar I depression. Br J Psychiatry . 2012;201:376-
382.
122. Katagiri H, Tohen M, McDonnell DP, et al. Safety and efficacy of olanzapine in the long-
term treatment of Japanese patients with bipolar I disorder, depression: an integrated
analysis. Psychiatry Clin Neurosci . 2014;68:498-505.
123. Wang M, Tong JH, Huang DS, Zhu G, Liang GM, Du H. Efficacy of olanzapine
monotherapy for treatment of bipolar I depression: a randomized, double-blind, placebo
controlled study. Psychopharmacology . 2014;231:2811-2818.
124. Ostacher MJ, Tandon R, Suppes T. Florida best practice psycho-therapeutic medication
guidelines for adults with bipolar disorder: a novel, practical, patient-centered guide for
clinicians. J Clin Psychiatry . 2016;77:920-926.
125. Hahn MK, Wolever TMS, Arenovich T, et al. Acute effects of single-dose olanzapine on
metabolic, endocrine, and inflammatory markers in healthy controls. J Clin
Psychopharmacol . 2013;33:740-746.
126. McGirr A, Vohringer PA, Ghaemi SN, Lam RW, Yatham LN. Safety and efficacy of
adjunctive second-generation antidepressant therapy with a mood stabiliser or an atypical
antipsychotic in acute bipolar depression: a systematic review and meta-analysis of
randomised placebo-controlled trials. Lancet Psychiatry . 2016;3:1138-1146.
127. Bond DJ, Lam RW, Yatham LN. Divalproex sodium versus placebo in the treatment of acute
bipolar depression: a systematic review and meta-analysis. J Affect Disord .2010;124:228-
234.
128. Wang PW, Nowakowska C, Chandler RA, et al. Divalproex extended-release in acute
bipolar II depression. J Affect Disord . 2010;124:170-173.
129. Miura T, Noma H, Furukawa TA, et al. Comparative efficacy and tolerability of
pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic
review and network meta-analysis. Lancet Psychiatry . 2014;1:351-359.
130. Geddes JR, Goodwin GM, Rendell J, et al. Lithium plus valproate combination therapy
versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised
open-label trial. Lancet . 2010;375:385-395.
131. Ghaemi SN, Goodwin FK. Divalproex vs. lithium in the treatment of bipolar disorder: a
naturalistic 1.7-year comparison. J Affect Disord . 2001;65:281-287.
132. Gyulai L, Bowden CL, McElroy SL, et al. Maintenance efficacy of divalproex in the
prevention of bipolar depression. Neuropsychopharmacology . 2003;28:1374-1382.
133. Patel N, Viguera AC, Baldessarini RJ. Mood-stabilizing anticonvulsants, spina bifida, and
folate supplementation: commentary. J Clin Psychopharmacol . 2018;38:7-10.
134. Reinares M, Rosa AR, Franco C, et al. A systematic review on the role of anticonvulsants in
the treatment of acute bipolar depression. Int J Neuropsychopharmacol . 2013;16:485-496.
135. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety
Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD)
collaborative update of CANMAT guidelines for the management of patients with bipolar
disorder: update 2013. Bipolar Disord . 2013;15:1-44.
136. El-Mallakh RS, Vöhringer PA, Ostacher MM, et al. Antidepressants worsen rapid-cycling
course in bipolar depression: A STEP-BD randomized clinical trial. J Affect Disord .
2015;184:318-321 .
138. Amsterdam JD, Brunswick DJ. Antidepressant monotherapy for bipolar type II major
depression. Bipolar Disord . 2003;5:388-395.
139. Kupfer DJ, Chengappa KNR, Gelenberg AJ, et al. Citalopram as adjunctive therapy in
bipolar depression. J Clin Psychiatry . 2001;62:985-990.
140. Altshuler LL, Sugar CA, McElroy SL, et al. Switch rates during acute treatment for bipolar II
depression with lithium, sertraline, or the two combined: a randomized double-blind
comparison. Am J Psychiatry . 2017;174(3):266-276.
141. Amsterdam JD, Shults J. Efficacy and safety of long-term fluoxetine versus lithium
monotherapy of bipolar II disorder: a randomized, double-blind, placebo-substitution study.
Am J Psychiatry . 2010;167:792-800.
142. Suppes T. Is there a role for antidepressants in the treatment of bipolar II depression? Am J
Psychiatry . 2010;167:738-740.
143. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant
treatment for bipolar depression. N Engl J Med . 2007;356:1711-1722.
144. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th
edn). Washington, DC: American Psychiatric Press; 2013.
145. Suppes T, Vieta E, Gustafsson U, Ekholm B. Maintenance treatment with quetiapine when
combined with either lithium or divalproex in bipolar I disorder: analysis of two large
randomized, placebo-controlled trials. Depress Anxiety . 2013;30:1089-1098.
146. Geddes JR, Gardiner A, Rendell J, et al. Comparative evaluation of quetiapine plus
lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in
bipolar depression (CEQUEL): a 2 x 2 factorial randomised trial. Lancet Psychiatry .
2016;3:31-39.
147. Vieta E, Suppes T, Eggens I, Persson I, Paulsson B, Brecher M. Efficacy and safety of
quetiapine in combination with lithium or divalproex for maintenance of patients with
bipolar I disorder (international trial 126). J Affect Disord . 2008;109:251-263.
148. Suppes T, Vieta E, Liu S, Brecher M, Paulsson B. Maintenance treatment for patients with
bipolar I disorder: results from a north american study of quetiapine in combination with
lithium or divalproex (trial 127). Am J Psychiatry . 2009;166:476-488.
149. van der Loos MLM, Mulder PGH, Hartong EGTM, et al. Efficacy and safety of lamotrigine
as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-
controlled trial. J Clin Psychiatry . 2009;70:223-231.
150. Lorenzo-Luaces L, Amsterdam JD, Soeller I, DeRubeis RJ. Rapid versus non-rapid cycling
bipolar II depression: response to venlafaxine and lithium and hypomanic risk. Acta
Psychiatr Scand . 2016;133:459-469.
151. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or
mania in patients with bipolar depression during acute and continuation trials of venlafaxine,
sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry . 2006;163:232-
239.
152. Hammett S, Youssef NA. Systematic review of recent guidelines for pharmacological
treatments of bipolar disorders in adults. Ann Clin Psychiatry . 2017;29:266-282.
153. Ciapparelli A, Dell’Osso L, Tundo A, et al. Electroconvulsive therapy in medication-
nonresponsive patients with mixed mania and bipolar depression. J Clin Psychiatry .
2001;62:552-555.
154. Grunhaus L, Schreiber S, Dolberg OT, Hirshman S, Dannon PN. Response to ECT in major
depression: are there differences between unipolar and bipolar depression? Bipolar Disord .
2002;4(Suppl 1):91-93.
155. Sampaio-Junior B, Tortella G, Borrione L, et al. Efficacy and safety of transcranial direct
current stimulation as an add-on treatment for bipolar depression: a randomized clinical trial.
JAMA Psychiatry . 2018;75:158-166 .
156. Sit DK, McGowan J, Wiltrout C, et al. Adjunctive bright light therapy for bipolar depression:
a randomized double-blind placebo- controlled trial. Am J Psychiatry . 2018;175:131-139.
157. McElroy SL, Martens BE, Mori N, et al. Adjunctive lisdexamfetamine in bipolar depression:
a preliminary randomized, placebo- controlled trial. Int Clin Psychopharmacol . 2015;30:6-
13.
158. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive
modafinil in the treatment of bipolar depression. Am J Psychiatry . 2007;164:1242-1249.
159. Ketter TA, Wang PW, Miller S. Bipolar therapeutics update 2014: a tale of 3 treatments. J
Clin Psychiatry . 2015;76:69-70.
160. Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-
controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar
depression. Am J Psychiatry . 2004;161:564-566.
161. Zarate CA, Payne JL, Singh J, et al. Pramipexole for bipolar II depression: a placebo-
controlled proof of concept study. Biol Psychiatry . 2004;56:54-60.
162. El-Mallakh RS, Penagaluri P, Kantamneni A, Gao Y, Roberts RJ. Long-term use of
pramipexole in bipolar depression: a naturalistic retrospective chart review. Psychiatr Q
.2010;81:207-213.
163. Dell’Osso B, Ketter TA, Cremaschi L, Spagnolin G, Altamura AC. Assessing the roles of
stimulants/stimulant-like drugs and dopamine-agonists in the treatment of bipolar depression.
Curr Psychiatry Rep . 2013;15:378.
164. Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ. Clinical outcome in a
randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-
resistant illness and a history of mania. Am J Psychiatry . 1999;156:1164-1169.
165. Fehr BS, Ozcan ME, Suppes T. Low doses of clozapine may stabilize treatment-resistant
bipolar patients. Eur Arch Psychiatry Clin Neurosci . 2005;255:10-14.
166. Ciapparelli A, Dell’Osso L, di Poggio AB, et al. Clozapine in treatment-resistant patients
with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder: a naturalistic 48-
month follow-up study. J Clin Psychiatry . 2003;64:451-458.
167. Chang JS, Ha KS, Young Lee K, Sik Kim Y, Min AY. The effects of long-term clozapine
add-on therapy on the rehospitalization rate and the mood polarity patterns in bipolar
disorders. J Clin Psychiatry . 2006;67:461-467.
168. Saunders EF, Ramsden CE, Sherazy MS, Gelenberg AJ, Davis JM, Rapoport SI. Omega-3
and Omega-6 polyunsaturated fatty acids in bipolar disorder: a review of biomarker and
treatment studies. J Clin Psychiatry . 2016;77:e1301-e1308.
169. Frangou S, Lewis M, McCrone P. Efficacy of ethyl-eicosapentaenoic acid in bipolar
depression: randomised double-blind placebo- controlled study. Br J Psychiatry .
2006;188:46-50.
170. Sarris J, Mischoulon D, Schweitzer I. Omega-3 for bipolar disorder: meta-analyses of use in
mania and bipolar depression. J Clin Psychiatry . 2012;73:81-86.
171. Ketter TA, Wang PW, Chandler RA, Culver JL, Alarcon AM. Adjunctive aripiprazole in
treatment-resistant bipolar depression. Ann Clin Psychiatry . 2006;18:169-172.
172. McElroy SL, Suppes T, Frye MA, et al. Open-label aripiprazole in the treatment of acute
bipolar depression: a prospective pilot trial. J Affect Disord . 2007;101:275-281.
173. Kelly T, Lieberman DZ. The utility of low-dose aripiprazole for the treatment of bipolar II
and bipolar NOS depression. J Clin Psychopharmacol . 2017;37:99-101.
174. Dunn RT, Stan VA, Chriki LS, Filkowski MM, Ghaemi SN. A prospective, open-label study
of Aripiprazole mono- and adjunctive treatment in acute bipolar depression. J Affect Disord .
2008;110:70-74.
175. Mazza M, Squillacioti MR, Pecora RD, Janiri L, Bria P. Beneficial acute antidepressant
effects of aripiprazole as an adjunctive treatment or monotherapy in bipolar patients
unresponsive to mood stabilizers: results from a 16-week open-label trial. Expert Opin
Pharmacother . 2008;9:3145-3149.
176. Kemp DE, Dago PL, Straus JL, Fleck J, Karaffa M, Gilmer WS. Aripiprazole augmentation
for treatment-resistant bipolar depression: sustained remission after 36 months. J Clin
Psychopharmacol . 2007;27:304-305 .
177. Sokolski KN. Adjunctive aripiprazole in bipolar I depression. Ann Pharmacother .
2007;41:35-40.
178. Thase ME, Bowden CL, Nashat M, et al. Aripiprazole in bipolar depression: a pooled, post-
hoc analysis by severity of core depressive symptoms. Int J Psychiatry Clin Pract .
2012;16:121-131.
179. Benedetti F, Riccaboni R, Locatelli C, Poletti S, Dallaspezia S, Colombo C. Rapid treatment
response of suicidal symptoms to lithium, sleep deprivation, and light therapy
(chronotherapeutics) in drug-resistant bipolar depression. J Clin Psychiatry . 2014;75:133-
140.
180. Wu JC, Kelsoe JR, Schachat C, et al. Rapid and sustained antidepressant response with sleep
deprivation and chronotherapy in bipolar disorder. Biol Psychiatry . 2009;66:298-301.
181. Kelly T, Lieberman DZ. The use of triiodothyronine as an augmentation agent in treatment-
resistant bipolar II and bipolar disorder NOS. J Affect Disord . 2009;116:222-226.
182. Goodman LA, Salyers MP, Mueser KT, et al. Recent victimization in women and men with
severe mental illness: prevalence and correlates. J Trauma Stress . 2001;14:615-632.
183. Quarantini LC, Miranda-Scippa Â, Nery-Fernandes F, et al. The impact of comorbid
posttraumatic stress disorder on bipolar disorder patients. J Affect Disord . 2010;123:71-76.
184. Wallace J. Treatment of trauma with lithium to forestall the development of posttraumatic
stress disorder by pharmacological induction of a mild transient amnesia. Med Hypotheses .
2013;80:711-715.
185. Bajor LA, Ticlea AN, Osser DN. The psychopharmacology algorithm project at the Harvard
South Shore Program: an update on post- traumatic stress disorder. Harv Rev Psychiatry .
2011;19:240-258.
186. Hertzberg MA, Butterfield MI, Feldman ME, et al. A preliminary study of lamotrigine for
the treatment of posttraumatic stress disorder. Biol Psychiatry . 1999;45:1226-1229.
187. Viktorin A, Rydén E, Thase ME, et al. The risk of treatmentemergent mania with
methylphenidate in bipolar disorder. Am J Psychiatry . 2017;174:341-348.
188. Peruzzolo TL, Tramontina S, Rohde LA, Zeni CP. Pharmacotherapy of bipolar disorder in
children and adolescents: an update. Rev Bras Psiquiatr . 2013;35:393-405.
189. Niemegeers P, Maudens KE, Morrens M, et al. Pharmacokinetic evaluation of armodafinil
for the treatment of bipolar depression. Expert Opin Drug Metab Toxicol . 2012;8:1189-
1197.
190. Gao K, Wu R, Kemp DE, et al. Efficacy and safety of quetiapine-XR as monotherapy or
adjunctive therapy to a mood stabilizer in acute bipolar depression with generalized anxiety
disorder and other comorbidities: a randomized, placebo-controlled trial. J Clin Psychiatry .
2014;75:1062-1068.
191. Jentink J, Loane MA, Dolk H, et al. Valproic acid monotherapy in pregnancy and major
congenital malformations. N Engl J Med . 2010;362:2185-2193.
192. Cummings C, Stewart M, Stevenson M, Morrow J, Nelson J. Neurodevelopment of children
exposed in utero to lamotrigine, sodium valproate and carbamazepine. Arch Dis Child .
2011;96:643-647.
193. Cunnington M, Tennis P. International lamotrigine pregnancy registry scientific advisory C.
Lamotrigine and the risk of malformations in pregnancy. Neurology . 2005;64:955-960.
194. Berwaerts K, Sienaert P, De Fruyt J. Teratogenic effects of lamotrigine in women with
bipolar disorder. Tijdschr Psychiatr . 2009;51:741-750.
195. Clark CT, Klein AM, Perel JM, Helsel J, Wisner KL. Lamotrigine dosing for pregnant
patients with bipolar disorder. Am J Psychiatry . 2013;170:1240-1247.
196. Dolk H, Wang H, Loane M, et al. Lamotrigine use in pregnancy and risk of orofacial cleft
and other congenital anomalies. Neurology . 2016;86:1716-1725.
197. Vajda FJ, Dodd S, Horgan D. Lamotrigine in epilepsy, pregnancy and psychiatry–a drug for
all seasons? J Clin Neurosci .2013;20:13-16.
198. Patorno E, Huybrechts KF, Bateman BT, et al. Lithium use in pregnancy and the risk of
cardiac malformations. N Engl J Med . 2017;376:2245-2254.
199. Leiknes KA, Cooke MJ, Jarosch-von Schweder L, Harboe I, Hoie B. Electroconvulsive
therapy during pregnancy: a systematic review of case studies. Arch Womens Ment Health .
2015;18(1):1-39.
200. McCauley-Elsom K, Gurvich C, Elsom SJ, Kulkarni J. Antipsychotics in pregnancy. J
Psychiatr Ment Health Nurs . 2010;17:97-104 .
201. Taylor DPC, Kapur S. South London and Maudsley NHS Trust. The Maudsley prescribing
guidelines in psychiatry (11th edn). Chichester, West Sussex: John Wiley & Sons; 2012.
202. Maina G, Rosso G, Aguglia A, Bogetto F. Recurrence rates of bipolar disorder during the
postpartum period: a study on 276 medication-free Italian women. Arch Womens Ment
Health . 2014;17(5):367–372.
203. Bergink V, Kushner SA. Lithium during pregnancy. Am J Psychiatry . 2014;171:712-715.
204. Trixler M, Gati A, Fekete S,Tenyi T. Use of antipsychotics in the management of
schizophrenia during pregnancy. Drugs . 2005;65:1193-1206.
205. Salloum IM, Cornelius JR, Daley DC, Kirisci L, Himmelhoch JM, Thase ME. Efficacy of
valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind
placebo-controlled study. Arch Gen Psychiatry . 2005;62:37-45.
206. Brown ES, Gorman AR, Hynan LS. A randomized, placebo-controlled trial of citicoline add-
on therapy in outpatients with bipolar disorder and cocaine dependence. J Clin
Psychopharmacol . 2007;27:498-502.
207. Tolliver BK, Desantis SM, Brown DG, Prisciandaro JJ, Brady KT. A randomized, double-
blind, placebo-controlled clinical trial of acamprosate in alcohol-dependent individuals with
bipolar disorder: a preliminary report. Bipolar Disord . 2012;14:54-63.
208. Brown ES, Carmody TJ, Schmitz JM, et al. A randomized, double- blind, placebo-controlled
pilot study of naltrexone in outpatients with bipolar disorder and alcohol dependence.
Alcohol Clin Exp Res . 2009;33:1863-1869.
209. Chung AK, Chua SE. Effects on prolongation of Bazett’s corrected QT interval of seven
second-generation antipsychotics in the treatment of schizophrenia: a meta-analysis. J
Psychopharmacol . 2011;25:646-666.
210. NICE, National Institute for Health and Care Excellence: Clinical Guideline No. 38. Bipolar
disorders: the management of bipolar disorder in adults, children and adolescents, in primary
and secondary care. In: British Psychological Society. ISBN: 978-1-4731-0721-2; 2014.
https://www.nice.org.uk/
211. Malhi GS, Bassett D, Boyce P, et al. Royal Australian and New Zealand college of
psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry .
2015;49:1087-1206.
212. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar
disorder: revised third edition recommendations from the British Association for
Psychopharmacology. J Psychopharmacol . 2016;30(6):495–553.
213. Fountoulakis KN, Yatham L, Grunze H, et al. The International College of Neuro-
Psychopharmacology (CINP) treatment guidelines for Bipolar disorder in adults (CINP-BD-
2017), part 2: Review, grading of the evidence and a precise algorithm. Int J
Neuropsychopharmacol . 2017;20:121-179.
How to cite this article: Wang D, Osser DN. The
Psychopharmacology Algorithm Project at the Harvard South Shore
Program: An update on bipolar depression. Bipolar Disord .
2019;00:1–18. https://doi.org/10.1111/bdi.12860
1 Rivia Medical PLLC, New York, NY, USA
2 Department of Psychiatry, Harvard Medical School, VA Boston Healthcare System,
Brockton Division, Brockton, MA, USA
Correspondence: David Osser, 150 Winding River Road,
https://www.nice.org.uk/
https://doi.org/10.1111/bdi.12860
Needham, MA 02492.
Email: davidosser0846@gmail.com
DOI: 10.1111/bdi.12860
mailto:davidosser0846@gmail.com
I
UPDATE
BIPOLAR DEPRESSION ALGORITHM
n the several months since the publication of the last version of this
algorithm, the recommendations and flowchart remain the same. There
have been no new studies that seem to change the overall sequences of
the nodes. However, there are some additional and new studies deserving
mention.
Node 2: The Patient with Bipolar Depression Is Not Currently
on a Mood Stabilizer
In this long section of the algorithm paper, we discuss the merits of the
various options for treatment of an acute bipolar depression if the patient is
currently not on a mood stabilizer. One of the options is lamotrigine. It is
noted that it may be helpful to obtain a plasma level of lamotrigine to
optimize the oral dose, based on a small observational study suggesting that
the best results were at about 4 mcg/mL. However, we found another small
retrospective study that found that lamotrigine may have a therapeutic
window of 5–11 mcg/mL. 1 Given the two studies, we are now suggesting
that clinicians try to dose lamotrigine so the level will be between 4 and 11
mcg/mL.
Table 1 : Options to Consider for Treatment-Resistant
Bipolar Depression
There is misleading information in the brief discussion of the pramipexole
studies – the 4th item in the table. It is stated that pramipexole “was poorly
tolerated” in these two small studies. In the first study, done primarily in
bipolar I depressed patients, 58% reported nausea vs 20% on placebo.
However, this did not affect dropout rates in this 6 week study. In the
second study which was exclusively in bipolar II patients, 60% of the
pramipexole patients reported nausea vs 64% on placebo. Again, it didn’t
affect dropout rate: 90% of both groups completed the 6 week study. One
patient on pramipexole developed a psychotic mania in the first study vs
none on placebo, and in the bipolar IIs, one became hypomanic on active
medication and two on placebo. The authors noted that studies are needed
with longer-term treatment with pramipexole to see if there is more
switching over time including switching to psychosis in vulnerable people.
The last item presented in this table is “Add triiodothyronine (T3).” A
retrospective chart-review study from Canada presented positive data. Since
that publication, a review of the literature on T3 augmentation in bipolar
depression located several more studies including three open-label
prospective investigations. 2 The percentages of patients improved were
56%, 75%, and 79%. The studies were all considered “flawed but
promising” and there were suggestions that rapid cycling patients could
benefit. Finally, there was a small double-blind comparison of adjunctive
T3 compared with levothyroxine (T4) or placebo. 3 Thirty-two rapid-
cycling treatment-resistant patients who had failed a trial of lithium were
randomized to have one of these three treatments added to the lithium. They
were followed for at least four months. The study was powered for 60
patients but given the difficulty of recruiting these refractory patients they
were only able to study 32 and hence the statistical analyses had to be
limited. The findings were that the T4 group fared better than the T3 group
and the placebo. There was only a trend-level improvement for the T3
group versus the placebo, but it could have become significant if the N had
been larger. T4 patients had a 33% increase in the time in euthymia
compared to pretreatment, whereas the placebo group’s time in euthymia
declined by 6.5% (p = 0.033).
In conclusion, the evidence base for trying T3 instead of T4 is arguably
more persuasive, but more research is needed before thyroid augmentation
with either T3 or T4 should be located earlier in the algorithm for bipolar
depression.
Table 2 : Comorbidity and Other Features in Bipolar
Depression: How They Affect the Algorithm
In this table, there is a discussion of considerations for women of
childbearing potential. There is mention of a recent large National Institute
of Mental Health-sponsored study of the risk of cardiac malformations
including Ebstein’s abnormality. Data has emerged that provided a more
precise measure of what can be expected. The researchers found that the
adjusted risk ratio for any cardiac abnormality was 1.65 compared to
unexposed babies. 4 For Ebstein’s, the risk ratio was 2.66, and in absolute
numbers it was 0.6% for lithium-exposed infants versus 0.18% for those not
exposed. The impact was dose-related, with higher ratios if the dose was
over 900 mg daily. These results were included in a new meta-analysis of
13 high-quality studies published in January 2020. 5 This analysis found the
odds ratio for any cardiac abnormality to be slightly higher—1.86. The risk
was limited to fetuses exposed in the first trimester. The absolute risk was
1.2% for any cardiac abnormality. Note that these are comparisons between
women with bipolar disorder who did or did not receive lithium, not
between bipolar women on lithium and the general population of pregnant
women. The fetuses of nonbipolar women have fewer cardiac
abnormalities. The studies were generally unclear about whether they
excluded women who were on other teratogenic medications or were
misusing any substances like alcohol. The authors concluded that the risks
of lithium exposure during pregnancy are low, though they are higher in the
first trimester and doses should be kept in the lowest part of the therapeutic
range, especially during that time. The risks and harms associated with
mood episode relapse from stopping lithium or lowering the level below the
therapeutic range appear, for most women, to exceed the harms of fetal
abnormalities or other pregnancy complications associated with continuing
lithium.
There is also a brief discussion of substance use disorders as a
comorbidity in bipolar depression, and the recommendation is that
remission from those use disorders should be a high treatment priority. We
did not mention cannabis as one of the substances that could be a concern.
The evidence available points clearly to an association between usage and
worsening course of bipolar disorder over time. In a study of 4,915
subjects, there was (after control for many possible covariates) a strong
increased risk of manic symptoms associated with the use of cannabis over
a three-year follow-up period. 6 There was also an earlier age of onset of
bipolar disorder, greater overall illness severity, more rapid cycling, poorer
life functioning, and poorer adherence with prescribed treatments. In
another study, the course of bipolar patients who stopped cannabis use after
an illness episode was compared with a group who never had used cannabis
and a group that continued to use. 7 The total sample was 1,922 patients. In
a two-year period, the continued users had significantly lower rates of
recovery, greater work impairment, and lower rates of living with a partner.
The data were based on patient reports, so given likely underreporting,
there was probably an underestimate of the strength of the association
between cannabis use and lives worsened. A systematic review of the
effects of cannabis on mood and anxiety disorders confirmed a negative
association between cannabis use and long-term outcomes. 8 Thus, it seems
that bipolar patients should stay away from cannabis in all its forms.
Quitting cannabis should be on the short list of interventions to pursue if
patients are not doing well. This is a tough sell in today’s political
environment regarding cannabis legalization. Many newspaper editorials
and politicians are pushing it. Clinicians should not back off and accept
patients’ insistence on using this product but rather should continue efforts
to educate and to consider the problem to be a serious one that potentially
interferes with otherwise appropriate and effective bipolar treatments that
may be offered.
REFERENCES
1. Katayama Y, Terao T, Kamei K, et al. Therapeutic window of lamotrigine for mood disorders: a
2. Parmentier T, Sienaert P. The use of triiodothyronine (T3) in the treatment of bipolar depression:
a review of the literature. J Affect Disord 2018;229:410–4.
3. Walshaw PD, Gyulai L, Bauer M, et al. Adjunctive thyroid hormone treatment in rapid cycling
bipolar disorder: a double-blind placebo-controlled trial of levothyroxine (L-T4) and
triiodothyronine (T3). Bipolar Disord 2018;20:594–603.
4. Patorno E, Huybrechts KF, Bateman BT, et al. Lithium use in pregnancy and the risk of cardiac
malformations. N Engl J Med 2017;376:2245–54.
5. Fornaro M, Maritan E, Ferranti R, et al. Lithium exposure during pregnancy and the postpartum
period: a systematic review and meta-analysis of safety and efficacy outcomes. Am J Psychiatry
2020;177:76–92.
6. Henquet C, Krabbendam L, de Graaf R, ten Have M, van Os J. Cannabis use and expression of
mania in the general population. J Affect Disord 2006;95:103–10.
7. Zorrilla I, Aguado J, Haro JM, et al. Cannabis and bipolar disorder: does quitting cannabis use
during manic/mixed episode improve clinical/functional outcomes? Acta Psychiatr Scand
2015;131:100–10.
8. Mammen G, Rueda S, Roerecke M, Bonato S, Lev-Ran S, Rehm J. Association of cannabis with
long-term clinical symptoms in anxiety and mood disorders: a systematic review of prospective
studies. J Clin Psychiatry 2018;79.
The Psychopharmacology Algorithm Project at the
Harvard South Shore Program: An Algorithm for
Acute Mania
Othman Mohammad, MD and David N. Osser, MD
Abstract: This new algorithm for the pharmacotherapy of acute mania was developed by the
Psychopharmacology Algorithm Project at the Harvard South Shore Program. The authors
conducted a literature search in PubMed and reviewed key studies, other algorithms and guidelines,
and their references. Treatments were prioritized considering three main considerations: (1)
effectiveness in treating the current episode, (2) preventing potential relapses to depression, and (3)
minimizing side effects over the short and long term. The algorithm presupposes that clinicians have
made an accurate diagnosis, decided how to manage contributing medical causes (including
substance misuse), discontinued antidepressants, and considered the patient’s childbearing
potential. We propose different algorithms for mixed and nonmixed mania. Patients with mixed
mania may be treated first with a second-generation antipsychotic, of which the first choice is
quetiapine because of its greater efficacy for depressive symptoms and episodes in bipolar disorder.
Valproate and then either lithium or carbamazepine may be added. For nonmixed mania, lithium is
the first-line recommendation. A second-generation antipsychotic can be added. Again, quetiapine is
favored, but if quetiapine is unacceptable, risperidone is the next choice. Olanzapine is not
considered a first-line treatment due to its long-term side effects, but it could be second-line. If the
patient, whether mixed or nonmixed, is still refractory to the above medications, then depending on
what has already been tried, consider carbamazepine, haloperidol, olanzapine, risperidone, and
valproate first tier; aripiprazole, asenapine, and ziprasidone second tier; and clozapine third tier
(because of its weaker evidence base and greater side effects). Electroconvulsive therapy may be
considered at any point in the algorithm if the patient has a history of positive response or is
intolerant of medications.
INTRODUCTION
Bipolar mania is a mood state characterized by distinctively and abnormally
elevated mood or irritability. It has a recurrent course and, if not treated
successfully, can be associated with significant cognitive and functional
impairment, especially if associated with psychosis. 1 The successful treatment
of a bipolar manic episode should include three main goals: (1) treating the
current episode, (2) choosing treatment that can prevent relapses to depression,
and (3) whenever possible, choosing treatments that minimize side effects
associated with psychopharmacology. Achieving these goals poses a significant
challenge for the clinician because of the sometimes contradictory evidence
about the efficacy of the different treatment options for bipolar disorder, coupled
with a shifting understanding of the safety risks involved with different options.
Also, in some treatment settings (e.g., inpatient in the managed care
environment), the priority in selecting psychopharmacology may be to achieve
effectiveness, or at least the appearance thereof, as quickly as possible, thereby
facilitating the earliest possible discharge. For that purpose, two or three
medications might be administered nearly at once, and without establishing the
necessity or desirability of each for the long or even intermediate term. Decision
making is also affected by clinical experience, which may be all that the
clinician can rely on with very complex patients or in situations where evidence
is lacking. But clinical experience can be overvalued, and it obviously needs to
be reconsidered when evidence points in a different direction. In this article we
present an evidence-based approach to the pharmacotherapy of acute mania—
specifically in relation to the three goals stated above. This algorithm is part of
the Psychopharmacology Algorithm Project at the Harvard South Shore Program
(PAPHSS) and is meant to be considered in conjunction with this group’s
already published algorithm for the treatment of bipolar depression. 2
METHODS
The current methods used in developing new and revised PAPHSS algorithms
have been described previously.2 – 6 In brief, the authors reviewed other
algorithms and guidelines on bipolar mania and conducted literature searches
using PubMed with keywords such as mania, algorithm, management, and
psychopharmacology, focusing on new randomized, controlled trials (RCTs) not
considered in previous reviews, in an attempt to survey the entire body of
evidence. In constructing the decision tree, the authors gave preference in the
early nodes to treatments that are effective for the current mania episode but that
also may prevent subsequent depressive episodes. For the first episode, small
advantages in efficacy for the acute mania were considered outweighed if a
medication with slightly lesser efficacy had significant advantages in efficacy in
bipolar depression. The second major consideration was medication safety.
Since bipolar disorder is a recurrent and often chronic illness, early treatment
with medications with relatively fewer long-term side effects was preferred.
Applying these two preferences narrowed the number of choices in the early
nodes of the algorithm and encouraged the use of monotherapy if possible. It
also offered the potential to minimize the need for later medication switches
(e.g., because of metabolic side effects) that can have a destabilizing effect. In
later nodes, if the patient did not respond well to the earlier treatments, greater
emphasis was placed on antimanic efficacy (while still including a heightened
awareness of these agents’ potential toxicities). This framework for risk-benefit
assessment involves somewhat greater risk that recovery will be delayed or that
a hospital admission may be longer than otherwise during the first or early
episodes of mania, but taking the longer-term perspective seemed to be a
responsible approach that respects the complexity of managing this illness. The
British National Institute for Health and Clinical Excellence guidelines (2006)
recommended maintenance treatment for bipolar disorder after a single severe
manic episode with substantial risk of adverse outcome, or after two acute
episodes with less severe mania. 7 In the case of bipolar II hypomania,
maintenance was recommended in case of significant impairment in function,
frequent episodes, or risk of self-harm.
All hierarchical and other clinical recommendations are the result of
agreement by the two authors. Their conclusions were opinion-based distillations
of a large body of evidence consisting of reviews, meta-analyses, and individual
studies, large and small—which vary in quality and are subject to conflicting
interpretation by experts. Hence, the peer review process that followed
submission of this article is an essential part of the validation of this algorithm
(and other PAPHSS algorithms). If the reasoning, based on the authors’
interpretation of the pertinent evidence, was plausible to reviewers, then it was
retained. When differences of opinion were present on any particular issue,
adjustments were made or the relevant evidence further explored until consensus
was achieved or the authors could present a stronger argument in support of their
initial position.
DIAGNOSIS OF MANIA
This algorithm focuses on the treatment of acute mania in the context of bipolar
disorder. Secondary mania may arise through various processes, including those
related to substance abuse (e.g., the use of cocaine), physiologic conditions (e.g.
hyperthyroidism), or the use of particular medications (e.g.,
adrenocorticosteroids). Hence, patients who present with manic symptoms
should be carefully evaluated for any concomitant medical illness; their
medication lists should be reviewed; and any possible abuse-prone substances or
medications known to cause mania should be discontinued. The presence of
these precipitants, however, does not exclude the possibility of an underlying
predisposition to bipolar disorder that was triggered or kindled by those same
precipitants. 8 If the patient is on an antidepressant, it should be tapered and
discontinued since the antidepressant may be contributing to the maintenance of
the manic state. 9
Psychosis (more commonly delusions than hallucinations) 10 is present in at
least 50% of patients with acute mania, and it contributes significantly to overall
impairment. 11 Mania with psychotic features was considered an indicator of
severity in the fourth edition of the Diagnostic and Statistical Manual of Mental
Disorders [DSM-IV] and is a specifier in DSM-5. It is still one of the criteria for
distinguishing mania and bipolar I disorder from hypomania and bipolar II.
Classic studies of the course of untreated mania have demonstrated that
psychotic features typically make their appearance only as the manic episode
approaches peak severity, 12 although in DSM-5 they can occur at any time in the
episode. However, patients with initial onset of psychosis or persisting psychosis
after resolution of other manic symptoms will usually meet criteria for
schizoaffective disorder or schizophrenia. Diagnostic ambiguity may be
common with a first episode of mania and when the past history is unavailable.
Despite the apparent importance of psychosis in mania, one of the challenges
in producing a psychopharmacology algorithm for bipolar mania is that the
evidence base regarding optimal treatment of the psychosis is remarkably
uninformative. Are antipsychotics more effective than other medications used
for mood stabilization, such as lithium or anticonvulsants? Most empirical
studies of medications for acute mania have either not provided data on
differential outcomes in psychotic versus nonpsychotic mania or found no
differences.10 , 13 If one considers expert opinion, there does not appear to be a
consensus.8 , 14 – 16 In this algorithm, no difference is proposed for the treatment
of psychotic versus nonpsychotic mania. However, if schizophrenia and
schizoaffective disorder are not excluded as diagnostic possibilities, the
prescribing clinician might want to commence treatment in accordance with
evidence-supported practice for those disorders, which will usually mean starting
with an antipsychotic.
FLOWCHART FOR THE ALGORITHM
A summary and overview of the algorithm appears in Figure 1 . Each numbered
“node” represents a decision point delineating patient populations ranging from
unmedicated at the beginning to highly resistant at the bottom. The questions,
evidence analysis, and reasoning that support the recommendations at each node
will be presented below .
Figure 1. Flowchart for the algorithm for pharmacotherapy of acute mania. ECT, electroconvulsive
therapy;
SGA, second-generation antipsychotic.
NODE 1: DOES THE PATIENT MEET DSM-5
CRITERIA FOR MANIA?
First, confirm a diagnosis based on DSM-5 criteria and note any co-occurring
psychiatric or medical features and diagnoses that may be particularly important,
including active substance abuse or dependence, anxiety or anxiety disorders,
women with childbearing potential, and liver disease such as hepatitis C. Table 1
provides a brief summary of how these comorbidities and other considerations
would affect the algorithm. A more thorough description of this important
material is beyond the scope of this review, but the reader is encouraged to
consult the references provided.
Table 1 | Comorbidity and Other Features in Mania and How They Affect
the Algorithm
Comorbid
Conditions
Evidence considerationsa Recommendations
Agitation
requiring rapid
management 17 –
22
IM lorazepam, IM haloperidol, and IM
atypicals are superior to placebo in
controlling agitation
Lorazepam + haloperidol was more
beneficial than either haloperidol or
lorazepam alone
IM SGAs have a significantly lower
risk of acute extrapyramidal symptoms
compared to haloperidol when used
without lorazepam or an antiparkinson
agent; however, this risk difference
becomes insignificant when adding an
anticholinergic agent or lorazepam to
haloperidol
A Cochrane review evaluated
chlorpromazine for psychosis-induced
aggression and agitation. 23 Though the
quantity and quality of evidence were
limited, chlorpromazine was not more
effective than haloperidol; the
In efficacy and safety, IM haloperidol
+ lorazepam is still the treatment of
choice for rapid treatment of severe
agitation (with imminent risk of harm
to self or others)
For less severe agitation, oral as-
needed antipsychotics are often used
but are usually unnecessary;
benzodiazepines could be used instead
Avoid the use of IM chlorpromazine
effective than haloperidol; the
occurrence of serious hypotension
suggested that “it may be best to avoid
use of chlorpromazine” in view of the
better-evaluated options available
Delirious mania
24
Bipolar mania can present as delirium
in absence of evidence of any other
medical condition
Patients are mostly younger females;
incontinence/inappropriate toileting
and denudativeness are distinctive
features of their presentation
These cases are refractory to treatment
with mood stabilizers or antipsychotics
ECT and benzodiazepines are the
mainstays of treatment, rather than any
particular antipsychotic or mood-
stabilizing agent
Anxiety disorders
25
Up to 75% of bipolar patients have at
least one comorbid anxiety disorder at
some point
Comorbid anxiety disorders are
associated with more frequent mood
episodes and poorer treatment outcome
Antidepressants should probably be
avoided
SGAs with antianxiety properties (e.g.,
quetiapine), antianxiety agents (e.g.,
buspirone and benzodiazepines), and
valproate may have a role in treatment
Emphasize nonmedication approaches
Treatment of
women of
childbearing
potential and
women who
become pregnant
during treatment.
26 – 31
Valproate is by far the most teratogenic
medication used in bipolar disorder; 32
high dose folate (4-5 mg daily) has
been recommended 30 but may not
necessarily lower this risk; valproate
(but not lamotrigine) lowers
intelligence scores in young children
exposed to it in utero 33
Carbamazepine is associated with
increased spina bifida and (late in
pregnancy) vitamin K deficiencies
Lithium has fewer malformation risks
than valproate or carbamazepine, but
Ebstein’s abnormality occurs in up to
1 in 1000 pregnancies: a low absolute
risk but up to x20 the base rate 34
Although the safety of antipsychotics
in pregnancy has not been firmly
established (due to many limitations in
the studies), they seem relatively safe
Avoid valproate in any woman with the
potential to become pregnant: should
the patient become pregnant, cessation
of valproate may occur too late to
prevent harm
Avoid carbamazepine
Lithium is preferred over valproate and
carbamazepine
Antipsychotics are first choice26
ECT is a relatively safe and effective
treatment during pregnancy if steps are
taken to decrease potential risks 35 , 36
Prescribe as few drugs as possible—
ideally, just one
When pregnancy occurs during
treatment, it is usually best to continue
the current therapy to avoid exposure
to multiple agents—except for
valproate or carbamazepine, in which
29
The SGAs that cause weight gain
appear to increase risk of gestational
metabolic complications (e.g., diabetes
and babies large for gestational age);
olanzapine may be associated with low
and high birth weight, and a small risk
of malformation (e.g., hip dysplasia,
meningocele, ankyloblepharon, and
neural tube defects)
valproate or carbamazepine, in which
case switching is probably best
Adjust doses as pregnancy progresses
(blood volume expands 30% in third
trimester); plasma-level monitoring is
helpful
Consider the risk of relapse or
withdrawal when switching
medications or changing doses
Anticholinergic drugs should not be
prescribed to pregnant women except
for acute, short-term need
Depot antipsychotics should not be
routinely used in pregnancy (infants
may show extrapyramidal symptoms
for several months)
Active substance
use disorders
Substance use disorders occur in as
many as 65% of bipolar patients 37
Active substance misuse is associated
with poorer outcome with medication
treatments, but data are very limited 38
One prospective
study of patients with
active alcoholism on valproate
maintenance for bipolar disorder found
efficacy for the alcohol use disorder
but not for the mood disorder 39
Citicoline added to standard treatment
for comorbid cocaine dependence in
manic patients led to reduced substance
misuse 40
Abstinence from substance misuse is a
high treatment priority (if possible)
Valproate and citicoline may have
value as add-on treatments for some
patients to help with the substance use
component; however, other options
(e.g., naltrexone or acamprosate for
alcohol use disorders) might be
preferred
Cardiac disease
or presence of
QTc-prolonging
drugs 41
In a meta-analysis of 15 studies
comparing 6 SGAs for their effect on
QTc prolongation, only aripiprazole
had significantly less effect than the
others41
A seventh SGA, quetiapine, had 5
relevant studies, but the manufacturer
refused to provide authors with QTc
data; in 2011, however, the quetiapine
package insert was amended with new
QTc-prolongation warnings and
requirements for monitoring
Consider aripiprazole as the
antipsychotic of choice if the risk of
further QTc prolongation is a
significant concern; haloperidol,
quetiapine, and ziprasidone would be
relatively undesirable in that situation
Review the patient’s medications for
other QTc-prolonging agents, and
monitor for risk factors for Torsade’s
(e.g., bradycardia and electrolyte
abnormalities)
requirements for monitoring
Other medical
comorbidities
Whenever possible, offer bipolar
medications that do not worsen the
patients’ medical problems
Monitor the impact of whatever is
prescribed
In the presence of hepatitis or liver
cirrhosis: avoid when possible agents
that are known to irritate the liver and
to raise liver function tests, including
quetiapine, olanzapine, valproate, and
carbamazepine
In the presence of renal filtration
impairment: avoid lithium
In the presence of obesity,
hyperlipidemia, or metabolic
syndrome: consider aripiprazole,
asenapine, carbamazepine, and
ziprasidone (plus, to manage
depression, lamotrigine)
a The evidence for “agitation requiring rapid management” (first row) is mostly derived from studies on
mixed populations of schizophrenic and manic patients.
Next, the clinician should review past treatments. This may be easier said than
done, as previous records may be unavailable or may not adequately document
what was done or provide the rationale for what was done in a clear manner.
However, if adequate trials of the treatments recommended in the early nodes of
the algorithm have occurred with unsatisfactory results despite reasonable
indication of adherence, or if the previous trials resulted in intolerance that was
likely due to the recommended treatments, then consider selecting an option at
the next node of the algorithm. If the patient is presently on a first-line
recommendation, the response has been unsatisfactory, but the dose or level was
not adequate, consider optimizing the dose and giving that medication more time
before moving to the next option in the algorithm. If the patient is presently on a
medication or medications not recommended at the beginning of the algorithm
but seems to be having a partial benefit, consider adding the recommended
treatment. If the results are favorable, try to discontinue the other medication(s).
NODE 2: DOES THIS MANIC PATIENT HAVE A
MIXED PRESENTATION?
Increasing evidence suggests that the treatment of bipolar mania in a mixed or
“dysphoric” episode has a different psychopharmacological treatment than
“pure” mania. 42 – 44 The evidence is almost entirely derived from post hoc
analyses of trials that included both manic and mixed patients; only two
prospective, randomized trials have focused on the mixed/dysphoric population.
45 , 46 This evidence deficiency is unfortunate because up to 40% of acute bipolar
mania patients are in a mixed episode. 47 Another problem is that the criteria for
mixed mania have varied. In DSM-IV, the criteria required that patients meet
full criteria for mania and for major depression. These criteria did not capture the
complexity and extreme variability of the clinical picture and the rapid mood
shifts that are seen. 48 In DSM-5, the diagnosis has expanded to include patients
who meet full criteria for mania or hypomania and have three or more depressive
symptoms, but even this expansion may still not include the full spectrum of the
disorder. In the treatment analyses, the criteria shortcomings are often addressed
by monitoring clinical change on different rating scales for depression and
mania. The variability in measures used, however, makes it difficult to compare
the study outcomes.48
Despite these limitations with the evidence base and its interpretation, several
recent reviews have reached the conclusion that mixed episodes, though more
difficult to treat, especially with monotherapies, respond best to atypical
antipsychotics and valproate as first-line options.42 – 44 Lithium and
carbamazepine seem less effective but are reasonable second-line agents to be
used in combination with other medications.
Node 2a: Mixed Episodes. First Recommendation: Quetiapine or
Another Second-Generation Antipsychotic
Among the second-generation antipsychotics (SGAs), quetiapine is the preferred
choice in this algorithm. In a meta-analysis by Cipriani and colleagues, 49
quetiapine, when compared to its peers in this class of medications, had average
efficacy in treating acute mania (in six placebo-controlled trials at a usual
effective dose of around 600 mg daily). However, it is unique among SGAs
approved for treating mania in that it is also effective as monotherapy for
treating 50 and preventing 51 future episodes of bipolar depression. Therefore,
given the emphasis we place in this algorithm on choosing treatments that not
only deal with the present symptoms but address future mood changes,
quetiapine is the first-choice SGA. Mixed patients were included in a recent,
large, placebo-controlled RCT with 308 patients at a mean dose of 600 mg daily
employing quetiapine XR. 52 Improvement was significant (p < .001) after three
weeks on the primary outcome measure, the Young Mania Rating Scale
(YMRS), and on all secondary measures. Quetiapine was also recently studied in
comparison to paliperidone and placebo in a 12-week trial in 493 manic or
mixed patients. 53 It produced greater symptom improvement in depression than
paliperidone and was comparable on manic symptoms. A recent, small, placebo-
controlled, 8-week prospective trial of adjunctive quetiapine in 55 bipolar II
mixed hypomania patients found significant improvement in the Clinical Global
Impression and the Montgomery-Åsberg Depression Rating Scale (MADRS) but
no difference from placebo in the YMRS.46 Hypomania improved in both
groups. Adding this set of new data, we think it reasonable to consider
quetiapine to have advantages over other atypical antipsychotics for acute mixed
mania. Some mixed patients, however, may need higher than average doses. 54
Other antipsychotics could be considered if quetiapine is unsuitable because
of metabolic side effects, QTc prolongation, or other risks associated with it.
Two antipsychotics that should be mentioned right away are olanzapine and
risperidone. They are often favored by clinicians, who perceive them as having
strong efficacy in mania. Like most other SGAs, olanzapine and risperidone
have FDA approval for both mixed and nonmixed mania. Overall, the two had
somewhat larger effect sizes than quetiapine in Cipriani and colleagues’ meta-
analysis:49 0.43 standardized mean difference from placebo for olanzapine and
0.50 for risperidone, versus 0.37 for quetiapine. Close inspection of the data on
response to olanzapine in mixed patients, however, reveals that the comparative
efficacy is not that substantial. In one post hoc analysis of two large, pivotal
RCTs, sleep and paranoia improved on olanzapine, but almost all symptoms
related to depression did not. 55 Other, more positive reports in mixed
populations had significant methodological limitations, making it impossible to
be sure if olanzapine had clear antidepressant properties in these patients.48 , 56
Olanzapine did recently demonstrate statistically significant (p < .04) benefits
as a monotherapy for bipolar depression in a large RCT (n = 514). 57 The two-
point difference in MADRS scores at six weeks and the changes on individual
core depressive items on the MADRS, however, seem clinically insignificant.
The largest improvements, by far, were in the sleep and appetite items.
Another objection that can be raised regarding the initial use of olanzapine
concerns its long-term side effects—an important positioning factor in this
algorithm. Olanzapine has the highest risk among the atypical antipsychotics for
weight gain and metabolic disorders, including (eventually) diabetes. Weight
gain over one year in schizophrenia patients was almost twice as high as with
quetiapine and risperidone, which are considered to have intermediate risk for
weight gain. 58 Glucose dysregulation and insulin resistance occur early, even in
the absence of weight gain, and place the patient at risk for later diabetes. 59
Many guidelines and algorithms for treating schizophrenia, including the
PAPHSS algorithm, do not find olanzapine appropriate for first-line use in that
disorder. 3 In mania, the Texas Medication Algorithm Project separated
olanzapine from the first-line options for all mania patients (euphoric and
mixed). 60 The World Federation of Societies of Biological Psychiatry guidelines
declared in 2009 that olanzapine is “not to be used first” in mania, because of the
risks. 61
In mania studies, limited attention has focused on risperidone’s efficacy for
mixed patients. No adequate evaluation has been done, 43 , 48 and no studies have
been published for bipolar depression. Hence, risperidone does not seem to be a
good candidate for initial use in mixed mania despite its FDA approval.
In summary, on the issue of ability to deal with mixed mania and bipolar
depression, quetiapine’s evidence seems superior to that of olanzapine or
risperidone.
A second choice for an SGA might be ziprasidone. In a post hoc analysis of
179 dysphoric manic patients pooled from two ziprasidone mania studies, the
patients’ manic and also depressive symptoms showed significant improvement.
62 Ziprasidone was not found effective for bipolar depression, however, in two
recent placebo-controlled RCTs. 63 The authors proposed that methodological
weaknesses may have limited the ability to detect a difference in the treatments.
Aripiprazole deserves some consideration, again according to post hoc
analysis of data in mixed patients. 64 It also has had two failed trials, however, in
bipolar depression. 65
Further discussion of alternative antipsychotics for acute mania will be found
at Node 3, when quetiapine is again preferred for nonmixed patients.
Clinicians are advised to have a detailed discussion with their manic patients
about the risks and benefits of the medications under consideration, as discussed
here, and also of any other medications relevant to the individual case. This
discussion should include mention of which medications are FDA approved and
which are off-label, and why medications that are not FDA approved might be
recommended. This discussion should be documented in the record.
Node 2b: What If the Response to Quetiapine (or to Another
SGA, If Used) Is Unsatisfactory? Recommendation: Add
Valproate
As noted earlier, reviewers have concluded that mixed mania will often require
combination therapy of an antipsychotic with a mood stabilizer. The mood
stabilizer with the best evidence is valproate. In a retrospective analysis of 145
patients, Zarate and colleagues 66 noted that the combination of quetiapine and
valproate seemed particularly effective in mixed states. In a subsequent placebo-
controlled RCT, divalproex monotherapy was used to treat 364 patients, 44% of
whom had a mixed syndrome. 67 The dose averaged 3350 mg daily. Results were
positive, though not robustly, and outcomes seemed comparable in the mixed
and nonmixed patients. Studies in which antipsychotics (including haloperidol,
olanzapine, and risperidone) were added after initial unsatisfactory response to
valproate have generally shown positive results from the combination compared
to adding placebo.43 Taken together, these studies appear to provide support for
recommending valproate as an augmentation strategy to the antipsychotic in
mixed mania.
Nevertheless, the preference in this algorithm is to use the fewest medications
that are necessary. Valproate has many side effects, and it certainly should be
avoided in women of childbearing potential (see Table 1 ). Almost all of the
studies of combination treatment in mania that have found superior results with
the combination versus placebo have started with patients who were on the first
medication for two weeks or more and had not responded to it.8 Patients who had
started on a monotherapy and done well on it would not have entered those
studies. Therefore, it is reasonable to give the first medication at least a few days
in the inpatient setting (and longer for outpatients under good supervision) to see
if a trend toward effectiveness begins on monotherapy.
It is important to keep in mind that most studies of medications for treating
mania measure outcome at three weeks or more. Typical results with
antipsychotics are that improvement (as indicated by, for example, a 50% drop
in the YMRS) occurs in about 50% of patients by that time. 68 , 69 With placebo, a
typical result is that 30% of patients improve in three weeks. Remissions require
much more time. Thus, substantial improvement in the first few days of
treatment on an inpatient unit is usually due to a combination of the antimanic
medication starting to work and (more importantly) the effect of the supportive
milieu, psychotherapy, and any nonspecific sedatives that are administered in the
early days (see Table 1 ). The clinician should use these other resources
liberally, rather than adding unnecessary antimanic medications (or rushing to
high doses), since no evidence suggests that these extra measures speed
improvement in the core disorder. In a recent RCT of intramuscular sedative
treatments for 100 agitated patients in an emergency room setting (36 of whom
were manic), haloperidol 2.5 mg plus the benzodiazepine midazolam 7.5 mg had
the best outcome with the fewest side effects at all time points (30, 60, and 90
minutes).22 The other options were haloperidol plus promethazine 25 mg (which
produced less sedation and almost four times more extrapyramidal reactions),
olanzapine 10 mg (which had 1.6 times more side effects than haloperidol plus
midazolam), and ziprasidone 10 mg (which had low sedative effectiveness). It
should be noted that intramuscular olanzapine should not be combined with
benzodiazepines, due to the increased risk of respiratory depression. 70
Benzodiazepines also present some risk of complicating the mania with
delirium. After stopping any anticholinergic agents, electroconvulsive therapy
(ECT) may be helpful in that situation.24 Clinicians should be cognizant of the
risk of tardive dyskinesia with the long-term use of any typical neuroleptic, such
as haloperidol, for mania. Mood-disordered patients have a higher risk of this
side effect from neuroleptics. 71
It is routine to add an oral benzodiazepine such as lorazepam or clonazepam
to antipsychotics for additional short-term sedation as an alternative to
increasing the dose of the primary antimanic agent(s).8 , 15 The evidence
supporting this practice with mania patients, however, is sparse. 21 Busch and
colleagues 72 found in a retrospective study (n = 30) that adding a
benzodiazepine (average dose = 1.6 mg/day of lorazepam equivalents) to a
moderate dose of neuroleptic (300 mg of chlorpromazine equivalents) led to
fewer seclusions and restraints in manic patients.
Carbamazepine also could be considered, instead of valproate, as a potential
addition to the antipsychotic at this node. Although it did not perform as well in
mixed as in nonmixed patients in the pivotal studies leading for FDA approval
for acute mania, it seemed to be of some benefit, especially by the third week of
treatment.43
Node 2c: What If the Response to Antipsychotic Plus
Anticonvulsant Is Unsatisfactory? Recommendation: Add
Lithium
Though, as noted earlier, the results with lithium in mixed states are generally
regarded as disappointing, the data are sparse.43 Lithium is a well-established
antimanic treatment (see more detailed review of lithium in Node 2d), and it has
been suggested that it not be eliminated from consideration in the population
with mixed symptoms.44 Another factor is that mixed-episode patients have
increased suicidality and are more likely to have future mixed states than other
patients,42 and data have shown that lithium can be effective for preventing
suicidal behavior even when it is not effective for preventing affective episodes.
73 Therefore, the recommendation is to add lithium at this point if the patient is
still manic.
Node 2d: For Most Other Manic Patients Who Are Not Mixed:
Recommendation Is to Initiate Lithium
In a 2004 review of 101 studies of medications for bipolar disorder, 74 only
lithium was found to be effective in treating acute mania, in preventing
recurrences of mania, and also in treating and preventing recurrences of bipolar
depression.74 Other recent studies and analyses confirm and extend these
conclusions, and add that none of the atypical antipsychotics, despite some
having FDA approval for use in maintenance, has convincing evidence of
efficacy for that purpose. 75 , 76 Ghaemi75 and Goodwin and colleagues76 argue
that the flaw in the methodology of all the maintenance studies of SGAs is that
they start with preselected acute responders to the SGA being tested for
maintenance. This “enriched” population of responders is then randomly
assigned to either stay on the SGA or switch (often abruptly) to placebo or an
active comparator (e.g., lithium). It is argued that this research design is not a
test of maintenance but, instead, a demonstration of withdrawal effects.
Lithium may also be the only medication for bipolar disorder with evidence of
ability to reduce the risk of suicide and suicide attempts. 77 – 79 As noted, its
antisuicidal effect appears distinct from its mood-stabilizing properties. 80
However, the STEP-BD study did not confirm that lithium had an antisuicidal
effect, but the lack of confirmation may reflect the patient sample, which had a
low risk of suicide. 81 Lithium’s neuroprotective effects also seem unique.
Excellent lithium responders (about one-third of lithium-treated patients) appear
to have preserved, in contrast to other lithium-treated patients (who had results
comparable to non-bipolar controls), spatial working memory, sustained
attention on long-term maintenance, and higher plasma levels of brain-derived
neurotrophic factor. 82 Growing neuroimaging evidence suggests that lithium, but
not valproate, increases cortical gray matter and maintains hippocampal volume
compared to patients not treated 83 , 84 (who seem to suffer from hippocampal
volume loss related to the illness). Lithium also normalizes concentrations of N-
acetyl aspartate in prefrontal cerebral cortex, which is a proposed marker of
neuronal activity in bipolar patients. 85 – 87 Antipsychotics, by contrast, reduce
cortical gray matter and glial cell volume by as much as 20% more than in
controls, in studies performed in Macaque monkeys. 88 , 89 Observations in
humans also strongly suggest similar harms, at least in patients diagnosed with
schizophrenia. 90
Unfortunately, cognitive impairment associated with bipolar disorder can
persist despite lithium in some patients. 91
Further support for choosing lithium first comes from a multivariate modeling
study of a community sample of bipolar patients. Baldessarini and colleagues 92
found that patients receiving lithium as monotherapy were less likely to need any
alterations of their drug regimens during the following year when compared to
patients receiving anticonvulsants (e.g., valproate), antipsychotics, or
antidepressants. Also, in a large (n = 4268) observational cohort study from
Denmark, the rate of patients needing switches or additions of psychotropic
medication was much greater when on valproate than on lithium (hazard ratio =
1.86). 93 Admissions were also greater when on valproate, both for mania and
depression.
Good evidence supports the short-term efficacy of lithium in cases of acute
mania with moderate psychotic symptoms.71 One study compared response to
lithium versus valproate in four subtypes of mania (anxious-depressive,
psychotic, classic, and irritable-dysphoric subtypes). In the psychotic type,
lithium was significantly more likely to lower mania ratings by 50%. 94 , 95
Based on the results of one early, heavily promoted comparison with
valproate, 96 some have argued that lithium is not first-line for mania when the
patient has a history of rapid cycling. A subsequent meta-analysis of studies
involving 905 rapid-cycling patients found no disadvantage for lithium. 97 One
observational study of 360 bipolar patients found no difference in lithium
response in the rapid versus the non-rapid cyclers. 98 Controlled maintenance
studies also showed no advantage of valproate over lithium for rapid cyclers. 99
Two other studies compared lithium to valproate and found no significant
difference between them except for more adverse events with valproate. 100 , 101
Lithium use may result, however, both in marked increases in rates of suicidal
behavior and in early recurrences of bipolar episodes following abrupt or rapid
(less than two weeks) discontinuation. 102 , 103 Clinicians need to initiate an
ongoing discussion with patients on the importance of adherence and on the risks
associated with sudden interruptions of all long-term psychotropic drug
treatments (but especially lithium), and be available to offer treatment
alternatives should patients find lithium to be intolerable. 104
In summary, lithium appears to have strong support for being the first-line
treatment for acute nonmixed mania with or without mild to moderate psychosis.
Patient and physician biases against it need to be addressed.75
Because of its narrow therapeutic index, trough serum concentrations of
lithium should be closely monitored. The British National Institute for Health
and Clinical Excellence guidelines (2006) recommend that levels be taken seven
days after initiation and then seven days after every dose or formulation change
and the introduction or discontinuation of interacting medications.7 Levels
should be taken 12 hours after the last dose. Treatment of acute mania may
require lithium levels of 0.8 mEq/L or more, but the suggested optimal target
maintenance level for preventing recurrences of manic or depressive episodes is
0.60-0.75 mEq/L.2 , 105
Other possible first-line pharmacotherapeutic agents for treating a first
episode of mania with or without moderate psychosis include valproate, SGAs,
and carbamazepine. We will comment further on each of these.
Valproate Valproate in its various forms (e.g., divalproex) is chosen by many
clinicians as an initial treatment for acute mania. Examination of a forest plot of
valproate efficacy, however, indicates that in the four subsequent placebo-
controlled RCTs since the first large trial in 1994 that led to FDA approval, the
effect size has been progressively diminishing. 106 In the last two RCTs, one in
adolescents 107 and one in adults, 108 VPA produced no better results than
placebo. In Cipriani and colleagues’ meta-analysis of antimanic agents,49 the
effect size of valproate was only –0.16, which barely met statistical significance.
Moreover, valproate has not been found efficacious for maintenance treatment of
either mania or depression 109 and does not have FDA approval for maintenance
of bipolar disorders. Consequently, valproate does not seem to be an appropriate
first-line option in this evidence-focused algorithm for nonmixed mania, even
though clinical experience and results in trials not involving placebo seem to
support its value. It was proposed as a reasonable choice for mixed mania in
Node 2b and will be proposed as an option in subsequent nodes.
Second-Generation Antipsychotics As noted earlier, most SGAs have been
found effective for acute mania, and most are FDA approved for this indication
(and for mixed mania).49 We have noted that of these, only quetiapine has been
found effective and is FDA approved as a monotherapy for acute depression in
bipolar disorder. Some evidence suggests, moreover, that quetiapine
monotherapy can prevent future episodes of depression.51 For these reasons, and
because of the importance we place on prevention, quetiapine may be seen as
competing with lithium as a first-line treatment for acute mania. That said, the
quality of the Nolen and Weisler maintenance study, 110 like others done with
SGAs, is suspect. In that study, which compared quetiapine with lithium and
placebo for maintenance, all patients were initial quetiapine responders. They
were randomized to either stay on quetiapine or switch to lithium or placebo.
Given that the patients were not known to be responders to lithium, the fact that
lithium did as well as quetiapine (with both better than placebo) for maintenance
seems to be a more impressive result for lithium than for quetiapine. Indeed, in a
recent post hoc analysis of data from that study, patients did even better on
lithium maintenance, compared to the lithium group as a whole, if levels were a
more adequate 0.6 mEq/L or greater. The FDA has not approved quetiapine as a
monotherapy maintenance treatment for bipolar disorder. It has approved
quetiapine as an adjunctive maintenance therapy when added to another mood
stabilizer, because of other data. 111
Adverse effects are significant with both lithium and quetiapine, but since the
publication of our previous, 2010 analysis of their comparative risks,2 QTc
prolongation has been identified as a potential new risk with quetiapine. A
manufacturer’s package-insert warning in July 2011 cautioned against
combining quetiapine with 12 other cardiac depressants and emphasized the
need for clinical monitoring for cardiac safety. Furthermore, a recent meta-
analysis of 77 studies concluded that the side effects of lithium are generally
moderate and appear acceptable when compared to the risks of antipsychotics. 112
, 113 Short-term weight gain, for example, was three times greater with quetiapine
compared to lithium in one head-to-head trial in mania. 114 Lithium also causes
less weight gain than valproate.96 In the CAFE study of early psychosis,
quetiapine was second only to olanzapine for weight gain and metabolic
morbidity, 115 as discussed further in Node 4. Renal disease, however, is a major
concern with lithium. The number needed to harm for severe renal damage
associated with lithium was approximately 300, with an estimated absolute
placebo-adjusted risk of about 3.3/1000 treated cases. 116
Carbamazepine Carbamazepine is effective in mania,49 , 117 with recent FDA
approval for acute mania and mixed states of a new slow-release formulation. It
has many drug interactions, however; due to the induction of several oxidative
and glucuronidation enzymes, it increases the clearance of many other agents. It
also induces its own metabolism, which produces falling serum concentrations
and creates difficulties in adjusting dose. Other adverse effects include
hyponatremia, liver toxicity, teratogenesis (e.g., neural tube defects), and blood
dyscrasias. The evidence supporting its effectiveness for treating or preventing
bipolar depression comes only from uncontrolled studies.
NODE 3: WHAT IF THE RESPONSE TO LITHIUM
IN ACUTE NONMIXED MANIA IS
UNSATISFACTORY? RECOMMENDATION: ADD
QUETIAPINE OR ANOTHER SGA
If the results are unsatisfactory with lithium, the next option would be to
introduce an SGA. This might be done quickly in some cases, as discussed in
Node 2b (regarding the addition of a mood-stabilizing anticonvulsant to the
initial SGA for mixed patients). Moreover, as discussed in Node 2d, quetiapine
comes closest to lithium in possessing a broad mood-stabilizing capacity, though
it was argued that the evidence regarding quetiapine is less convincing than that
for lithium. In Node 2a, we also discussed the reasons for preferring quetiapine,
instead of other SGAs, such as olanzapine and risperidone, that have somewhat
greater potency in managing acute mania. In summary, it was noted there that
quetiapine is reasonably effective in acute mania if used at adequate doses of
600 mg daily, and that the slightly superior efficacy of the others may not be
visible to clinicians in the acute inpatient setting because of the confounding
effect of the other concomitant treatments, including therapeutic containment,
psychotherapy, IM “chemical restraints,” and sedating oral adjunctive
medications such as benzodiazepines. In the case of olanzapine, important acute
(e.g., insulin resistance) and long-term (metabolic syndrome) side effects render
it undesirable for first-line use in mania. According to several meta-analyses,
however, risperidone has the numerically largest effect size of the SGAs in acute
mania and has a more acceptable side-effect profile than olanzapine.49 , 106 , 118
Hence, risperidone is a reasonable option at this node instead of quetiapine if the
prescriber prefers to focus on initial efficacy without worrying about long-term
maintenance—which in some manic patients may be less critical. First-
generation neuroleptics such as haloperidol (though not FDA approved) are also
highly effective for acute mania and may even work faster than any SGAs.49 , 119
They are generally unacceptable, however, because of a high risk of inducing
neuroleptic dysphoria or depression and because of the greater risk of tardive
dyskinesia in bipolar patients. 120 , 121
Quetiapine has evidence of efficacy versus placebo when added to lithium for
acute treatment of mania (after at least two weeks of unsatisfactory response to
lithium), and it helps to prevent future episodes.111 , 122
Some clinicians might consider adding valproate rather than an antipsychotic
to lithium. We reviewed in Node 2d the evidence that valproate seems less
effective than previously assumed. The recent “game changing” 2010
BALANCE study should also be noted. In comparing the results over two years
of combining valproate and lithium versus using either treatment alone, the
combination showed very little additional benefit compared to lithium alone.109
Hence, valproate is not recommended as the first-line addition after
unsatisfactory results with lithium.
NODE 4: HAS THE RESPONSE TO LITHIUM AND
QUETIAPINE BEEN UNSATISFACTORY?
RECOMMENDATION: CHANGE QUETIAPINE
TO A DIFFERENT SGA. CONSIDER AN
ANTICONVULSANT MOOD STABILIZER
Having utilized without success lithium and quetiapine, the two agents with the
broadest spectrum of efficacy in bipolar disorder, we would now give greater
consideration to the options that seem to have efficacy limited to acute mania.
These options include the anticonvulsants valproate and carbamazepine as well
as other SGAs. Other anticonvulsants, including gabapentin, lamotrigine,
levetiracetam, and topiramate, have little or no apparent efficacy in the manic
phase of bipolar disorder, and oxcarbazepine remains inadequately evaluated.49
First-generation antipsychotics are still not desirable because they increase risk
of tardive dyskinesia, to which bipolar patients are highly susceptible, and they
may increase the risk of bipolar depression.30 ECT is a consideration addressed
below.
When introducing a Node 4 medication, eliminate any current medication that
has been considered ineffective, although such medication might be retained if it
has demonstrated efficacy for preventing future episodes of mania or bipolar
depression.
A switch to one of the SGAs that is more effective in mania is the first
recommended option. Since this manic episode can now be characterized as
treatment resistant, the priority becomes the termination of the episode.
Risperidone, if not already tried, and olanzapine are SGAs with larger effect
sizes in the meta-analyses and are the best options here. It is unfortunate that no
randomized trials have evaluated whether, after failure on an adequate trial of
one SGA for acute mania (e.g., quetiapine), switching to another SGA would
produce a different outcome. The best evidence we have are the comparative
trials in non-treatment-resistant cases, which suggest a hierarchy of acute
efficacy in which risperidone and olanzapine are the leaders among the SGAs.49
Risperidone was approved for treatment of acute mania in the United States in
2003. The dose range that has proved effective in reducing YMRS scores more
than placebo is 1-6 mg daily. 123 In one study, remission rates (defined as a
sustained YMRS score <8 for three weeks) at 10 months were 42% for
risperidone and 13% for placebo.123 A 2006 Cochrane review found equal
efficacy in psychotic and non- psychotic mania. 124 In that analysis, risperidone
was equally sedating as olanzapine, produced more extrapyramidal and sexual
side effects, but resulted in less weight gain.
Olanzapine was approved in the United States in 2000. The usually effective
doses ranged between 5 and 20 mg, with three-week improvement rates in
pooled analysis averaging 55% versus 30% with placebo. Three-week remission
rates were 18% versus 7%, respectively.68 These findings illustrate the point
made earlier that one cannot expect remission in three-week trials in acute
mania, even from the most effective antimanic medications. It takes many weeks
or sometimes months. If patients improve sooner than that, the credit probably
should be shared with the other treatments offered in the therapeutic
environment of the hospital. For further perspective on olanzapine, it is worth
noting a new three-week, placebo-controlled RCT comparing olanzapine and
lithium for acute mania in 40 women from Iran. Mania scores on the Manic State
Rating Scale were reduced 20.3 points on lithium at a mean blood level of 0.8
meq/L versus 7.6 points on olanzapine at a mean dose of 20.5 mg daily (p =
.0002 favoring lithium). 125 In the two other comparisons of these agents,
olanzapine was superior in one, and no efficacy difference was found in the
other.49
Other options that could be considered at this node include the anticonvulsant
mood stabilizers. Valproate was reviewed as an option in Node 2d, and we noted
the marginal or negative results in recent RCTs in adolescents and adults with
acute mania.107 , 108 In their recent study of valproate in adults, Hirschfeld and
colleagues108 proposed that the problem could have been use of a “moderate”
dose of 2200 mg daily. In their previous, modestly positive study, they had used
a mean dose of 3350 mg daily.67 In the earlier study, however, the side effects of
somnolence, nausea, vomiting, and dizziness were much more common. Also,
the authors noted that the protocol of the later study encouraged earlier hospital
discharge, which may have affected outcomes. The later study also allowed
longer use of adjunctive lorazepam, which may have decreased the drug/placebo
differences. Pressure for shorter hospital stays are a reality today, however, and,
as noted, experts encourage liberal use of adjunctive benzodiazepines. Thus,
some of the conditions that may potentially explain valproate’s lack of efficacy
in the study by Hirschfeld and colleagues are likely to be present in typical
hospital practice.
Other reasons for postponing valproate include the results of the BALANCE
study.109 The large (n = 330), open-label, two-year maintenance RCT found that
valproate was far less effective than lithium and that it added little to lithium in
combination therapy. In conjunction with the unimpressive data on acute
efficacy (see discussion under Node 2d), this important study reduces the
preference for valproate in this algorithm, in which maintenance is a central
priority. Similar results favoring lithium over valproate were reported in an
observational cohort study, cited earlier, from a Danish registry of bipolar
patients.93 Another matter of concern is that valproate use has been associated
with neurotoxicity when used in patients with dementia, in whom it accelerated
brain volume loss over one year of treatment and did not, when compared to
placebo, reduce behavioral dysregulation, agitation, or psychosis. 126 , 127 This
risk of neurotoxicity contrasts with lithium, which, as mentioned earlier,
demonstrates a neuro- protective effect in a variety of neurological conditions,
though lithium carries its own risk of neurotoxicity, including delirium in the
elderly. Finally as noted in Table 1 , valproate is a medication of last choice in
women of childbearing potential because of severe teratogenicity and
impairment of subsequent cognitive ability in exposed fetuses.
Despite these negative considerations, the initial trials of valproate in mania
were strongly positive, leading to FDA approval.96 , 128 , 129 There is evidence that
valproate may be effective in a different set of bipolar patients than lithium: one
analysis concluded that valproate was sometimes more effective than lithium in
treating acute mania with dysphoria, irritability, impulsivity, and hostility.94
Many clinicians who use it regularly today have experiences convincing them
that it is effective in a variety of patients and has an acceptable margin of safety.
Valproate also might be effective in acute bipolar depression. Three small
published RCTs were positive (total n = 142), but publication bias may have
affected the results; larger studies are needed before conclusions can be drawn.
130 Nevertheless, these positive considerations suggest that valproate is a possible
choice at Node 4, following the failure of lithium and quetiapine or the
unacceptability of the better SGA options because of the patient’s side-effect
vulnerabilities.
Additional safety concerns with valproate not mentioned previously include
liver toxicity, drug interactions (e.g., with lamotrigine), and masculinizing
effects in young women. 131 In one report, triglycerides were severely elevated
when valproate was added to quetiapine. 132 Potential explanations include
cytochrome P450 isoenzyme 3A4 inhibition by valproate, protein binding
displacement, or a pharmacodynamic effect. Systematic research is needed to
elucidate the frequency and causes of this interaction between two medications
that are commonly combined.
Nutritional deficits induced by valproate might have a role in the outcome of
mania treatment. In one study, folic acid given with valproate resulted in
significantly greater reductions of mania symptom ratings than valproate alone,
specifically in areas of language disorder, thought content, and disruptive-
aggressive behavior. 133
According to the British National Institute for Health and Clinical Excellence
guidelines, serum concentrations of valproate should be monitored only if
toxicity, lack of response, or poor adherence is suspected.7 No clear-cut
therapeutic range has been established, and expert opinion indicates that the
therapeutic index for valproate, compared to lithium, is fairly wide. It has been
suggested that plasma levels for acute mania fall in the range of 50 to 125
ng/mL.15
Carbamazepine is an option again here, as it was in node 3. It is more
frequently prescribed than valproate in Japan (where Okuma carried out
important early clinical trials of this agent for bipolar disorder) and in regions of
Europe. In the United States, clinicians use it much less often than valproate
because of the safety and dosing issues noted earlier and also, one suspects,
because of the aggressive marketing of valproate in the decade after FDA
approval. The relatively low risk of weight gain with carbamazepine compared
to other options 134 can be an advantage.
If the patient is medically unstable or needs rapid relief of mania-related
psychosis or delirium, ECT can be considered here or earlier in the algorithm.
Also consider ECT for women in their first month of pregnancy, when
organogenesis is taking place and the risk of teratogenicity is highest. The
evidence for ECT’s effectiveness in treating mania is not secure, however, due to
difficulties in conducting trials with appropriate randomization and blinding, and
in obtaining informed consent from some patients, including those with possibly
compromised legal competence. A recent review of the evidence for ECT in
treating mania concluded that no study is consistently adequate
methodologically. 135 Nevertheless, one prospective study found ECT to be more
effective than lithium in the first eight weeks of treatment of acute mania. 136
Other studies are mostly retrospective analyses, finding that ECT treatment for
mania was as effective as lithium or chlorpromazine (the only first-generation
antipsychotic that is FDA approved for treating mania, though we do not
recommend it, because of safety issues related to alpha blockade and
hypotension). 137 , 138
NODE 5: WHAT IF THREE RECOMMENDED
TREATMENTS FOR EITHER BIPOLAR MIXED
OR NONMIXED MANIC PATIENTS HAVE BEEN
INEFFECTIVE OR ONLY PARTIALLY
EFFECTIVE? RECOMMENDATION: MANY
OPTIONS
Three tiers of options are proposed, based on the quantity of supporting evidence
for their efficacy in less treatment-resistant patients. The first tier of options
includes the high-efficacy SGAs (e.g., olanzapine or risperidone if not already
tried) and the anticonvulsants valproate and carbamazepine. The merits and
drawbacks of all these options have already been reviewed. Haloperidol could
also be considered because of its very strong efficacy.49 Second-tier agents for
consideration at Node 5 include aripiprazole, asenapine, and ziprasidone.
Clozapine could be a third-tier choice, though it has multiple, and potentially
severe, adverse effects.
As indicated in Figure 1 , the flowchart of this algorithm, it is suggested at this
point that any medications that appear to be ineffective be stopped before adding
new ones. The idea here is to avoid unnecessary accumulated side effects, which
is one of the key goals and priorities for algorithm sequencing. While
discontinuing such medications would appear to be a reasonable principle of
conservative practice, no good evidence actually shows that one can remove an
apparently ineffective medication during treatment of acute mania without any
impact on the effectiveness of what will be added. Indeed, as noted earlier, in the
design of just about all the studies of adding new medications, the previous
ineffective medication is continued, and either the new one or a control
medication (or none) is added. 139 Hence, here at Node 5, if you have
discontinued a medication before adding another medication that does not then
produce satisfactory results or that causes further decompensation, you could
consider resuming the discontinued medication to see if that could be helpful.
It is recommended to avoid combining two antipsychotics (other than during
crossover from one to another), due to both the lack of any evidence of added
efficacy and the increased risk of side effects, including metabolic syndrome,
extrapyramidal symptoms, hyperprolactinemia, sexual dysfunction,
sedation/somnolence, cognitive impairment, diabetes, and tardive dyskinesia. 140
We provide below additional discussion of some of these agents as
monotherapies and in combination with lithium and anticonvulsants—if they
were not reviewed in sufficient detail before.
Carbamazepine
In 2004, the FDA approved the extended-release form of carbamazepine for
treating acute mania. As discussed under Node 4, the efficacy of carbamazepine
as an antimanic agent is established, with doses of the recently introduced long-
acting formulation ranging from 600 to 1600 mg daily. In a review of RCTs
comparing carbamazepine and lithium, and combining results in meta-analyses
when possible, the two were similar in efficacy for acute mania as well as in
safety and the ability to prevent relapses. 141 Notably, carbamazepine is not FDA
approved for long-term use, and the review found that in maintenance studies,
carbamazepine patients were more likely than patients on lithium to withdraw
from the studies due to adverse effects.141 Patients with rapid cycling might
benefit from adding carbamazepine to lithium: in one study, the long-term
response was better with the combination than with either of the medications
alone (28% response with lithium, 19% with carbamazepine, and 56% with the
combination). 142 A similar study found better results with the combination but
more side effects and increased need for additional adjunctive medications. 143
For acute mania with prominent agitation, the combination might also be more
helpful than monotherapy with an antipsychotic; 144 in one study, adding
carbamazepine to lithium produced benefits comparable to those from adding
haloperidol to lithium. 145
Aripiprazole
The use of aripiprazole for treating acute mania was approved by the FDA in
2004. Compared to other SGAs, aripiprazole has a more benign side-effect
profile regarding weight gain, cardiac and metabolic effects, and some
extrapyramidal symptoms, although it frequently causes akathisia and, because
of its partial dopamine-agonist effect, may worsen Parkinson’s disease. The
evidence regarding its efficacy in acute mania is less strong than for other SGAs,
and in several published studies it failed to outperform placebo.106 , 146 , 147
Aripiprazole can be added to lithium or valproate, and such combinations have
yielded superior response and remission rates among outpatients than with either
agent alone. 148 Although approved in the United States for maintenance
treatment of bipolar disorder, most of the support for that indication is based on
a single, relatively brief (six-month) study that showed benefits only for
preventing mania and not for the more common depressive episodes of the
illness. 149 Only 12% of the patients continued to take aripiprazole for the full six
months, suggesting a lack of patient acceptability.149
Ziprasidone
The use of ziprasidone for treating acute mania was approved by the FDA in
2004. Two RCTs compared ziprasidone to placebo for acute mania and found
significantly better response with this SGA than with placebo. 150 , 151 One RCT
for acute mania compared ziprasidone to haloperidol; the latter produced higher
rates of response and remission (54.7% vs. 36.9%, and 31.9% vs. 22.7%,
respectively). 152 Inferior results with ziprasidone in comparison to other
antipsychotics (its effect size was only –0.20 in Cipriani and colleagues’ meta-
analysis),49 which also can be seen in studies of patients with schizophrenia, may
in part be due to suboptimal dosing, the requirement for taking it with 500 kcal
meals, and (for outpatients) problems complying with twice-daily
administration. A recent study failed to find any effectiveness for ziprasidone as
an add-on to lithium or valproate in acute mania, but methodological problems
were offered to explain this finding. 153 , 154 On the positive side for ziprasidone,
it may not only cause less weight gain in obese patients but produce better mania
outcomes when added to the existing regimens of such patients. 155 Also, a recent
six-week RCT in acute bipolar mixed depression at a dose of 130 mg daily found
significant benefit (p = .004) in depression scores. 156 These patients were not
manic, but the study suggests a role for ziprasidone in preventing depressive
episodes.
Asenapine
The use of asenapine as a treatment for acute mania was approved by the FDA in
2009 and as an adjunctive treatment to augment lithium or valproate in 2012. As
an adjunctive treatment for acute mania, asenapine performed no better than
placebo on all primary outcome measures at week 3 but did separate at week 12.
157 Two placebo-controlled RCTs of asenapine monotherapy are also available.
In one study, it was significantly superior to placebo, but not to olanzapine, in
reducing YMRS mania symptom ratings, and in the other, it was not more
effective than placebo in either response or remission rates. 158 – 161 Asenapine is
administered twice daily as sublingual tablets, which may not be as simple to use
as ordinary oral preparations. It has a favorable side-effect profile, however, with
respect to weight gain, metabolic problems, extrapyramidal symptoms, prolactin
elevation, and cardiovascular toxicity.
Clozapine
Clozapine is not approved in the United States for bipolar disorder but is
sometimes used off-label to manage treatment-resistant mania. No RCTs of
clozapine in mania have been published, but uncontrolled clinical trials suggest
that clozapine might be a reasonable option for patients at node 5 and beyond. 162
– 165
NODE 6: WHAT IF ALL THE ABOVE AGENTS
HAVE NOT BEEN EFFECTIVE?
It seems unlikely that a patient could reach this point and still remain in a manic
state if the diagnosis is correct and if the algorithm has been followed rigorously
with adequate trials. Certainly, a reconsideration of diagnosis is appropriate.
Indeed, diagnostic reconsideration should actually occur after every step of this
and any other algorithm when the response is unsatisfactory and no clear
explanation is apparent. For example, there might be some unidentified organic
cause, or strong psychosocial stresses could be preventing the mood disorder
from stabilizing. Nevertheless, it is possible that unexpected positive results
could occur with further adjustment of medications. It is suggested that the
clinician review the options offered in Node 5 and consider picking another from
those.
We would also note here some experimental approaches to mania treatment
that have been reported. Selected examples are listed in Table 2 , but we have no
particular recommendations regarding when or whether any should be tried in
preference to the more established treatments.
Table 2 | New and Experimental Treatments Proposed for Acute Mania
Medication Action Comments
Gabapentin Antiepileptic No evidence for efficacy as a primary or
secondary treatment despite numerous trials and
widespread use in the past 166
Levetiracetam Antiepileptic No RCTs in mania
May be helpful when added to haloperidol 167
No added benefit when combined with valproate
168
Oxcarbazepine Antiepileptic One RCT as monotherapy with response rate 42%
vs. placebo 26%; no data on remission rates 169
As adjunct to lithium in 52 patients, more
effective and better tolerated than carbamazepine
170
A Cochrane review found that the trials were
insufficient to make a recommendation 171
Topiramate Antiepileptic Multiple RCTs failed to find any efficacy in acute
mania as primary or secondary agent49 , 172 , 173
May help patients on olanzapine (and perhaps
other SGAs) lose some weight 174
Amisulpridea Antipsychotic In an RCT, when added to valproate, had results
comparable to haloperidol + valproate;
Amisulpridea
comparable to haloperidol + valproate;
haloperidol + valproate had more side effects 175
Paliperidone Antipsychotic Metabolite of risperidone
Has been tested and found effective for mania in
two RCTs13 Surprisingly, not effective when used
as an adjunct to lithium 176 Has no significant
advantages over generic risperidone
Allopurinol Hypouricemic agent Three placebo-controlled RCTs as adjunct to
lithium; more improvement on allopurinol at
doses of 600 mg daily; well-tolerated 177 – 179
May work better if patients abstain from caffeine
178
Aspirin Nonsteroidal anti-
inflammatory agent
Netherlands database showed that low-dose
aspirin (up to 80 mg daily) is associated with 17%
reduction of risk of relapse on maintenance
lithium 180
Omega-3 fatty acids
(e.g., in fish oils)
Lipid supplement A Cochrane review of 5 RCTs found some
positive results for bipolar depression but not for
mania 181
A more recent study was negative 182
May possibly help prevent depression
Tamoxifen Estrogen receptor
modulator and protein
kinase C inhibitor
Two RCTs with placebo controls and some pilot
studies support effectiveness in mania at doses of
20 to 80 mg daily117 , 183 – 186
Has been used as monotherapy and as adjunct to
lithium
No information about its role in depression or in
maintenance treatment
Transcranial magnetic
stimulation
Though it may be more promising for bipolar
depression, some emerging data support its use for
COMPARISON WITH OTHER GUIDELINE AND
ALGORITHM RECOMMENDATIONS
This algorithm for selecting psychopharmacological treatment for acute mania is
in accord with most features of other recently published guidelines and
algorithms. There are also various points of disagreement, however, in part
because the current algorithm incorporates the results of studies not available
earlier. For example, we concluded that olanzapine is not a first-line treatment
for acute mania—which is in agreement with some guidelines but not others.
One unique difference in this algorithm is the de-emphasis on valproate as an
option, due to the newer evidence suggesting inferior efficacy. Table 3
summarizes four guidelines and algorithms published by different groups in
recent years. We have noted some points of contrast between their
recommendations and ours.
Table 3 | Comparison of Present Algorithm to Other Recent Algorithms
and Guidelines for Acute Mania
Algorithm/guideline Year Other
algorithms/guidelines
Present algorithm
Canadian Network for
Mood and Anxiety
Treatments guidelines for
managing patients with
bipolar disorders, as updated
in collaboration with
International Society for
Bipolar Disorders 188
2013 No distinction in early nodes
between different subtypes
of bipolar mania
No preference is given
among the first-line agents;
SGAs, valproate, lithium, or
their combinations can be
first-line
Makes this distinction early
in the algorithm and
accordingly suggests
narrower, subtype-specific
treatment options
Suggests starting with a
monotherapy trial
Gives priority to lithium in
nonmixed mania and to
quetiapine in mixed mania
British Association for
Psychopharmacology
evidence-based guidelines
for treating bipolar disorder,
revised second edition 189
2009 Has different treatment
suggestions depending on
the level of severity
Makes the assumption that
in severe mania, lithium is
not a first-line agent
Suggests the use of SGAs
Makes a distinction early in
the algorithm between
mixed and nonmixed states,
and suggests narrower,
subtype-specific treatment
options
Review found that lithium
Suggests the use of SGAs
Lists valproate as a first-line
agent in severe mania
Does not favor any SGA
over another
Review found that lithium
can be effective in severe
mania and suggests adding
an adjunct SGA for partial
response, thus favoring
lithium-based combinations
Review of recent evidence
resulted in valproate being
dropped to lower nodes in
the algorithm for nonmixed
mania and being second-line
for mixed mania
Favors the use of quetiapine
and recommends
considering olanzapine later
as an option due to
safety/side-effect profile
World Federation of
Societies of Biological
Psychiatry guidelines for the
biological treatment of
bipolar disorders: update on
treating acute mania61
2009 Detailed discussion and
clear hierarchy based on
level of evidence and side-
effect profile of each
medication
No distinction in medication
choice based on mania
subtype, although clinicians
are encouraged to make
diagnostic distinction
Aripiprazole, risperidone,
and valproate (except for
women of childbearing
potential) are first-line
agents in terms of efficacy
and risk/benefit ratio
Makes subtype-specific
recommendations such as
preferring lithium first-line
for nonmixed mania due to
its broad efficacy,
antisuicidal properties,
neuroprotective benefits,
and other advantages
The Texas implementation
of medication algorithms:
update to the algorithms for
treating bipolar 1 disorder
190
2005 After making a distinction
between mixed and
nonmixed mania, gives a
wider variety of agents to
use as first-line in both
states
Excludes quetiapine and
favors other SGAs and
valproate as first-line agents
in mixed mania
Provides narrower choices
based on appraised evidence
in both mixed and nonmixed
states
Recommends use of
quetiapine as first-line in
mixed states and makes
valproate second-line
SGA, second-generation antipsychotic.
SGA, second-generation antipsychotic.
CONCLUSIONS AND FINAL COMMENT
The psychopharmacological treatment of mania in bipolar disorder is replete
with challenges. Though many medications are effective or partly effective for
acute episodes, relatively few are of benefit in all phases of the disorder and
have the effect of truly stabilizing mood and behavior. Even fewer treatments
offer satisfactory safety, especially in the long term. Clinicians, typically under
pressure of limited time, often resort to targeting symptoms with different
medicines in complex and largely untested combinations, often without
satisfactory clinical results. Many experts believe that patients may do better
with a more systematic approach that emphasizes the most evidence-supported,
safest treatments and fewer medications per patient. The recommendations
provided here offer a reasonable, but tentative, path to improved outcomes of
pharmacotherapy, with fewer complications, for patients with mania.
Nevertheless, the proposals are subject to ongoing revision as additional research
findings become available.
Declaration of interest: The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of the article.
The authors thank Drs. Ross J. Baldessarini and Mark S. Bauer for their
comments and suggestions on an early draft of this article.
REFERENCES
1. Levy B, Weiss RD. Neurocognitive impairment and psychosis in bipolar I disorder during early
remission from an acute episode of mood disturbance. J Clin Psychiatry 2010;71:201-6.
2. Ansari A, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore Program:
an update on bipolar depression. Harv Rev Psychiatry 2010;18:36-55.
3. Osser DN, Jalali-Roudsari M, Manschreck T. The Psychopharmacology Algorithm Project at the
Harvard South Shore Program: an update on schizophrenia. Harv Rev Psychiatry 2013;21:18-40.
4.
Bajor LA, Ticlea AN, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South
Shore Program: an update on posttraumatic stress disorder. Harv Rev Psychiatry 2011;19:240-58.
5. Hamoda HM, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: an update on psychotic depression. Harv Rev Psychiatry 2008;16:235-47.
6. Osser DN, Dunlop LR. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: an update on generalized social anxiety disorder. Psychopharm Rev 2010;45:91-8.
7. National Collaborating Centre for Mental Health; National Institute for Health and Clinical Excellence.
Bipolar disorder: the management of bipolar disorder in adults, children, and adolescents in primary
and secondary care. London: NICE, 2006.
8. Goodwin FK, Jamison KR. Manic-depressive illness: bipolar disorders and recurrent depression. 2nd
ed. New York: Oxford University Press, 2007.
9. Rosa AR, Cruz N, Franco C, et al. Why do clinicians maintain antidepressants in some patients with
acute mania? Hints from the European Mania in Bipolar Longitudinal Evaluation of Medication
(EMBLEM), a large naturalistic study. J Clin Psychiatry 2010;71:1000-6.
10. McElroy SL, Keck PE Jr, Strakowski SM. Mania, psychosis, and antipsychotics. J Clin Psychiatry
1996;57 suppl 3: 14-26; discussion 47-9.
11. Swann AC, Daniel DG, Kochan LD, Wozniak PJ, Calabrese JR. Psychosis in mania: specificity of its
role in severity and treatment response. J Clin Psychiatry 2004;65:825-9.
12. Carlson GA, Goodwin FK. The stages of mania. A longitudinal analysis of the manic episode. Arch
Gen Psychiatry 1973; 28:221-8.
13. Yildiz A, Vieta E, Tohen M, Baldessarini RJ. Factors modifying drug and placebo responses in
randomized trials for bipolar mania. Int J Neuropsychopharmacol 2011;14:863-75.
14. Schatzberg AF, Cole JO, DeBattista C. Manual of clinical psychopharmacology. 7th ed. Washington,
DC: American Psychiatric Press, 2010.
15. Janicak PG, Marder SR, Pavuluri MN. Principles and practice of psychopharmacotherapy. 5th ed.
Philadelphia: Lippincott Williams & Wilkins, 2011.
16. American Psychiatric Association. American Psychiatric Association practice guidelines for the
treatment of psychiatric disorders. Arlington, VA: American Psychiatric Publishing, 2006.
17. Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam, or both for psychotic agitation? A
multicenter, prospective, double-blind, emergency department study. Am J Emerg Med 1997;15:335-
40.
18. Garza-Trevino ES, Hollister LE, Overall JE, Alexander WF. Efficacy of combinations of
intramuscular antipsychotics and sedative-hypnotics for control of psychotic agitation. Am J
Psychiatry 1989;146:1598-601.
19. Andrezina R, Josiassen RC, Marcus RN, et al. Intramuscular aripiprazole for the treatment of acute
agitation in patients with schizophrenia or schizoaffective disorder: a double-blind, placebo-
controlled comparison with intramuscular haloperidol. Psychopharmacology (Berl) 2006;188:281-92.
20. Satterthwaite TD, Wolf DH, Rosenheck RA, Gur RE, Caroff SN. A meta-analysis of the risk of acute
extrapyramidal symptoms with intramuscular antipsychotics for the treatment of agitation. J Clin
Psychiatry 2008;69:1869-79.
21. Zeller SL, Rhoades RW. Systematic reviews of assessment measures and pharmacologic treatments
for agitation. Clin Ther 2010;32:403-25.
22. Mantovani C, Labate CM, Sponholz A Jr, et al. Are low doses of antipsychotics effective in the
management of psychomotor agitation? A randomized, rated-blind trial of 4 intramuscular
interventions. J Clin Psychopharmacol 2013;33:306-12 .
23. Ahmed U, Jones H, Adams CE. Chlorpromazine for psychosis induced aggression or agitation.
Cochrane Database Syst Rev 2010;(4):CD007445.
24. Karmacharya R, England ML, Ongur D. Delirious mania: clinical features and treatment response. J
Affect Disord 2008; 109:312-6.
25. Provencher MD, Guimond AJ, Hawke LD. Comorbid anxiety in bipolar spectrum disorders: a
neglected research and treatment issue? J Affect Disord 2012;137:161-4.
26. Trixler M, Gati A, Fekete S, Tenyi T. Use of antipsychotics in the management of schizophrenia
during pregnancy. Drugs 2005;65:1193-206.
27. Gentile S. Clinical utilization of atypical antipsychotics in pregnancy and lactation. Ann
Pharmacother 2004;38:1265-71.
28. Collins KO, Comer JB. Maternal haloperidol therapy associated with dyskinesia in a newborn. Am J
Health Syst Pharm 2003;60:2253-5.
29. Reis M, Kallen B. Maternal use of antipsychotics in early pregnancy and delivery outcome. J Clin
Psychopharmacol 2008; 28:279-88.
30. Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry. 11th ed. Chichester,
UK: Wiley-Blackwell, 2012.
31. McKean M. Psychiatric care during pregnancy and postpartum. Part 1: diagnosis and management of
mood disorders. Psychopharm Rev 2013;48:17-24.
32. Jentink J, Loane MA, Dolk H, et al. Valproic acid monotherapy in pregnancy and major congenital
malformations. N Engl J Med 2010;362:2185-93.
33. Cummings C, Stewart M, Stevenson M, Morrow J, Nelson J. Neurodevelopment of children exposed
in utero to lamotrigine, sodium valproate and carbamazepine. Arch Dis Child 2011; 96:643-7.
34. Cohen LS, Friedman JM, Jefferson JW, Johnson EM, Weiner ML. A reevaluation of risk of in utero
exposure to lithium. JAMA 1994;271:146-50.
35. Miller LJ. Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry
1994;45:444-50.
36. Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar disorder during pregnancy and the
postpartum period. Am J Psychiatry 2004;161:608-20.
37. McElroy SL, Altshuler LL, Suppes T, et al. Axis I psychiatric comorbidity and its relationship to
historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry 2001; 158:420-6.
38. Pettinati HM, O’Brien CP, Dundon WD. Current status of cooccurring mood and substance use
disorders: a new therapeutic target. Am J Psychiatry 2013;170:23-30.
39. Salloum IM, Cornelius JR, Daley DC, Kirisci L, Himmelhoch JM, Thase ME. Efficacy of valproate
maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo- controlled
study. Arch Gen Psychiatry 2005;62:37-45.
40. Brown ES, Gorman AR, Hynan LS. A randomized, placebo- controlled trial of citicoline add-on
therapy in outpatients with bipolar disorder and cocaine dependence. J Clin Psychopharmacol
2007;27:498-502.
41. Chung AK, Chua SE. Effects on prolongation of Bazett’s corrected QT interval of seven second-
generation antipsychotics in the treatment of schizophrenia: a meta-analysis. J Psychopharmacol
2011;25:646-66.
42. Swann AC, Lafer B, Perugi G, et al. Bipolar mixed states: an international society for bipolar
disorders task force report of symptom structure, course of illness, and diagnosis. Am J Psychiatry
2013;170:31-42.
43. Fountoulakis KN, Kontis D, Gonda X, Siamouli M, Yatham LN. Treatment of mixed bipolar states.
Int J Neuropsychopharmacol 2012;15:1015-26.
44. McIntyre RS, Yoon J. Efficacy of antimanic treatments in mixed states. Bipolar Disord 2012;14
suppl 2:22-36.
suppl 2:22-36.
45. Houston JP, Tohen M, Degenhardt EK, Jamal HH, Liu LL, Ketter TA. Olanzapine-divalproex
combination versus divalproex monotherapy in the treatment of bipolar mixed episodes: a double-
blind, placebo-controlled study. J Clin Psychiatry 2009;70:1540-7 .
46. Suppes T, Ketter TA, Gwizdowski IS, et al. First controlled treatment trial of bipolar II hypomania
with mixed symptoms: quetiapine versus placebo. J Affect Disord 2013;150:37-43.
48. Kruger S, Trevor Young L, Braunig P. Pharmacotherapy of bipolar mixed states. Bipolar Disord
2005;7:205-15.
49. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in
acute mania: a multipletreatments meta-analysis. Lancet 2011;378:1306-15.
50. Janicak PG, Rado JT. Quetiapine for the treatment of acute bipolar mania, mixed episodes and
maintenance therapy. Expert Opin Pharmacother 2012;13:1645-52.
51. Weisler RH, Nolen WA, Neijber A, Hellqvist A, Paulsson B. Continuation of quetiapine versus
switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a
randomized controlled study). J Clin Psychiatry 2011; 72:1452-64.
52. Cutler AJ, Datto C, Nordenhem A, Minkwitz M, Acevedo L, Darko D. Extended-release quetiapine
as monotherapy for the treatment of adults with acute mania: a randomized, double-blind, 3-week
trial. Clin Ther 2011;33:1643-58.
53. Vieta E, Nuamah IF, Lim P, et al. A randomized, placebo- and active-controlled study of
paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I
disorder. Bipolar Disord 2010;12:230-43.
54. Khazaal Y, Tapparel S, Chatton A, Rothen S, Preisig M, Zullino D. Quetiapine dosage in bipolar
disorder episodes and mixed states. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:727-30.
55. Baker RW, Tohen M, Fawcett J, et al. Acute dysphoric mania: treatment response to olanzapine
versus placebo. J Clin Psychopharmacol 2003;23:132-7.
56. Gonzalez-Pinto A, Lalaguna B, Mosquera F, et al. Use of olanzapine in dysphoric mania. J Affect
Disord 2001;66:247-53.
57. Tohen M, McDonnell DP, Case M, et al. Randomised, double-blind, placebo-controlled study of
olanzapine in patients with bipolar I depression. Br J Psychiatry 20l2;201:376-82.
58. McEvoy JP, Lieberman JA, Perkins DO, et al. Efficacy and tolerability of olanzapine, quetiapine, and
risperidone in the treatment of early psychosis: a randomized, double-blind 52week comparison. Am
J Psychiatry 2007;164:1050-60.
59. Hahn MK, Wolever TM, Arenovich T, et al. Acute effects of single-dose olanzapine on metabolic,
endocrine, and inflammatory markers in healthy controls. J Clin Psychopharmacol 2013;33:740-6.
60. Suppes T, Dennehy EB, Hirschfeld RM,et al. The Texas implementation of medication algorithms:
update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry 2005;66: 870-86.
61. Grunze H,Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry
(WFSBP) guidelines for the biological treatment of bipolar disorders: update 2009 on the treatment
of acute mania. World J Biol Psychiatry 2009; 10:85-116.
62. Stahl S, Lombardo I, Loebel A, Mandel FS. Efficacy of ziprasidone in dysphoric mania: pooled
analysis of two double-blind studies. J Affect Disord 2010;122:39-45.
analysis of two double-blind studies. J Affect Disord 2010;122:39-45.
63. Lombardo I, Sachs G, Kolluri S, Kremer C, Yang R. Two 6-week, randomized, double-blind,
placebo-controlled studies of ziprasidone in outpatients with bipolar I depression: did baseline
characteristics impact trial outcome? J Clin Psychopharmacol 2012;32:470-8.
64. Suppes T, Eudicone J, McQuade R, Pikalov A 3rd, Carlson B. Efficacy and safety of aripiprazole in
subpopulations with acute manic or mixed episodes of bipolar I disorder. J Affect Disord
2008;107:145-54.
65. Thase ME, Jonas A,Khan A, et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression:
results of 2 randomized, placebo- controlled studies. J Clin Psychopharmacol 2008;28:13-20.
66. Zarate CA Jr, Rothschild A, Fletcher KE, Madrid A, Zapatel J. Clinical predictors of acute response
with quetiapine in psychotic mood disorders. J Clin Psychiatry 2000;61:185-9.
67. Bowden CL, Swann AC, Calabrese JR, et al. A randomized, placebo-controlled, multicenter study of
divalproex sodium extended release in the treatment of acute mania. J Clin Psychiatry 2006;67:1501-
10 .
68. Chengappa KN, Baker RW, Shao L, et al. Rates of response, euthymia and remission in two placebo-
controlled olanzapine trials for bipolar mania. Bipolar Disord 2003;5:1-5.
69. Keck PE Jr, Marcus R, Tourkodimitris S, et al. A placebo- controlled, double-blind study of the
efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry
2003;160:1651-8.
70. Marder SR, Sorsaburu S, Dunayevich E, et al. Case reports of post-marketing adverse event
experiences with olanzapine intramuscular treatment in patients with agitation. J Clin Psychiatry
2010;71:433-41.
71. Keck PE Jr, Mendlwicz J, Calabrese JR, et al. A review of randomized, controlled clinical trials in
acute mania. J Affect Disord 2000;59 suppl 1:S31-S7.
72. Busch FN, Miller FT, Weiden PJ. A comparison of two adjunctive treatment strategies in acute
mania. J Clin Psychiatry 1989;50:453-5.
73. Muller-Oerlinghausen B. Arguments for the specificity of the antisuicidal effect of lithium. Eur Arch
Psychiatry Clin Neurosci 2001;251 suppl 2:II72-5.
74. Bauer MS, Mitchner L. What is a “mood stabilizer”? An evidence-based response. Am J Psychiatry
2004;161:3-18.
75. Ghaemi SN. From BALANCE to DSM-5: taking lithium seriously. Bipolar Disord 2010;12:673-7.
76. Goodwin FK, Whitham EA, Ghaemi SN. Maintenance treatment study designs in bipolar disorder:
do they demonstrate that atypical neuroleptics (antipsychotics) are mood stabilizers? CNS Drugs
2011;25:819-27.
77. Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J, Revicki D. Suicide risk in bipolar
disorder during treatment with lithium and divalproex. JAMA 2003;290:1467-73.
78. Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J. Decreased risk of suicides
and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord 2006;8:625-
39.
79. Cipriani A, Pretty H, Hawton K, Geddes JR. Lithium in the prevention of suicidal behavior and all-
cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J
Psychiatry 2005;162:1805-19.
80. Ahrens B, Muller-Oerlinghausen B. Does lithium exert an independent antisuicidal effect?
Pharmacopsychiatry 2001;34:132-6.
81. Marangell LB, Dennehy EB, Wisniewski SR, et al. Case-control analyses of the impact of
pharmacotherapy on prospectively observed suicide attempts and completed suicides in bipolar
disorder: findings from STEP-BD. J Clin Psychiatry 2008; 69:916-22.
82. Rybakowski JK, Suwalska A. Excellent lithium responders have normal cognitive functions and
plasma BDNF levels. Int J Neuropsychopharmacol 2010;13:617-22.
83. Lyoo IK, Dager SR, Kim JE, et al. Lithium-induced gray matter volume increase as a neural correlate
of treatment response in bipolar disorder: a longitudinal brain imaging study.
Neuropsychopharmacology 2010;35:1743-50.
84. Moore GJ, Cortese BM, Glitz DA, et al. A longitudinal study of the effects of lithium treatment on
prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder
patients. J Clin Psychiatry 2009;70:699-705.
85. Hajek T, Bauer M, Pfennig A, et al. Large positive effect of lithium on prefrontal cortexN-
acetylaspartate in patients with bipolar disorder: 2-centre study. J Psychiatry Neurosci 2012; 37:185-
92.
86. Hajek T, Cullis J, Novak T, et al. Hippocampal volumes in bipolar disorders: opposing effects of
illness burden and lithium treatment. Bipolar Disord 2012;14:261-70.
87. Hajek T, Kopecek M, Hoschl C, Alda M. Smaller hippocampal volumes in patients with bipolar
disorder are masked by exposure to lithium: a meta-analysis. J Psychiatry Neurosci 2012;37:333-43.
88. Konopaske GT, Dorph-Petersen KA, Pierri JN, Wu Q, Sampson AR, Lewis DA. Effect of chronic
exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys.
Neuropsychopharmacology 2007;32:1216-23.
89. Konopaske GT, Dorph-Petersen KA, Sweet RA, et al. Effect of chronic antipsychotic exposure on
astrocyte and oligodendrocyte numbers in macaque monkeys. Biol Psychiatry 2008; 63:759-65.
90. Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term antipsychotic treatment and
brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry
2011;68:128-37 .
91. Mora E, Portella MJ, Forcada I, Vieta E, Mur M. Persistence of cognitive impairment and its
negative impact on psychosocial functioning in lithium-treated, euthymic bipolar patients: a 6-year
follow-up study. Psychol Med 2013;43:1187-96.
92. Baldessarini RJ, Leahy L, Arcona S, Gause D, Zhang W, Hennen J. Patterns of psychotropic drug
prescription for U.S. patients with diagnoses of bipolar disorders. Psychiatr Serv 2007;58:85-91.
93. Kessing LV, Hellmund G, Geddes JR, Goodwin GM, Andersen PK. Valproate v. lithium in the
treatment of bipolar disorder in clinical practice: observational nationwide register-based cohort
study. Br J Psychiatry 2011;199:57-63.
94. Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Pattern of response to divalproex,
lithium, or placebo in four naturalistic subtypes of mania. Neuropsychopharmacology 2002;26:530-6.
95. Lenox RH, Gould TD, Manji HK. Endophenotypes in bipolar disorder. Am J Med Genet
2002;114:391-406.
96. Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex vs lithium and placebo in the
treatment of mania. The Depakote Mania Study Group. JAMA 1994;271:918-24.
98. Baldessarini RJ, Tondo L, Floris G, Hennen J. Effects of rapid cycling on response to lithium
maintenance treatment in 360 bipolar I and II disorder patients. J Affect Disord 2000;61:13-22.
99. Calabrese JR, Rapport DJ, Youngstrom EA, Jackson K, Bilali S, Findling RL. New data on the use of
lithium, divalproate, and lamotrigine in rapid cycling bipolar disorder. Eur Psychiatry 2005;20:92-5.
100. Hirschfeld RM, Allen MH, McEvoy JP, Keck PE Jr, Russell JM. Safety and tolerability of oral
loading divalproex sodium in acutely manic bipolar patients. J Clin Psychiatry 1999; 60:815-8.
101. Kowatch RA, Suppes T, Carmody TJ, et al. Effect size of lithium, divalproex sodium, and
carbamazepine in children and adolescents with bipolar disorder. J Am Acad Child Adolesc
Psychiatry 2000;39:713-20.
102. Suppes T, Baldessarini RJ, Faedda GL, Tondo L, Tohen M. Discontinuation of maintenance
treatment in bipolar disorder: risks and implications. Harv Rev Psychiatry 1993;1:131-44.
103. Goodwin GM. Recurrence of mania after lithium withdrawal. Implications for the use of lithium in
the treatment of bipolar affective disorder. Br J Psychiatry 1994;164:149-52.
104. Cavanagh J, Smyth R, Goodwin GM. Relapse into mania or depression following lithium
discontinuation: a 7-year follow-up. Acta Psychiatr Scand 2004;109:91-5.
105. Severus WE, Kleindienst N, Seemuller F, Frangou S, Moller HJ, Greil W. What is the optimal
serum lithium level in the long-term treatment of bipolar disorder—a review? Bipolar Disord
2008;10:231-7.
106. Tamayo JM, Zarate CA Jr, Vieta E, Vazquez G, Tohen M. Level of response and safety of
pharmacological monotherapy in the treatment of acute bipolar I disorder phases: a systematic
review and meta-analysis. Int J Neuropsychopharmacol 2010;13:813-32.
107. Wagner KD, Ridden L, Kowatch RA, et al. A double-blind randomized, placebo-controlled trial of
divalproex extended- release in the treatment of bipolar disorder in children and adolescents. J Am
Acad Child Adolesc Psychiatry 2009;48: 519-32.
108. Hirschfeld RM, Bowden CL, Vigna NV, Wozniak P, Collins M. A randomized, placebo-controlled,
multicenter study of divalproex sodium extended-release in the acute treatment of mania. J Clin
Psychiatry 2010;71:426-32.
109. Geddes JR, Goodwin GM, Rendell J, et al. Lithium plus valproate combination therapy versus
monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label
trial. Lancet 2010;375:385-95.
110. Nolen WA, Weisler RH. The association of the effect of lithium in the maintenance treatment of
bipolar disorder with lithium plasma levels: a post hoc analysis of a double-blind study comparing
switching to lithium or placebo in patients who responded to quetiapine (Trial 144). Bipolar Disord
2013; 15:100-9.
111. Yatham LN, Paulsson B, Mullen J, Vagero AM. Quetiapine versus placebo in combination with
lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol 2004; 24:599-606
.
112. McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile:
a systematic review and meta-analysis. Lancet 2012;379:721-8.
113. Malhi GS, Berk M. Is the safety of lithium no longer in the balance? Lancet 2012;379:690-2.
Bowden CL, Grunze H, Mullen J, et al. A randomized, double-blind, placebo-controlled efficacy
114. Bowden CL, Grunze H, Mullen J, et al. A randomized, double-blind, placebo-controlled efficacy
and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin
Psychiatry 2005;66:111-21.
115. Patel JK, Buckley PF, Woolson S, et al. Metabolic profiles of second-generation antipsychotics in
early psychosis: findings from the CAFE study. Schizophr Res 2009;111:9-16.
116. Bendz H, Schon F, Attman PO, Aurell M. Renal failure occurs in chronic lithium treatment but is
uncommon. Kidney Int 2010;77:219-24.
117. Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of
randomized, controlled trials. Neuropsychopharmacology 2011;36:375-89.
118. Correll CU, Sheridan EM, DelBello MP. Antipsychotic and mood stabilizer efficacy and
tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute,
randomized, placebo-controlled trials. Bipolar Disord 2010; 12:116-41.
119. Goikolea JM, Colom F, Capapey J, et al. Faster onset of antimanic action with haloperidol
compared to second-generation antipsychotics. A meta-analysis of randomized clinical trials in
acute mania. Eur Neuropsychopharmacol 2013;23:305-16.
120. Tohen M, Zarate CA Jr. Antipsychotic agents and bipolar disorder. J Clin Psychiatry 1998;59 suppl
1:38-48; discussion 9.
121. Zarate CA Jr, Tohen M. Double-blind comparison of the continued use of antipsychotic treatment
versus its discontinuation in remitted manic patients. Am J Psychiatry 2004; 161:169-71.
122. Yatham LN, Maj M. Bipolar disorder: clinical and neurobiological foundations. Chichester, UK:
Wiley, 2010.
123. Gopal S, Steffens DC, Kramer ML, Olsen MK. Symptomatic remission in patients with bipolar
mania: results from a doubleblind, placebo-controlled trial of risperidone monotherapy. J Clin
Psychiatry 2005;66:1016-20.
124. Rendell JM, Gijsman HJ, Bauer MS, Goodwin GM, Geddes GR. Risperidone alone or in
combination for acute mania. Cochrane Database Syst Rev 2006;(1):CD004043.
125. Shafti SS. Olanzapine vs. lithium in management of acute mania. J Affect Disord 2010;122:273-6.
126. Tariot PN, Schneider LS, Cummings J, et al. Chronic divalproex sodium failed to attenuate
agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry 2011;68:853-61.
127. Fleisher AS, Truran D, Mai JT, et al. Chronic divalproex sodium use and brain atrophy in
Alzheimer disease. Neurology 2011;77:1263-71.
128. Pope HG Jr, McElroy SL, Keck PE Jr, Hudson JI. Valproate in the treatment of acute mania. A
placebo-controlled study. Arch Gen Psychiatry 1991;48:62-8.
129. Muller J, Luderer HJ. [DEWIPA—a standardized questionnaire for assessing knowledge about
symptoms, etiology and psychopharmacologic treatment in patients with depressive episodes].
Psychiatr Prax 1999;26:167-70.
130. Reinares M, Rosa AR, Franco C, et al. A systematic review on the role of anticonvulsants in the
treatment of acute bipolar depression. Int J Neuropsychopharmacol 2013;16:485-96.
131. Akdeniz F, Taneli F, Noyan A, Yuncu Z, Vahip S. Valproate- associated reproductive and
metabolic abnormalities: are epileptic women at greater risk than bipolar women? Prog
Neuropsychopharmacol Biol Psychiatry 2003;27:115-21.
132. Liang CS, Yang FW, Lo SM. Rapid development of severe hypertriglyceridemia and
hypercholesterolemia during augmentation of quetiapine with valproic acid. J Clin
hypercholesterolemia during augmentation of quetiapine with valproic acid. J Clin
Psychopharmacol 2011;31:242-3.
133. Behzadi AH, Omrani Z, Chalian M, Asadi S, Ghadiri M. Folic acid efficacy as an alternative drug
added to sodium valproate in the treatment of acute phase of mania in bipolar disorder: a double-
blind randomized controlled trial. Acta Psychiatr Scand 2009;120:441-5.
134. Ketter TA, Kalali AH, Weisler RH. A 6-month, multicenter, open-label evaluation of beaded,
extended-release carbamazepine capsule monotherapy in bipolar disorder patients with manic or
mixed episodes. J Clin Psychiatry 2004;65:668-73 .
135. Versiani M, Cheniaux E, Landeira-Fernandez J. Efficacy and safety of electroconvulsive therapy in
the treatment of bipolar disorder: a systematic review. J ECT 2011;27:153-64.
136. Small JG, Klapper MH, Kellams JJ, et al. Electroconvulsive treatment compared with lithium in the
management of manic states. Arch Gen Psychiatry 1988;45:727-32.
137. Thomas J, Reddy B. The treatment of mania. A retrospective evaluation of the effects of ECT,
chlorpromazine, and lithium. J Affect Disord 1982;4:85-92.
138. McCabe MS, Norris B. ECT versus chlorpromazine in mania. Biol Psychiatry 1977;12:245-54.
139. Geoffroy PA, Etain B, Henry C, Bellivier F. Combination therapy for manic phases: a critical
review of a common practice. CNS Neurosci Ther 2012;18:957-64.
140. Gallego JA, Nielsen J, De Hert M, Kane JM, Correll CU. Safety and tolerability of antipsychotic
polypharmacy. Expert Opin Drug Saf 2012;11:527-42.
141. Ceron-Litvoc D, Soares BG, Geddes J, Litvoc J, de Lima MS. Comparison of carbamazepine and
lithium in treatment of bipolar disorder: a systematic review of randomized controlled trials. Hum
Psychopharmacol 2009;24:19-28.
142. Denicoff KD, Smith-Jackson EE, Disney ER, Ali SO, Leverich GS, Post RM. Comparative
prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. J Clin
Psychiatry 1997;58:470-8.
143. Baethge C, Baldessarini RJ, Mathiske-Schmidt K, et al. Longterm combination therapy versus
monotherapy with lithium and carbamazepine in 46 bipolar I patients. J Clin Psychiatry
2005;66:174-82.
144. Klein E, Bental E, Lerer B, Belmaker RH. Carbamazepine and haloperidol v placebo and
haloperidol in excited psychoses. A controlled study. Arch Gen Psychiatry 1984;41:165-70.
145. Small JG, Klapper MH, Marhenke JD, Milstein V, Woodham GC, Kellams JJ. Lithium combined
with carbamazepine or haloperidol in the treatment of mania. Psychopharmacol Bull 1995;31:265-
72.
146. Perlis RH, Welge JA, Vornik LA, Hirschfeld RM, Keck PE Jr. Atypical antipsychotics in the
treatment of mania: a metaanalysis of randomized, placebo-controlled trials. J Clin Psychiatry
2006;67:509-16.
147. Fountoulakis KN, Vieta E. Efficacy and safety of aripiprazole in the treatment of bipolar disorder:
a systematic review. Ann Gen Psychiatry 2009;8:16.
148. Vieta E, T’joen C, McQuade RD, et al. Efficacy of adjunctive aripiprazole to either valproate or
lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: a
placebo-controlled study. Am J Psychiatry 2008; 165:1316-25.
149. Tsai AC, Rosenlicht NZ, Jureidini JN, Parry PI, Spielmans GI, Healy D. Aripiprazole in the
maintenance treatment of bipolar disorder: a critical review of the evidence and its dissemination
maintenance treatment of bipolar disorder: a critical review of the evidence and its dissemination
into the scientific literature. PLoS Med 2011;8:e1000434.
150. Keck PE Jr, Versiani M, Potkin S, West SA, Giller E, Ice K. Ziprasidone in the treatment of acute
bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry
2003;160:741-8.
151. Potkin SG, Keck PE Jr, Segal S, Ice K, English P. Ziprasidone in acute bipolar mania: a 21-day
randomized, double-blind, placebo-controlled replication trial. J Clin Psychopharmacol
2005;25:301-10.
152. Vieta E, Ramey T, Keller D, English PA, Loebel AD, Miceli J. Ziprasidone in the treatment of
acute mania: a 12-week, placebo-controlled, haloperidol-referenced study. J Psychopharmacol
2010;24:547-58.
153. Sachs GS, Vanderburg DG, Edman S, et al. Adjunctive oral ziprasidone in patients with acute
mania treated with lithium or divalproex, part 2: influence of protocol-specific eligibility criteria on
signal detection. J Clin Psychiatry 2012;73:1420-5.
154. Sachs GS, Vanderburg DG, Edman S, et al. Adjunctive oral ziprasidone in patients with acute
mania treated with lithium or divalproex, part 1: results of a randomized, double-blind, placebo-
controlled trial. J Clin Psychiatry 2012;73:1412-9.
155. Miller S, Ittasakul P, Wang PW, et al. Enhanced ziprasidone combination therapy effectiveness in
obese compared to nonobese patients with bipolar disorder. J Clin Psychopharmacol 2012; 32:814-
9.
156. Patkar A, Gilmer W, Pae CU, et al. A 6 week randomized double-blind placebo-controlled trial of
ziprasidone for the acute depressive mixed state. PLoS One 2012;7:e34757 .
157. Szegedi A, Calabrese JR, Stet L, Mackle M, Zhao J, Panagides J. Asenapine as adjunctive
treatment for acute mania associated with bipolar disorder: results of a 12-week core study and 40-
week extension. J Clin Psychopharmacol 2012;32:46-55.
158. McIntyre RS. Asenapine: a review of acute and extension phase data in bipolar disorder. CNS
Neurosci Ther 2011;17:645-8.
159. McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. Asenapine for long-term
treatment of bipolar disorder: a double-blind 40-week extension study. J Affect Disord 2010;
126:358-65.
160. McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. Asenapine in the treatment of
acute mania in bipolar I disorder: a randomized, double-blind, placebo-controlled trial. J Affect
Disord 2010;122:27-38.
161. McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. A 3-week, randomized,
placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed
states. Bipolar Disord 2009;11:673-86.
162. McElroy SL, Dessain EC, Pope HG Jr, et al. Clozapine in the treatment of psychotic mood
disorders, schizoaffective disorder, and schizophrenia. J Clin Psychiatry 1991;52:411-4.
163. Calabrese JR, Kimmel SE, Woyshville MJ, et al. Clozapine for treatment-refractory mania. Am J
Psychiatry 1996;153:759-64.
164. Barbini B, Scherillo P, Benedetti F, Crespi G, Colombo C, Smeraldi E. Response to clozapine in
acute mania is more rapid than that of chlorpromazine. Int Clin Psychopharmacol 1997;12:109-12.
Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ. Clinical outcome in a randomized 1-
165.
Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ. Clinical outcome in a randomized 1-
year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a
history of mania. Am J Psychiatry 1999;156:1164-9.
166. Melvin CL, Carey TS, Goodman F, Oldham JM, Williams JW Jr, Ranney LM. Effectiveness of
antiepileptic drugs for the treatment of bipolar disorder: findings from a systematic review. J
Psychiatr Pract 2008;14 suppl 1:9-14.
167. Grunze H, Langosch J, Born C, Schaub G, Walden J. Levetiracetam in the treatment of acute
mania: an open add-on study with an on-off-on design. J Clin Psychiatry 2003;64:781-4.
168. Kruger S, Sarkar R, Pietsch R, Hasenclever D, Braunig P. Levetiracetam as monotherapy or add-on
to valproate in the treatment of acute mania—a randomized open-label study. Psychopharmacology
(Berl) 2008;198:297-9.
169. Wagner KD, Kowatch RA, Emslie GJ, et al. A double-blind, randomized, placebo-controlled trial
of oxcarbazepine in the treatment of bipolar disorder in children and adolescents. Am J Psychiatry
2006;163:1179-86.
170. Vieta E, Cruz N, Garcia-Campayo J, et al. A double-blind, randomized, placebo-controlled
prophylaxis trial of oxcarbazepine as adjunctive treatment to lithium in the long-term treatment of
bipolar I and II disorder. Int J Neuropsychopharmacol 2008;11:445-52.
171. Vasudev A, Macritchie K, Vasudev K, Watson S, Geddes J, Young AH. Oxcarbazepine for acute
affective episodes in bipolar disorder. Cochrane Database Syst Rev 2011;(12): CD004857.
172. Kushner SF, Khan A, Lane R, Olson WH. Topiramate monotherapy in the management of acute
mania: results of four double-blind placebo-controlled trials. Bipolar Disord 2006; 8:15-27.
173. Vigo DV, Baldessarini RJ. Anticonvulsants in the treatment of major depressive disorder: an
overview. Harv Rev Psychiatry 2009;17:231-41.
174. Arnone D. Review of the use of topiramate for treatment of psychiatric disorders. Ann Gen
Psychiatry 2005;4:5.
175. Thomas P, Vieta E. Amisulpride plus valproate vs haloperidol plus valproate in the treatment of
acute mania of bipolar I patients: a multicenter, open-label, randomized, comparative trial.
Neuropsychiatr Dis Treat 2008;4:675-86.
176. Berwaerts J, Lane R, Nuamah F, et al. Paliperidone XR as adjunctive therapy to lithium or
valproate in the treatment of acute mania: a randomized, placebo-controlled study. J Affect Disord
2011;129:252-60 .
177. Machado-Vieira R, Soares JC, Lara DR, et al. A doubleblind, randomized, placebo-controlled 4-
week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole
adjunctive to lithium in acute bipolar mania. J Clin Psychiatry 2008;69:1237-45.
178. Fan A, Berg A, Bresee C, Glassman LH, Rapaport MH. Allopurinol augmentation in the outpatient
treatment of bipolar mania: a pilot study. Bipolar Disord 2012;14:206-10.
179. Akhondzadeh S, Milajerdi MR, Amini H, Tehrani-Doost M. Allopurinol as an adjunct to lithium
and haloperidol for treatment of patients with acute mania: a double-blind, randomized, placebo-
controlled trial. Bipolar Disord 2006; 8:485-9.
180. Stolk P, Souverein PC, Wilting I, et al. Is aspirin useful in patients on lithium? A
pharmacoepidemiological study related to bipolar disorder. Prostaglandins Leukot Essent Fatty
Acids 2010;82:9-14.
181. Montgomery P, Richardson AJ. Omega-3 fatty acids for bipolar disorder. Cochrane Database Syst
Rev 2008;(2):CD005169.
Rev 2008;(2):CD005169.
182. Murphy BL, Stoll AL, Harris PQ, et al. Omega-3 fatty acid treatment, with or without cytidine,
fails to show therapeutic properties in bipolar disorder: a double-blind, randomized add-on clinical
trial. J Clin Psychopharmacol 2012;32:699-703.
183. Yildiz A, Guleryuz S, Ankerst DP, Ongur D, Renshaw PF. Protein kinase C inhibition in the
treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch Gen Psychiatry
2008;65:255-63.
184. Kulkarni J, Garland KA, Scaffidi A, et al. A pilot study of hormone modulation as a new treatment
for mania in women with bipolar affective disorder. Psychoneuroendocrinology 2006;31:543-7.
185. Zarate CA Jr, Singh JB, Carlson PJ, et al. Efficacy of a protein kinase C inhibitor (tamoxifen) in
the treatment of acute mania: a pilot study. Bipolar Disord 2007;9:561-70.
186. Amrollahi Z, Rezaei F, Salehi B, et al. Double-blind, randomized, placebo-controlled 6-week study
on the efficacy and safety of the tamoxifen adjunctive to lithium in acute bipolar mania. J Affect
Disord 2011;129:327-31.
187. Gilmer WS, Zarnicki JN. Review of transcranial magnetic stimulation for bipolar disorder.
Psychopharm Rev 2012; 47:25-30.
188. Yatham LN1, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments
(CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of
CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar
Disord 2013;15:1-44.
189. Goodwin GM; Consensus Group of the British Association for Psychopharmacology. Evidence-
based guidelines for treating bipolar disorder: revised second edition—recommendations from the
British Association for Psychopharmacology. J Psychopharmacol 2009;23:346-88.
190. Suppes T, Dennehy EB, Hirschfeld RM, et al.; Texas Consensus Conference Panel on Medication
Treatment of Bipolar Disorder. The Texas implementation of medication algorithms: update to the
algorithms for treatment of bipolar I disorder. J Clin Psychiatry 2005;66:870-86.
n the last five years since the publication of this algorithm, the
recommendations and flowchart remain mostly the same. There have
been no new studies that seem to change the overall sequences of the
nodes. However, there have been a variety of studies usually adding support
to what was proposed in the 2014 algorithm, but sometimes making
adjustments to the risk to benefit analysis for certain recommendations.
There is one new medication approved for acute mania—cariprazine in
2015 (a second-generation antipsychotic, previously approved for
schizophrenia). Also, there have been some new developments that if
confirmed and expanded by more studies might result in changes to the
algorithm.
New data have emphasized the prognostic significance of a first attack of
mania and the importance of evidence-supported treatment. In a review of
eight studies, the rate of recurrence of mania after a first episode over the
next four years was 60%. 1 Younger age of onset was associated with
higher recurrence rates. Other evidence (mentioned in the original
algorithm) suggests early and adequate treatment can improve outcome.
The new data highlight the prognostic importance of a single manic episode
and that it should be taken seriously. There was also an editorial worth
noting that cautioned against contributing to the development of “the
malignant transformation of bipolar disorder” into a disabling and rapid
cycling condition through application of less than an expert level of care
following the onset of the disorder. 2 The author (Robert Post, who
contributed to formulating the “kindling” model of how bipolar disorder
can progress) argued that the comparison with cancer was appropriate
because of the high suicide rate in bipolar disorder.
Node 1: Diagnosis and Other Features in Mania That Might
Affect the Algorithm
In Table 1 , there is a discussion of considerations for women of child-
bearing potential. In a recent large National Institute of Mental Health-
sponsored study of the risk of cardiac malformations including Ebstein’s
abnormality, data emerged that provided a more precise measure of what
can be expected. The researchers found that the adjusted risk ratio for any
cardiac abnormality was 1.65 compared to unexposed babies. 3 For
Ebstein’s, the risk ratio was 2.66, and in absolute numbers it was 0.6% for
lithium-exposed infants versus 0.18% for those not exposed. The impact
was dose-related, with higher ratios if the dose was over 900 mg daily.
These results were included in a meta-analysis of 13 high-quality studies
published in January 2020. 4 This analysis found the odds ratio for any
cardiac abnormality to be slightly higher—1.86. The risk was limited to
fetuses exposed in the first trimester. The absolute risk was 1.2% for any
cardiac abnormality. Note that these comparisons are with women with
bipolar disorder who did not receive lithium, not with the general
population of pregnant women. The fetuses of nonbipolar women have
fewer cardiac abnormalities. The studies were generally unclear about
whether they excluded women who were on other teratogenic medications
or were misusing any substances like alcohol. The authors concluded that
the risks of lithium exposure during pregnancy are low, though they are
higher in the first trimester and doses should be kept in the lowest part of
the therapeutic range especially during that time. The risks and harms
associated with mood episode relapse from stopping lithium or lowering the
level below the therapeutic range appear, for most women, to far exceed the
harms of fetal abnormalities or other pregnancy complications associated
with continuing lithium.
In the same row, we discussed the severe teratogenicity of valproate for
women of childbearing potential and suggested it should be nearly a last
choice for treating mania in such women. An editorial in 2017 strongly
confirmed that recommendation. 5
Finally, in this row, there were old citations suggesting a relatively
favorable impression of using electroconvulsive therapy (ECT) for pregnant
women with bipolar disorder. However, a study compiling all known case
reports of use of ECT as of 2015 found that there was a surprising and
concerning 7% mortality rate in the fetuses. 6 ECT should now be
considered a last resort and certainly riskier than previously thought.
Node 2d: The First-Line Treatment for Nonmixed, Classic
Mania Is Still Lithium
In addition to all the reasons given in the algorithm paper, there are some
new citations confirming the remarkable and unique neuroprotective effects
of lithium that should be added. 7 , 8
Node 3: What to Add to Lithium If the Response Is
Unsatisfactory in Classic Mania
Nothing is changed here, but there is a new citation of work by Goikolea
and colleagues adding support to the contention that use of haloperidol is
ill-advised because of the very high rate of haloperidol-treated patients
slipping into depression after resolution of the mania. 9
Node 5: First-Tier Next Options After Three Trials and
Unsatisfactory Response in Acute Mania
Cariprazine was approved in 2015 for acute mania and mixed mania at
doses of 3 to 6 mg once daily. 10 It is a partial dopamine agonist, like
aripiprazole and brexpiprazole. There has been little attention paid to it and
many pharmacy benefit managers have not been including it in their
formularies because new products have high costs. However, it does add to
the relatively few options for mania that are mild in weight gain and
metabolic side effects. It seemed reasonable to add it as one of the options
at Node 5. However, the latest development is that it was also approved by
the FDA for acute bipolar depression, in June 2019 based on four studies,
three published so far, and three that were positive for the product. 11 The
approved doses were 1.5 and 3 mg, with the 1.5 mg dose appearing to be
best in benefit to harm ratio.11 It now joins quetiapine as one of only two
medications specifically approved for both acute bipolar depression and
acute mania. However, the best dose for depression is significantly lower
than the best doses for mania, so it is unclear how much mania protection is
going to be afforded by the antidepressant dose, and it is unclear if the
initial treatment with a high dose for mania is going to have a preventive
effect on subsequent depressions and be tolerable over the long term. More
research and experience are needed before a firmer and higher spot on the
algorithm can be considered for cariprazine. However, the advantage in
weight gain could influence patients and their clinicians to want to consider
it earlier if it is available.
Table 1 : Comorbidity and Other Features in Mania and How
They Affect the Algorithm
There is a brief discussion of substance use disorders as a comorbidity in
mania and the recommendation is that remission from those use disorders
should be a high treatment priority. We did not mention cannabis as one of
the substances that could be a concern. The evidence available points
clearly to an association between usage and worsening course of bipolar
disorder over time. In a study of 4915 subjects, Henquet and colleagues
(after control for many possible covariates) found a strong increased risk of
manic symptoms associated with the use of cannabis over a three-year
follow-up period. 12 They also found an earlier age of onset of bipolar
disorder, greater overall illness severity, more rapid cycling, poorer life
functioning, and poorer adherence with prescribed treatments. Zorrilla and
colleagues evaluated the subsequent course of bipolar patients who stopped
cannabis use after an illness episode, and compared their outcome with
bipolar patients who never had used cannabis and a group that continued to
use. 13 The total sample was 1922 patients. In a two-year period, the
continued users had significantly lower rates of recovery, greater work
impairment, and lower rates of living with a partner. The data were based
on patient reports, so given likely underreporting, there was probably an
underestimate of the strength of the association between cannabis use and
lives worsened. A systematic review of the effects of cannabis on mood and
anxiety disorders confirmed a negative association between cannabis use
and long-term outcomes. 14 Thus, it seems that bipolar patients should stay
away from cannabis in all its forms. Quitting cannabis should be on the
short list of interventions to pursue if patients are not doing well. This is a
tough sell in today’s political environment regarding cannabis legalization.
Many newspaper editorials and politicians are pushing it. Clinicians should
not back off and accept patients’ insistence on using this product but rather
should continue efforts to educate and to consider the problem to be a
serious one that potentially interferes with otherwise appropriate and
effective bipolar treatments that may be offered.
Table 2 : New and Experimental Treatments Proposed for
Acute Mania
One intriguing proposed addition to this list is the use of probiotic
microorganisms that might modulate inflammatory mechanisms
contributing to the pathophysiology of bipolar disorder. A pilot
randomized, placebo-controlled trial in 66 recently hospitalized manic
patients found fewer rehospitalization days for the probiotic treatment
group compared to placebo over 24 weeks (2.8 vs. 8.3 days, p = .017). 15
This clearly needs replication and extension, and the specific probiotics
used may or may not be the only ones that could be effective.
Another interesting direction for research stems from the fact that light
therapy can help depression. Could dark therapy help mania? A study of 23
patients hospitalized for mania were randomized to wear orange-tinted
blue-light-blocking glasses or clear glasses from 6 PM to 8 AM for seven
nights. 16 Retinal ganglion cells contain melanopsin, which is blue light
sensitive, and these cells convey daylight information to the brain. It was
proposed that the blue-light-blocking glasses could be equivalent to the
effect of total darkness but still enable the person to see enough to
participate in activities. The blue-blocking glasses caused a dramatic 14-
point drop in YMRS compared to 2 points with the control glasses. All
patients were also on standard pharmacotherapy.
REFERENCES
1. Gignac A, McGirr A, Lam RW, Yatham LN. Recovery and recurrence following a first episode
of mania: a systematic review and meta-analysis of prospectively characterized cohorts. J Clin
Psychiatry 2015;76:1241-8.
2. Post RM. Preventing the malignant transformation of bipolar disorder. JAMA 2018;319:1197-8.
3. Patorno E, Huybrechts KF, Bateman BT, et al. Lithium use in pregnancy and the risk of cardiac
malformations. N Engl J Med 2017;376:2245-54.
4. Fornaro M, Maritan E, Ferranti R, et al. Lithium exposure during pregnancy and the postpartum
period: a systematic review and meta-analysis of safety and efficacy outcomes. Am J Psychiatry
2020;177:76-92.
5. Balon R, Riba M. Should women of childbearing potential be prescribed valproate? A call to
action. J Clin Psychiatry 2016;77:525-6.
6. Leiknes KA, Cooke MJ, Jarosch-von Schweder L, Harboe I, Hoie B. Electroconvulsive therapy
during pregnancy: a systematic review of case studies. Arch Womens Ment Health 2015;18:1-
39.
7. Giakoumatos CI, Nanda P, Mathew IT, et al. Effects of lithium on cortical thickness and
hippocampal subfield volumes in psychotic bipolar disorder. J Psychiatr Res 2015;61:180-7.
8. Gildengers AG, Butters MA, Aizenstein HJ, et al. Longer lithium exposure is associated with
better white matter integrity in older adults with bipolar disorder. Bipolar Disord 2015;17:248-
56.
9. Goikolea JM, Colom F, Torres I, et al. Lower rate of depressive switch following antimanic
treatment with second-generation antipsychotics versus haloperidol. J Affect Disord
2013;144:191-8.
2013;144:191-8.
10. Calabrese JR, Keck PE Jr, Starace A, et al. Efficacy and safety of low- and high-dose
cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind,
placebo-controlled study. J Clin Psychiatry 2015;76:284-92.
11. Citrome L. Cariprazine for bipolar depression: what is the number needed to treat, number
needed to harm and likelihood to be helped or harmed? Int J Clin Pract 2019;73:e13397.
12. Henquet C, Krabbendam L, de Graaf R, ten Have M, van Os J. Cannabis use and expression of
mania in the general population. J Affect Disord 2006;95:103-10.
13. Zorrilla I, Aguado J, Haro JM, et al. Cannabis and bipolar disorder: does quitting cannabis use
during manic/mixed episode improve clinical/functional outcomes? Acta Psychiatr Scand
2015;131:100-10.
14. Mammen G, Rueda S, Roerecke M, Bonato S, Lev-Ran S, Rehm J. Association of cannabis
with long-term clinical symptoms in anxiety and mood disorders: a systematic review of
prospective studies. J Clin Psychiatry 2018;79.
15. Dickerson F, Adamos M, Katsafanas E, et al. Adjunctive probiotic microorganisms to prevent
rehospitalization in patients with acute mania: a randomized controlled trial. Bipolar Disord
2018;20:614-21.
16. Henriksen TE, Skrede S, Fasmer OB, et al. Blue-blocking glasses as additive treatment for
mania: a randomized placebo-controlled trial. Bipolar Disord 2016;18:221-32.
A
The Psychopharmacology Algorithm Project at the
Harvard South Shore Program: An Update on
Unipolar Nonpsychotic Depression
Christoforos Iraklis Giakoumatos, MD and David Osser, MD
Background: The Psychopharmacology Algorithm Project at the Harvard South Shore Program
presents evidence-based recommendations considering efficacy, tolerability, safety, and cost. Two
previous algorithms for unipolar nonpsychotic depression were published in 1993 and 1998. New
studies over the last 20 years suggest that another update is needed.
Methods: The references reviewed for the previous algorithms were reevaluated, and a new
literature search was conducted to identify studies that would either support or alter the previous
recommendations. Other guidelines and algorithms were consulted. We considered exceptions to the
main algorithm, as for pregnant women and patients with anxious distress, mixed features, or
common medical and psychiatric comorbidities.
Summary: For inpatients with severe melancholic depression and acute safety concerns,
electroconvulsive therapy (or ketamine if ECT refused or ineffective) may be the first-line treatment.
In the absence of an urgent indication, we recommend trialing venlafaxine, mirtazapine, or a
tricyclic antidepressant. These may be augmented if necessary with lithium or T3 (triiodothyronine).
For inpatients with non-melancholic depression and most depressed outpatients, sertraline,
escitalopram, and bupropion are reasonable first choices. If no response, the prescriber (in
collaboration with the patient) has many choices for the second trial in this algorithm because there
is no clear preference based on evidence, and there are many individual patient considerations to
take into account. If no response to the second medication trial, the patient is considered to have a
medication treatment-resistant depression. If the patient meets criteria for the atypical features
specifier, a monoamine oxidase inhibitor could be considered. If not, reconsider (for the third trial)
some of the same options suggested for the second trial. Some other choices can also considered at
this stage. If the patient has comorbidities such as chronic pain, obsessive-compulsive disorder,
attention-deficit/hyperactivity disorder, or posttraumatic stress disorder, the depression could be
secondary; evidence-based treatments for those disorders would then be recommended.
s reported by the World Health Organization in its 2004 update on the global
burden of disease, unipolar nonpsychotic depression was the third largest
cause of disease burden worldwide. 1 It was the eighth largest cause of
disease burden in low-income countries and the largest cause in middle- and
high-income countries. Around the same time, a United States national
household survey showed that 6.7% of adults had experienced a major
depressive episode in the previous 12 months. 2 In 2016, Olfson and colleagues 3
showed that 8.4% of adults in the United States screened positively for
depression but that only 28.7% received any treatment even if they had visited
their primary care provider within the previous year. When treated, the modality
was an antidepressant 87% of the time. The primary care system may have the
best opportunity to diagnose and treat depression.
Kessler and colleagues2 reported that the lifetime prevalence of depression
was 16.2%. Their group showed that just 51.6% of the depressed patients
received treatment and that, among them, only 41.9% were adequately treated.
Furthermore, approximately 50% of depressed patients failed to achieve
response to the first adequate trial of an antidepressant agent.
The efficacy of antidepressants has been a subject of debate. Unpublished
negative studies, when included in metaanalyses, have markedly lowered effect
sizes. 4 Kirsch and colleagues 5 , 6 reviewed the data and reported that the overall
efficacy of the new-generation antidepressants is below the National Institute for
Health and Care Excellence criteria for clinical relevance. Investigators
challenged this study and considered the Kirsch analysis to be flawed; many
methodological weaknesses of antidepressant trials have been identified. 7 , 8
Most experts think that antidepressants do work moderately well in properly
selected patients entered into well-conducted trials. 9 Among the poorer
responders are the following: patients with subthreshold depression (i.e., not
fully meeting Diagnostic and Statistical Manual of Mental Orders [DSM]
criteria); 10 patients whose depression is secondary to intense dyadic discord
(stress or conflict within an important or intimate relationship); 11 patients with
bipolar spectrum depressions (including those with mixed features), 12 , 13
anxious distress, 14 or onset in the context of some debilitating medical illnesses.
15 Also, the Sequenced Alternatives to Relieve Depression (STAR*D) study
found that response to antidepressants and their augmentations diminishes with
successive trials having unsatisfactory response. 16 Therefore, to get the best
results with medication, clinicians should start with an accurate diagnosis and
consider important predictors of response. Clinical experience will likely be an
insufficient basis for decision making, given the high placebo response in many
depressed patient populations. An analysis of four long-term, placebo-controlled
antidepressant trials suggested that the great majority of relapses in patients who
continued to take their antidepressants were in the patients whose initial
response was a placebo effect. 17 The clinician may remember the positive initial
effect and fail to notice or not be around when the treatment fails, with the
clinician therefore prescribing the same ineffective treatment over and over.
Michael O’Donnell, former editor of the British Medical Journal, offered a
definition of clinical experience: “making the same mistakes over and over with
increasing confidence over an impressive number of years.” 18
Evidence-supported psychopharmacology algorithms could simplify the
process of choosing medications, especially for clinicians, such as primary care
physicians, not strongly familiar with the evidence base. 19 Algorithms are more
prescriptive than guidelines and easier to incorporate into practice. The need for
such algorithms can be better appreciated when taking into account the study
done by Observational Health Data Sciences and Informatics, which is an
international collaboration of more than 120 researchers from 12 countries. 20
They looked at the medical records of 250 million patients treated for depression
and found hundreds of different sequences of first, second, and third
antidepressants used by various prescribers. Eleven percent of patients with
depression had a treatment pathway that was unique. Algorithm-guided
treatment could help minimize this gross level of practice variation in clinical
care and improve clinical outcomes by achieving remission in shorter amounts
of time and with fewer medication changes than with treatment as usual. 21 , 22
Also, algorithms have the potential to produce more cost-effective results if
generic options are recommended over more expensive, brand-name products
when there is no apparent disadvantage in outcome or safety.
Since 1995, the Psychopharmacology Algorithm Project at the Harvard South
Shore Program (PAPHSS) has been creating evidence-derived treatment
algorithms. Seven peer-reviewed PAPHSS algorithms have been published and
can be accessed through a publicly available website (www.psychopharm.mobi
). This article updates previous versions of algorithms for unipolar nonpsychotic
depression, as published by one of the authors (DO).
This and all the other PAPHSS algorithms focus on psychopharmacological
treatment, but this focus should not be taken to suggest that the authors do not
consider psychotherapeutic or other nonpharmacological treatments for
depression unimportant. Indeed, in many cases, psychotherapy could be first-line
or combined at any point with pharmacotherapy. 23 The intention is only to
suggest, if psychopharmacology is chosen as a treatment approach, what would
be the best-supported and safest options for the first, second, and further trials,
and what considerations would alter these preferences.
http://www.psychopharm.mobi
METHODS
Prior publications have described the PAPHSS methods of algorithm
development. 24 – 29 The algorithms are created in a way to simulate a curbside
psychopharmacological consultation. They present a series of questions
describing the clinical situation (diagnoses and history of previous treatment)
that the consultant might ask. Then, recommendations are made that are derived
from an analysis of the literature pertinent to that clinical scenario. The authors
reviewed their previously published unipolar nonpsychotic depression
algorithms,19 , 30 consulted other recent algorithms and guidelines, 31 – 34 and
focused on key randomized, controlled trials (RCTs), especially recent ones not
considered in previous reviews. In constructing the decision tree, the authors
considered efficacy, tolerability, safety, and cost as the main bases for
prioritizing treatments. All recommendations were the result of agreement by the
two authors. Their conclusions were opinion-based distillations of the body of
evidence reviewed—which could be subject to conflicting interpretations by
other experts. However, the peer review process that follows initial submission
of the article adds some validation to the reasoning in this algorithm and other
PAPHSS algorithms. If the reasoning, based on the authors’ interpretation of the
pertinent evidence, is plausible to reviewers, then it is retained. When
differences of opinion occur, the authors make adjustments to achieve consensus
with the reviewers or probe the relevant evidence further in order to present a
stronger argument in support of their position. At each decision point, different
but approximately equivalent options are offered for consideration, enabling
prescribers to select what seems best and most acceptable to the patient in each
particular clinical situation.
FLOWCHART FOR THE ALGORITHM
A summary and overview of the algorithm appears in Figure 1 . Each “node”
represents a clinical scenario where a treatment choice must be made. The
algorithm delineates patient populations ranging from those beginning treatment
to those, at the end, who are highly treatment resistant. The questions, evidence
review, and reasoning that support the recommendations at each node will be
presented below .
Figure 1. Flowchart of the algorithm for nonpsychotic unipolar depression. ECT, electroconvulsive
therapy; MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitors; T3 ,
triiodothyronine; TCA, tricyclic antidepressant; TMS, transcranial magnetic stimulation. *Inpatients
without melancholia and outpatients with or without melancholia.
NODE 1: DIAGNOSIS OF UNIPOLAR
NONPSYCHOTIC DEPRESSION
NONPSYCHOTIC DEPRESSION
The treatment recommendations of this algorithm apply only to patients who
have been diagnosed with unipolar nonpsychotic depression based on the DSM-
5 criteria. 35 Though the validity of these criteria may be questioned, the
psychopharmacology evidence base is almost entirely tied to these criteria. One
can only speculate about the psychopharmacological responsiveness of
depressions diagnosed in other ways. Notably, treatment recommendations may
differ depending on the specifier of the depressive disorder (with anxious
distress, atypical features, mixed features, melancholic features, or seasonal
pattern). 36 We will discuss these recommendation differences at appropriate
points in the algorithm. The default recommendations apply to patients with no
specifiers or significant comorbidities.
Table 1 presents considerations and recommendations when some frequently
encountered medical and psychiatric comorbidities or other circumstances are
present that could change the basic algorithm recommendations. In cases with
significant medical conditions, it is advised that care be coordinated among the
different specialists involved in the patient’s care.
Table 1 | Comorbidity and Other Features in Major Depression and How
They Affect the Algorithm
Comorbidity and
other
circumstances
Considerations Recommendations
Coronary artery
disease
Untreated depression worsens
prognosis in cardiovascular disease 37
SSRIs may protect against myocardial
infarction15
Data with sertraline indicated that
effectiveness is limited to patients with
a history of major depressions that
predated the onset of the CAD 38
Escitalopram was shown to be safe and
effective for depression in patients with
CAD, but the relationship with time of
onset of the depression was not
evaluated 39
Chronic kidney
disease
Sertraline might not be effective in
patients with CKD not requiring
dialysis 40
Skip Node 4 and go directly to Node
4B
Cardiac
arrhythmias
TCAs and MAOIs may cause cardiac
arrhythmias due to their effects on
cardiac sodium and potassium channels
41
Avoid TCAs and MAOIs
EKG monitoring of TCA-treated
patients is a more accurate way to
detect toxicity than plasma-level
monitoring
Sertraline appears to be safe in patients
at risk of arrhythmia following
myocardial infarction38
We do not recommend citalopram,
because of concerns about QTc
prolongation 42
Gastrointestinal
bleeding
SSRIs increase hemorrhage risk
Gastrointestinal bleeding can be
increased 9-fold by
SSRIs combined with NSAIDs 43
Other antidepressants such as
mirtazapine and bupropion are not well
studied but may not be safer 44
Adding proton-pump inhibitors such as
omeprazole decreases the risk to only
slightly above controls not on SSRIs43
Older adults
(greater than
65 years of age)
SSRIs may increase risk of bleeding;
however, in a Cochrane meta-analysis
of poststroke patients, bleeding risk
was nonsignificant 45
SSRIs and venlafaxine are associated
with higher rates of hyponatremia
secondary to SIADH in older adults; 46
in a meta-analysis of 15 RCTs,
venlafaxine and duloxetine were
associated with increased risk of
dizziness in the elderly compared to
SSRIs; 47 SSRIs, TCAs, and other
antidepressant classes have been
associated with increased risk of falls,
particularly in frail older women 48
Right, unilateral, ultra-brief ECT has
been shown to have good efficacy and
favorable tolerability in older adults
with severe depression 49
Evidence to support the effectiveness
Consider side-effect profiles of
antidepressant medications prior to
initiation or titration in elderly adults
In patients with intolerable
hyponatremia secondary to SSRI use,
consider mirtazapine46
Consider ECT, particularly right
unilateral ultra-brief ECT, in older
adults with severe depression
Risks and benefits of adding
methylphenidate to an SSRI in
treatment-resistant depression in the
elderly should be carefully considered,
in light of limited evidence of efficacy
and FDA black-box warning.
Evidence to support the effectiveness
of methylphenidate as an adjuvant to
SSRIs in treatment-resistant depression
is limited; 50 additionally,
methylphenidate carries an FDA black-
box warning for increased
cardiovascular mortality 51
Women of
childbearing
potential and
pregnant women
About 10% of pregnant women will
experience
depression 52
Untreated or suboptimally treated
depression during pregnancy leads to
poor adherence with prenatal care
Relapse of major depressive disorder
during pregnancy is common (43%)
and can occur significantly more often
in women who discontinued their
medication just prior to conception or
during early stages of the pregnancy 53
Patients on antidepressants at high risk
of relapse are best maintained on an
antidepressant during and after
pregnancy
Risk of exposure to medications must
be weighed against the risks of
untreated depression, which can affect
both mother and child
Late exposure (after 20th week of
pregnancy) is associated with increased
risk of prematurity, postpartum
hemorrhage, 54 and persistent
pulmonary hypertension of the
newborn; 55 these could be due to
confounding by indication
SSRI use during pregnancy may
increase risk for speech, language, and
motor disorders; 56 again, there could
be confounding by indication
Avoid paroxetine because of risk of
atrial septal defects (odds ratio = 1.8
[95% CI, 1.1–3.0]); 57 if already on it,
consider risks involved with switching
Depression with
mixed features
This new specifier in DSM-5 is for
patients with three comorbid manic
symptoms on most days of the
depression; most commonly, these
include racing thoughts, pressured
speech, decreased need for sleep, and
increased energy
Bipolar depression must be ruled out
(by past history of hypomania or
mania, though this history is easy to
miss); bipolar depression would
involve a different treatment algorithm
26
Only one randomized, controlled study
of a medication for this new diagnostic
category exists: lurasidone was more
effective than placebo (number needed
to treat = 3), especially if there were
only two manic features (effect size =
1.0) rather than three, as required in
DSM-5 (effect size = 0.5) 59
In the absence of evidence of
effectiveness of other (usually less
expensive) medications for major
depression with mixed features, and
given the robust benefit shown in this
26
Unipolar depression with mixed
features may be an intermediate
condition on a spectrum from unipolar
to bipolar disorder or may be indicative
of a patient who is going to become
bipolar at some point
Antidepressants seem much less
effective for mixed states and are
potentially harmful especially if the
patient has an underlying bipolar
disorder.12 , 58
given the robust benefit shown in this
study, the recommendation at this time
is lurasidone, despite the cost
Depression with
anxious distress
or high levels of
anxiety
STAR*D and other studies find this
situation to be common and associated
with poorer response to antidepressants
and most augmenters14
Sedating atypical antipsychotics such
as quetiapine can be effective as
monotherapy or as augmenters of
antidepressants, though with
considerable side-effect burden; 60 , 61
aripiprazole is effective as an
augmenter36
NODE 2: IS THIS AN INPATIENT WITH SEVERE
MELANCHOLIC DEPRESSION?
Having diagnosed the patient with a DSM-5 major depression and having
considered the comorbidities and conditions in Table 1 that might change the
basic algorithm, the next step to further differentiate treatment is to determine if
the patient is hospitalized with severe depression and the melancholia specifier.
The specifier requires that the patient have both prominent loss of pleasure and
reactivity to usually pleasurable stimuli and additional somatic manifestations,
including psychomotor agitation or retardation, weight loss, diurnal variation
(worse in morning), and excessive guilt.
Some evidence indicates that such inpatients require different somatic and
pharmacological therapy than other inpatients with non-melancholic depression
and outpatients with either melancholic or non-melancholic depression.
Evidence suggests, for example, that inpatients with melancholia respond less
well to selective serotonin reuptake inhibitors (SSRIs) than tricyclic
antidepressants (TCAs). 62 Evidence of good efficacy in these inpatients is also
available for venlafaxine and mirtazapine—agents with dual actions that include
norepinephrine reuptake inhibition, like TCAs. 63 In outpatients with the
melancholia specifier, however, meta-analyses have found no difference
between the efficacy of SSRIs and TCAs. Hence, a different algorithm is
proposed for these inpatients, though it does not always start with medication.
NODE 3: IN TREATING A PATIENT WITH
SEVERE MELANCHOLIC DEPRESSION, IS
THERE AN URGENT INDICATION FOR ECT?
Node 3A: If Yes, ECT or Ketamine
Electroconvulsive therapy (ECT) is urgently indicated in patients with severe
suicidality, catatonia, insufficient oral intake, or medical conditions (e.g.,
pregnancy) that may limit the use of psychotropics. Therefore, before
considering any medication, severely ill melancholic patients at acute risk of
suicide should be considered for ECT. The Consortium for Research in ECT
reported a 75% remission rate among 217 patients who completed a short course
of ECT during an acute episode of depression, with 65% of patients having
remission by the fourth week of therapy. 64 Despite this strong evidence of
effectiveness, cognitive side effects such as amnesia, which are commonly
reported as adverse effects of ECT, may influence patients’ decisions to accept
it. 65 Several studies have failed to show a difference in effectiveness between
high-dose right unilateral ECT and bilateral ECT, and have indicated that
unilateral electrode placement on the right side is associated with a lower
incidence of cognitive side effects. 66 , 67 Patients with the longest episodes of
depression may be the most likely to respond to ECT. 68
As previously mentioned, ECT is the treatment of choice for inpatients with
severe melancholic depression at imminent risk of suicide. If the patient refuses
a trial of ECT or if such is unsuccessful, however, ketamine can be considered. 69
Some evidence suggests that ketamine can produce desirable rapid results, even
within an hour, but such results may be shortlived.69 – 71 Maintenance studies
have not been done. The use of ketamine for this indication is not yet approved
by the U.S. Food and Drug Administration (FDA). In this clinical scenario,
however—with an imminent risk of self-harm, with contraindications for ECT,
with the patient refusing ECT, or with ECT’s having been unsuccessful—
ketamine can be considered and may be acceptable to the patient as a bridging
therapy to lower the acute suicidal risk and help stabilize the patient until
another form of treatment can be administered. It should be noted that the
benefits of ketamine may not be limited to suicidal depressed patients with
melancholia; there is at least one report of response in a nonsuicidal melancholic
patient. 72
Node 3B: If No, Try Venlafaxine, Mirtazapine, or a TCA
If an inpatient with severe melancholia does not have an urgent indication for
ECT or ketamine, the first-line psychopharmacology recommendation options
are (as noted above) venlafaxine, mirtazapine, or a TCA. The last of these may
be preferred because of their evidence of superiority to placebo and SSRIs for
treating inpatients with melancholic depression.62 TCAs, however, come with
potential cardiac-conduction side effects, and the risk of death from overdose is
greater than with other agents. 73 , 74
Venlafaxine also shows some evidence of effectiveness in this type of
depression. Benkert and colleagues 75 reported a significantly faster response and
a significant difference in the proportion of sustained responders when
venlafaxine was compared to imipramine in inpatients with melancholia. Since
venlafaxine has a risk of increase in blood pressure, blood pressure needs to be
monitored in patients taking this agent, and the risk of death by overdose is
higher than with SSRIs.74 The effectiveness of venlafaxine in hospitalized
patients with melancholic depression was further supported by Guelfi and
colleagues, 76 who reported a significantly greater response rate of venlafaxine
compared to placebo.
A multicenter, randomized, double-blind study in hospitalized, severely
depressed patients with melancholic features compared the efficacy of
mirtazapine and venlafaxine. Although the differences were not statistically
significant, mirtazapine produced more responders and remitters than
venlafaxine, and with fewer dropouts due to adverse events.63 Notably, the mean
daily doses used in this study were high (49.5 ± 8.3 mg/day for mirtazapine and
255.0 ± 59.8 mg/day for venlafaxine).
Thus, mirtazapine, venlafaxine, and TCAs can be effective for treating
inpatients with severe melancholic depression. We consider mirtazapine and
venlafaxine to be preferred, however, due to their better tolerability and safety
profiles compared to TCAs.
Augmentation, the addition of an agent to an antidepressant regimen in order
to improve efficacy, 77 is also a potential option. Two well-studied augmenters of
TCAs are lithium and T3 (triiodothyronine). A meta-analysis of ten placebo-
controlled studies found that lithium augmentation of TCAs was significantly
more effective than placebo augmentation. 78 Two meta-analyses of T3
augmentation showed enhanced response of patients who did not fully respond
to a trial of TCAs alone. 79 , 80
The data for lithium or T3 augmentation of SSRIs is not as convincing as their
evidence in TCA augmentation. In the STAR*D study, remission rates following
lithium and T3 augmentation of citalopram were not very robust and did not
differ significantly, though a trend favored T3 (25% remissions vs. 15% with
lithium). 81 Rapid effects are sometimes observed in T3 and lithium
augmentation of TCAs, but this effect does not seem to occur to the same degree
with SSRIs. 82 The lower adverse effects and ease of administration of T3
augmentation give it a slight advantage over lithium augmentation as a choice at
this point.
Since TCAs and the dual-action agents with noradrenergic properties are the
recommended first-line treatments for severely ill inpatients with melancholia,
the preference for augmenters is centered on agents that have a good evidence
base for augmenting TCAs—namely, lithium and T3. Their effect as augmenters
for the dual-action agents must be considered speculative, however, in that no
controlled trials are available for these specific combinations.
NODE 4: IN TREATING OUTPATIENTS WITH
DEPRESSION, HAS THE PATIENT HAD AN
ADEQUATE TRIAL OF SERTRALINE,
ESCITALOPRAM, OR, IF PATIENT DOES NOT
WANT TO RISK HAVING SSRI-RELATED
SEXUAL SIDE EFFECTS, BUPROPION?
Node 4A: If No, Proceed with Trial
If the patient is not an inpatient with severe melancholic depression, you arrive
at Node 4 (see Figure 1 ). This is where the rest of the population of depressed
patients can be found, including all outpatients (even if having the melancholic
specifier) and other depressed inpatients without melancholia. If none of the
comorbidity and other circumstances described in Table 1 apply, then the first-
line recommendation for pharmacotherapy of these patients is an SSRI. 32 , 83 – 90
Cipriani and colleagues, 91 , 92 in their two meta-analyses of head-to-head
comparative studies and placebo-controlled studies of antidepressants, found that
sertraline and escitalopram had slight advantages over most other
antidepressants for efficacy and tolerability. Further support for escitalopram as
a possibly superior SSRI for first-line use comes from the Combination
Medication to Enhance Depression Outcomes (CO-MED) study. 93 This large (n
= 665), prospective, comparative study was designed to address the question of
whether it would be better to start depressed patients on two antidepressants at
once rather than using just one. Escitalopram was chosen as the monotherapy. It
was compared to escitalopram plus bupropion and to mirtazapine plus
venlafaxine. Placebo was added to the escitalopram. The study found no
difference in outcomes (39% remissions) and more side effects with the
combinations. No other monotherapy was compared to escitalopram, but
escitalopram monotherapy held up well against what was expected to be tough
competition; the results can be seen as supporting escitalopram as a first-line
choice at Node 4. Many studies compared TCAs to newer antidepressants,
especially SSRIs, but with the exception of inpatients with severe melancholia,
the meta-analyses identified no difference in efficacy between them but more
serious side effects with TCAs.8 , 94
Another option for first-line use is bupropion. Zimmerman and colleagues 95
reviewed the evidence and concluded that bupropion is as effective as SSRIs and
TCAs, and wondered why bupropion is not the first choice antidepressant in
usual practice, given its lack of sexual side effects. Trivedi and colleagues 96
showed that it produces equal improvement in comorbid anxiety symptoms and
has the same amount of activation side effects, such as insomnia, as SSRIs. In
STAR*D, which included a comparison of augmenting citalopram with
bupropion versus buspirone, a trend favored bupropion when patients had high
levels of anxiety (18% remissions of depression on bupropion vs. 9% on
buspirone)14 —again suggesting that bupropion is not unreasonable as an option,
even in anxious depressions. So: why is bupropion not used more often? One
explanation is concern about its association with the risk of lowering the seizure
threshold. The risk of seizures with the sustained release (SA) formulation was
0.1%, however, which is comparable to, or better than, SSRIs and other
antidepressants, at least at doses up to 300 mg daily. 97 , 98 Importantly, on the
positive side regarding adverse effects, bupropion is associated with a lower risk
of weight gain than other augmenters. 99 Bupropion is, indeed, the least likely
agent to cause sexual side effects, and it may even improve sexual functioning in
patients who had developed sexual side effects while taking SSRIs. Sexual
dysfunction is one of the major causes of disability and treatment dropouts in the
outpatient treatment of depression in primary care. 100 It occurs in 40%-80% of
patients treated with SSRIs or serotonin norepinephrine reuptake inhibitors
(SNRIs), compared to 14% on placebo. 101 Spontaneous remission of sexual
dysfunction occurs in only about 10%, and partial remission in 11%, of patients.
102
In conclusion, this discussion of the risks and benefits of SSRIs versus
bupropion could form the basis of the discussion with the patient. If a male
patient chooses to start an SSRI and he develops sexual side effects, he can
either be switched to bupropion or may need sildenafil (or related agents) added
to the regimen, which is the most effective medication to improve SSRI-induced
erectile dysfunction in men. 103 The frequent need for an inconvenient and
(currently) expensive medication to address this side effect involving the
disabling of a central human physiological function is an important consideration
in deciding whether to choose an SSRI or SNRI for major depression rather than
bupropion.
Other possible first-line medications for major depression include
mirtazapine, paroxetine, or trazodone. The weight gain associated with the first
two, however, and the sedation with the last render them inferior Node 4 choices
unless either of those side effects would actually be desirable. A once-daily
formulation of trazodone is available that might cause less sedation, but a similar
controlled-release formulation was not more tolerable than regular-release
trazodone in a large study. 104 Other newer, expensive, brand-name
antidepressant products are available, but none has shown evidence of
superiority in efficacy or safety to justify the additional cost. Vortioxetine has
generated some interest regarding its possible special efficacy for cognitive
impairment in the context of depression. 105 These improvements in cognition
were greater in patients currently working. 106 The FDA psychopharmacology
advisory committee reportedly voted to approve an indication for this symptom
in patients with major depression. The FDA leadership, however, has been
reluctant to grant new drug indications targeting specific symptoms of a
syndrome like depression, and did not agree. They want to see more and better
comparative studies showing the effect to occur consistently. A final question is
whether duloxetine is better for patients with pain as a symptom along with their
depression. A meta-analysis of five studies addressing this question by
Spielmans and colleagues 107 showed that the effect size for the pain-reduction
effect was 0.115 by Cohen’s d, which is a clinically insignificant effect—despite
FDA approval having been granted for neuropathic pain and pain associated
with fibromyalgia. The authors concluded that the claims being made in
advertising and detailing regarding this effect on pain are not justified by the
evidence, though successful marketing resulted in annual sales in the billions of
dollars before duloxetine became available as a generic. More recently, in a
meta-analysis of 14 placebo-controlled antidepressant trials with SSRIs and
SNRIs, none of the medications demonstrated relative superiority for pain relief.
108 Each had a significant, but small, impact on pain, and for the SNRIs it
strongly correlated with improved mood.
Some guidelines and clinicians think it reasonable to select other SNRIs such
as venlafaxine for first-line use in outpatients. No advantages in efficacy have
been demonstrated, however, and the evidence indicates the likelihood of greater
harms from SNRIs in the cardiovascular realm, including hypertension,
tachycardia, strokes, and (in some populations) even deaths. 109
Node 4B. If the Response to the Option Selected at Node 4A Is
Unsatisfactory, Try One of These (Consider Patient’s Preference)
Very few data are available on what is best to do after the first medication fails
despite an adequate trial. 110 In the literature, the consensus of what constitutes
an adequate trial appears to be a 8-week period on an antidepressant at a
therapeutic dose, though some would say it should be 12 weeks. 111 Many
augmentation or switching options exceed placebo in randomized trials, but few
head-to-head comparisons are available concerning efficacy or safety—and even
fewer with placebo controls. 112 Note that the recent important VA [Veterans
Affairs] Augmentation and Switching Treatments for Improving Depression
Outcomes (VAST-D) clinical trial enrolled depressed patients who had an
unsatisfactory response to an average of 2.3–2.5 trials. Because Node 4B
patients would have failed only one trial, these VAST-D results are more
pertinent to the next node of this algorithm and will be discussed there.99
Given the lack of a strong evidence basis for identifying a preferred
medication for the second trial, it was decided that patient preference should be a
particularly strong consideration. That was, to some extent, what was done in
STAR*D: after failure with the initial antidepressant citalopram, subjects
decided whether they wanted a switch or an augmentation—for example, if they
thought they had a partial response and the side effects were acceptable, they
might pick augmentation. Then, they were randomized to one of two options for
the augmentation. In applying the present algorithm, prescribers are encouraged
to present to patients some of the most studied available options for
augmentation or for switching if the patient prefers a switch. Individual patients
may, or may not, want to choose an option that has had a smaller number of
efficacy studies if that means avoiding the risk of potential side effects
associated with other options that have undergone more studies, have FDA
approval, and therefore have been intensively marketed.
Many have wondered if it is better to augment or switch after one
antidepressant trial with unsatisfactory results. Gaynes and colleagues 113
evaluated the patients in STAR*D who chose augmentation and matched them
retrospectively with a control group of patients with similar demographics and
severity who chose to be in the switch study in the Level 2 trial. They found an
odds ratio of 1.14 favoring augmentation, which was not statistically or
clinically significant.
This algorithm provides four choices for switching and four choices for
augmenting the initial antidepressant. The prescriber may present some or all of
them to the patient for consideration. The authors do not have a preference, and
the order of presentation should not be taken as indicating such a preference.
Switch Options One could switch to one of the other two first-line
recommendations not yet tried (among sertraline, escitalopram, or bupropion).
Monotherapy switches (up to three) have been found to produce improvement
rates as high as 60%-70%. 114 Some studies support switch within, and some
between, classes of antidepressants. 115 , 116 The STAR*D study and various
evidence reviews have found essentially no difference in outcome between
switching within the same class or to a different class. 117 , 118
Switching to a dual-action agent—that is, one that has effects on both
serotonin and norepinephrine (e.g., SNRIs or mirtazapine) is a second switch
option. At least some reports suggest that patients on or switched to venlafaxine
were more likely to experience remission than patients on or switched to an
SSRI. 119 – 121 Most of these studies were funded by the dual-action agent
manufacturer. STAR*D found a numerical, but not statistically significant,
advantage to switching to venlafaxine rather than to sertraline or bupropion
(25% remissions vs. 18% and 21%, respectively). Disadvantages of venlafaxine
include the risk of blood pressure elevation, the risk of discontinuation
syndromes that are more frequent or more severe than with many other
antidepressants, and the difficulty of some patients in tolerating the nausea and
other gastrointestinal side effects, even on the extended-release formulation. 122
Mirtazapine has demonstrated efficacy in placebo-controlled studies and has
shown superiority to SSRIs in treating moderately to severely depressed
patients.63 Again, these studies were funded by the manufacturer of mirtazapine.
In a metaanalysis, mirtazapine showed a faster onset of action than SSRIs at 2
weeks; however, no significant differences were observed in remission at the end
of 6 to 12 weeks of treatment except in comparison to paroxetine. 123 The patient
should be actively informed of the risk of weight gain, and agranulocytosis is
probably only a rare concern despite the package insert warning suggesting an
alarming rate of 2:3000 in the registration studies.
The third switching option that might be considered is switching to repetitive
transcranial magnetic stimulation (rTMS). It involves repeated subconvulsive
magnetic stimulation to the brain, particularly the dorsolateral prefrontal cortex
as the primary target, an area that neuroimaging studies suggest is hypoactive in
depressed patients. 124 , 125 rTMS is less invasive than other neuromodulatory
interventions, and it has been associated with a better cognitive side-effect
profile than ECT. A randomized, controlled trial comparing rTMS and ECT to
placebo sham treatment found it to be not as effective as ECT. 126 The FDA has
approved rTMS for use after one failed trial of an antidepressant but not after
two trials (based on the submitted trial data). Hence, it is proposed as an option
at this point in the algorithm. A multicenter, randomized, controlled trial of
patients who failed at least one but no more than four adequate antidepressant
treatments showed remission rates for rTMS at 7%-14% after at least three
weeks of treatment and less than 18% after six weeks of treatment. 127
Finally, for patients who might prefer a neutraceutical or herbal option, S-
adenosylmethionine (SAMe) and St. John’s wort have reasonable evidence of
efficacy as monotherapies for depression and have generally fewer side effects
than antidepressants. 128 , 129
Augmentation Options The first set of proposed augmenting options is to select
a nutraceutical agent (omega-3 fatty acid, L-methylfolate, or n-acetylcysteine) or
light therapy. 130 – 134 These options have the important advantage of minimal
side effects, but efficacy is much less well established than some other options.
Yet, insufficient evidence is available to conclude that these options are less
effective than the others, and the side effect profiles could make them appealing
to some patients.
The effect size of omega-3 fatty acid products in treating depression may be
smaller than the others in this category. Doses have ranged widely in the studies,
but a median seems to be about 1 gram twice daily. L-methylfolate is backed by
a small quantity of more impressive data in non- or partial responders to SSRIs,
at a dose of 15 mg (but not 7.5 mg) daily. Folate (which is much less expensive)
might also work. It is unclear from the inconclusive studies what the best dose
would be, but it might be on the order of 1 mg daily. 135 One placebo-controlled
trial found improvement on secondary outcome measures only, at 1000 mg twice
daily. 131 An association has been found between light therapy and reduced
depressive symptoms when compared to placebo and control treatment, even in
patients without a seasonal pattern. 136
The second category of augmentation options is to use a second-generation
antipsychotic. Three are FDA approved: aripiprazole, brexpiprazole (not
included in our recommendations as it has similar efficacy to aripiprazole but a
much higher cost), and quetiapine. The fixed combination of fluoxetine and
olanzapine, which has FDA-approval, is not included in our recommendations
because of the significant weight gain and metabolic side effects associated with
olanzapine. Evidence also suggests that risperidone is an effective augmentation
option. 137 Extensive industry-sponsored marketing to prescribers and patients
has highlighted the second-generation psychotic augmentation option in the
minds of many clinicians and patients. However, thought provoking meta-
analyses of the data on efficacy, balanced by consideration of the side effects of
these medications, indicate that they should not be the automatic choice among
the augmentations.61 , 138 , 139 The number needed to treat for efficacy is a modest
8 in exchange for considerable metabolic, akathisic, extrapyramidal, and other
side effects. Long-term efficacy is unknown, and the side effects often become
more significant with time.
A third augmentation option would be to use the antidepressants bupropion or
mirtazapine. In STAR*D, bupropion produced 30% remissions as an
augmentation, which was equal to buspirone on the primary outcome measure
(Hamilton Rating Scale for Depression). On some secondary measures (Quick
Inventory of Depressive Symptomatology Self-Report [QIDS-SR], side-effect
burden, patient satisfaction), however, bupropion seemed somewhat more
effective. 140 Mirtazapine has been shown to be an effective augmentation for
SSRIs in several small randomized trials but can cause significant weight gain.
141 , 142 Mirtazapine can also be an effective switching option for sexual
dysfunction caused by SSRIs. 143
The fourth option to consider is augmentation with lithium or T3. These are
the oldest and among the best-evidenced augmentation strategies, though as
noted in the Node 3 discussion, lithium’s evidence is more robust as an
augmenter of TCAs. Tricyclics are used much less often today, however, and are
not recommended at Node 4 because of their side-effect burden. Lithium is itself
associated with a significant side-effect burden, though the doses used for
augmentation (usually 600–900 mg daily) are somewhat lower than for treating
bipolar disorder. T3 has had a mild side-effect burden in the published studies,
though clinicians still worry about the potential consequences of doses that for
some patients can become supraphysiological. As mentioned above, the data for
lithium or T3 augmentation of SSRIs are not as convincing as the data for TCA
augmentation.78 , 79 , 81
TREATMENT-RESISTANT DEPRESSION
If the patient did not respond satisfactorily to the chosen Node 4B option (switch
or augmentation), then for the purposes of this algorithm, the patient is
considered to have a treatment-resistant depression (TRD). At least two adequate
pharmacotherapy trials of reasonable mainstream options have taken into
account safety and patient preferences. The STAR*D study found that the odds
of the depression remitting with a third or fourth trial are much diminished, and
even if remissions occur, the chances of relapse within the next year are 65% or
greater.16 Ivanova and colleagues 144 showed that patients with TRD (defined
somewhat differently), when compared to patients with non-TRD, had at least
four times more psychiatric hospitalizations and approximately three times more
emergency room visits. It should be emphasized here that before proceeding
with more medication trials, it would be important to make another thorough
review of medical, psychological, and environmental/social factors (e.g., dyadic
discord) that could account for the unsatisfactory results so far.11 Also, it would
be wise to review Table 1 again.
NODE 5: DOES THE PATIENT HAVE TRD
WITHOUT COMORBIDITIES BUT WITH
ATYPICAL FEATURES?
The Columbia criteria for atypical depression codified in DSM-5 include having
significant mood reactivity combined with two of the following clinical
characteristics: hyperphagia, hypersomnia, leaden paralysis, and pathological
rejection sensitivity. Atypical depression is a pattern seen more often in bipolar
depression than unipolar. Clinicians should reconsider the diagnosis, as the
treatment would be different from what is proposed in this algorithm if the
patient has bipolar disorder.26 , 145
Node 5A: Patient Has the Atypical Features Specifier for Major
Depression
Up to now, the atypical features (ATF) has not been utilized to define a unique
treatment pathway in this algorithm. This is because SSRIs or bupropion are
generally effective in treating ATF, 146 , 147 and they are early recommendations
in Nodes 4A and 4B. At this point they probably would have been tried.
Monoamine oxidase inhibitors (MAOIs) are also effective in treating ATF, but
they have many side effects and for this reason were not previously
recommended in the default algorithm. But now, if the patient meets criteria for
the ATF specifier, it might be time to consider MAOIs. A metaanalysis in
patients with atypical depression found that MAOIs are more effective than
TCAs. 148 Phenelzine has been the most studied MAOI in atypical depression. It
seems also to have maintenance efficacy. 149 It requires, however, the use of a
tyramine-restricted diet. Side effects include weight gain, postural hypotension,
and sexual dysfunction. 150 It is necessary to wait two to five weeks after
discontinuing an SSRI (five weeks for fluoxetine) before an MAOI may be
started, because of the danger of the potentially fatal serotonin syndrome. The
transdermal formulation of selegiline may provide similar efficacy without so
many adverse events and without requiring dietary restrictions except in doses
over 6 mg per 24 hours. 151 – 153 The risk of serotonin syndrome, albeit very rare,
remains a concern. 154
Another option, besides an MAOI, would be to add aripiprazole to an SSRI. In
one of the studies evaluating aripiprazole as an augmentation for SSRIs,
response in atypical depression was included as an outcome measure.36 The
response in those subjects was particularly robust: indeed, it was more
significant than in the subjects with non-atypical depression (p <.001 vs. p <.05).
Node 5B: TRD Without Comorbidities and Without Atypical
Features (Consider Patient’s Preference)
As was the case for selection of the second treatment trial (Node 4B), little data
are available to guide the choice of the third trial. STAR*D remains as a source
of relevant information, having suggested possible effectiveness of switches to a
TCA or mirtazapine, or augmentation with lithium or T3 for a third trial. Some
informative signals have also come from the 2017 VAST-D study noted briefly
at Node 4.99 In that large study of 1500 depressed veterans (85% male, 47% with
comorbid PTSD), who had an average of 2.4 previous medication trials without
satisfactory outcome, three randomized treatment options were available:
augmentation of their current antidepressants with aripiprazole (raised to 10 mg
daily), augmentation with bupropion (raised to 400 mg daily), and switch to
bupropion monotherapy up to 400 mg daily. Patients could not have been on
bupropion before. They were treated for 12 weeks. Remission rates were 29% on
aripiprazole augmentation, 27% on bupropion augmentation, and 22% on switch
to bupropion. Number needed to treat for the superiority of aripiprazole
augmentation over bupropion switch was 14—indicating that this difference,
though statistically significant, is clinically small. These differences in
effectiveness have to be balanced by consideration of the side effects of each
treatment. Notably, 25% of the aripiprazole augmentation patients gained
substantial (7%) body weight, versus 5% on the bupropion treatment options,
and 12% of bupropion-treated patients lost substantial weight, versus 5% on
aripiprazole. Thus, the small advantage in effectiveness for aripiprazole was
balanced negatively by these weight considerations. In addition, it should be
noted that the population was predominantly male. Most non-veteran depressed
outpatients are female and may have different propensities to improve and have
changes in weight from medications. Also, civilian depressions have much lower
rates of comorbid PTSD. Bupropion has not shown efficacy versus placebo for
PTSD, 155 but aripiprazole has some moderate evidence of usefulness in PTSD 156
— which may account for all of the advantage for aripiprazole found in the
veteran population.
In view of the above, it is hard to differentiate among the treatment options for
a third trial in depressed outpatients. Decisions should again be individualized,
taking into account patient demographics, side-effect vulnerabilities, and
personal preferences. We therefore propose basically the same options as in
Node 4B, the second pharmacotherapy trial, and the patient should play a key
role in helping make the selection after being apprised of the advantages and
disadvantages of each. To these, we would add a few additional considerations.
Switch Options Two preferred choices here at Node 5B (third trial, no
comorbidities, not atypical depression) would be venlafaxine again or a TCA
(imipramine or nortriptyline). In STAR*D the remission rate with a switch to
venlafaxine after the initial trial with citalopram was 25%, which was
numerically higher than the 18% rate with a switch to another SSRI, sertraline.16
The ARGOS study had similar findings. 157 In regard to TCAs, Thase and
colleagues 158 reported that both the switch from sertraline to imipramine and the
switch from imipramine to sertraline resulted in significant improvements in
some patients with a history of treatment-resistant chronic depression. In
STAR*D the switch to nortriptyline in the third trial, after two failed
antidepressant trials, produced a remission rate of almost 20%, versus 12% for a
switch to mirtazapine (nonsignificant).
Antidepressant Combination Option Another combination option to consider
here at Node 5B (in addition to those mentioned in Node 4B) would be
mirtazapine plus venlafaxine. In STAR*D this option was offered in Level 4
(i.e., after three failed trials), and it was numerically superior, with 14%
remissions compared to the MAOI tranylcypromine, which produced 7%
remissions (nonsignificant, because of small number of patients at this point).
Another study (a randomized trial supported by the manufacturer of mirtazapine)
found better results with this combination than with three other combinations. 159
ECT remains the most effective type of treatment for patients who have not
yet responded adequately to a number of medication trials. 160 , 161
NODE 6: TRD WITH COMORBIDITIES
In Node 5 we considered additional medication choices in the case of patients
with no significant comorbidities. The patient’s treatment resistance might be
due, however, to the presence of a comorbidity that was previously considered
secondary in importance to the depression with the consequence that the initial
treatment trials were directed toward the depression. As noted in Figure 1 , you
skip Node 5 and go directly to Node 6 if comorbidities could potentially be
explaining the TRD; if the depression is potentially secondary to the
comorbidity, treatment directed toward the comorbidity might produce a more
satisfactory outcome for both the depression and the comorbidity itself. For the
four comorbidities considered, the evidence-based approaches may be different
from the recommended treatment for those who are depressed without the
comorbidity: chronic pain, obsessive-compulsive disorder, attention-
deficit/hyperactivity disorder (ADHD), and posttraumatic stress disorder
(PTSD).
Chronic Pain
Chronic pain persisting for more than three months is a common complaint
among patients with depression. It is predictive of a poor prognosis and is a
major risk factor for suicidal behavior. 162 Many antidepressants have been
evaluated for their ability to relieve pain from various causes in depressed
patients. As mentioned in Node 4, however, a recent meta-analysis of 14 studies
found them to be largely equivalent in effect (duloxetine, as noted earlier, had no
greater benefit), and the effect sizes were small and strongly correlated with their
antidepressant effects.108 Other meta-analyses have evaluated the effect of
psychotropic drugs, including antidepressants, for chronic pain syndromes in
patients who were not necessarily depressed. 163 The findings of these reviews
provide options to think about when chronic pain is present as a comorbid
problem and the depression is not responding to antidepressants.
TCAs have the longest track record of any antidepressant class for the
treatment of pain syndromes and depression with comorbid chronic pain. 164 , 165
The usual doses of TCAs for pain relief are typically lower than the doses
typically used for treating depression. As discussed by Shembalkar and Anand,
166 clomipramine and amitriptyline have been the most widely used
antidepressants in pain therapy. Amitriptyline has been preferred perhaps
because primary care clinicians are less familiar with clomipramine. In the two
direct comparisons of clomipramine and amitriptyline for pain syndromes,
however, clomipramine had superior effectiveness.163
Several randomized, controlled studies have reported the efficacy of
duloxetine over placebo. 167 – 170 Subsequently, duloxetine obtained FDA
approval for fibromyalgia pain, diabetic peripheral neuropathic pain, and
musculoskeletal pain. As noted earlier, however, a meta-analysis of five
duloxetine trials involving 1448 patients concluded that the effect size was too
small to be clinically meaningful (0.115 by Cohen’s d) and that the
manufacturer’s claims are not supported by good evidence.
Anticonvulsants may also be useful for patients with depression and comorbid
chronic pain. Carbamazepine is considered an effective treatment for trigeminal
neuralgia. Pregabalin has FDA approvals for post-herpetic neuralgia, spinal
injury neuropathic pain, fibromyalgia, and diabetic peripheral neuropathy. 171
Gabapentin, a similar compound, is FDA approved for post-herpetic neuralgia
and has some evidence for use in peripheral neuropathic pain. 172 , 173
Obsessive-Compulsive Disorder
SSRIs are the first-line treatment for obsessive-compulsive disorder. Notably,
however, the effective dose of the SSRIs is often higher, and the duration of the
SSRI trials may need to be longer, than when treating depression. 174 , 175 Some
studies show that the separation from placebo does not begin until week 5 and
then gradually increases up to week 10. 176
In cases of unsatisfactory OCD response, treatment with the SSRI can be
augmented with a second-generation antipsychotic, especially risperidone or
aripiprazole. 177
Attention-Deficit/Hyperactivity Disorder
Stimulants (e.g., dextroamphetamine, methylphenidate) are the first-line
pharmacotherapy for adults with ADHD. 178 Stimulants may even be useful in
some adult ADHD patients struggling with substance use disorders. 179 They
were not found effective, however, for moderate to severe major depression as
monotherapy or as augmentations of antidepressants. 180 Nevertheless, for
patients with treatment-resistant depression and comorbid ADHD, stimulant
treatments could be helpful, perhaps by addressing the emotional dysregulation
that is frequently associated with ADHD and that can respond to stimulant
therapy. 181
Atomoxetine has also been shown to be an effective treatment for adults with
ADHD, though effectiveness is probably less than with the stimulants, and it
takes 5–10 weeks to reach maximum effectiveness. 182
Randomized, controlled trials support the use of bupropion and desipramine
as second-line (less effective) choices in treating ADHD. 183 , 184 Venlafaxine has
also been reported to be effective in adult ADHD in open-label trials. 185 , 186
Some of these antidepressants may have already been tried at earlier points in
the algorithm.
Posttraumatic Stress Disorder
SSRIs are the only FDA-approved medications for treating PTSD, and they
would probably have been tried by this point.
Trauma-related nightmares, disturbed awakenings without nightmare
recollection, and daytime hypervigilance and irritability are some of the most
debilitating symptoms of PTSD, leading to impaired sleep, avoidant behavior,
and secondary depression. It may be that the patient has a primary problem with
PTSD. Doxazosin and prazosin are alpha-1 antagonists that can treat these
symptoms by reducing noradrenergic activity. 187 , 188 The effect size of the
benefits on PTSD symptoms has been much greater with prazosin than with
antidepressants, including SSRIs. 27
HIGHLY TREATMENT-RESISTANT
DEPRESSION
By this point (see Figure 1 ), the patient will have had four or more medication
trials and perhaps ECT. We are beyond the end of STAR*D, and we have given
due consideration to medical and psychiatric comorbidity and to psychosocial
factors that may be fueling the condition. Some somatic therapy options are still
potentially available in addition to the better-evidenced options discussed above
but not yet tried. These options range from minimally evidenced, often novel
psychopharmacology strategies to invasive, device-based or surgical techniques
such as vagus nerve stimulation. 189 Decisions to employ these options are highly
influenced by local interest, availability, and cost considerations. They seem to
be beyond the scope of what seems reasonable to prioritize and include in an
algorithm for general use.
COMPARISON WITH OTHER RECENT
GUIDELINES AND ALGORITHMS
Many other guidelines and some algorithms have been published in recent years.
We offer in Table 2 a brief comparison of key features of several of these and
how the present algorithm differs in key recommendations.
Table 2 | Comparison of Present Algorithm to Other Recent Algorithms
and Guidelines for Unipolar Depression
Algorithm/guideline Year Other algorithms/guidelines PAPHSS algorithm
Texas Medication
Algorithm Project:
Report of the Texas
Consensus
Conference Panel
on Medication
Treatment of Major
1999 No distinction between inpatient
and outpatient treatment of
depression First-line options
include SSRIs as a class,
nefazodone, bupropion SR,
venlafaxine XR, and mirtazapine
If no response to treatment,
recommendations include
For inpatients with severe
melancholic depression, we
recommend venlafaxine,
mirtazapine, or a TCA, whereas
for outpatients we recommend
sertraline, escitalopram, or
bupropion first-line
Treatment of Major
Depressive
Disorder31
recommendations include
(1) augmentation with a
different class medication
among the choices listed above
or with lithium, and
(2) combination treatment with
two medications from different
classes (from the options
mentioned above)
We do not recommend SNRIs,
mirtazapine, or nefazodone first-
line for outpatients because of
greater side effects
Augmentation options include,
but are not limited to,
nutraceutical agents, light
therapy, a second-generation
antipsychotic, bupropion,
mirtazapine, lithium, or T3
World Federation of
Societies of
Biological
Psychiatry
(WFSBP)
Guidelines for
Biological
Treatment of
Unipolar Depressive
Disorders, Part 1:
Update 2013 on the
Acute and
Continuation
Treatment of
Unipolar Depressive
Disorders32
2013 For initial treatment of
depression:
For mild and moderate
depression, SSRIs as a class and
escitalopram, sertraline,
mirtazapine, and venlafaxine are
recommended
For severe depression, SSRIs,
SNRIs, and TCAs are
recommended (without stating
preference of one agent over
another within different classes)
If no response to initial
treatment, one of the
recommendations is to augment
with lithium, thyroid hormone,
quetiapine or aripiprazole or
olanzapine (in combination with
fluoxetine), or St. John’s wort
For inpatients with severe
melancholic depression, we
recommend venlafaxine,
mirtazapine, or a TCA
For outpatients, we recommend
sertraline, escitalopram, or
bupropion first-line
We do not recommend SNRIs,
TCAs, or mirtazapine first-line
for outpatients because of
greater side effects
If no response to initial
treatment, we offer more
specific switches and
augmentations: patient can
switch to one of the initial
options not previously tried, to a
dual-action agent, to transcranial
magnetic stimulation, or to S-
adenosylmethionine/St. John’s
wort, or augment with selected
evidenced nutrients such as L-
methylfolate, light therapy,
second-generation
antipsychotics (aripiprazole,
quetiapine, or risperidone),
bupropion, mirtazapine, lithium,
or T3
We do not recommend
olanzapine or quetiapine,
because of greater side effects
(especially metabolic)
Canadian Network
for Mood and
2016 Based on CANMAT’s criteria
for the level of evidence and
stated principles of
For inpatients with severe
melancholic depression, we
recommend venlafaxine,
Anxiety Treatments
(CANMAT) 2016
Clinical Guidelines
for the Management
of Adults with
Major Depressive
Disorder 33
stated principles of
pharmacotherapy management,
the recommended first-line
antidepressants include
agomelatine, bupropion,
citalopram, desvenlafaxine,
duloxetine, escitalopram,
fluoxetine, fluvoxamine,
mianserin, milnacipran,
mirtazapine, paroxetine,
sertraline, venlafaxine, and
vortioxetine
If no response to initial
treatment, the recommendations
are to either switch or augment
First-line augmenters are
aripiprazole, quetiapine, and
risperidone
recommend venlafaxine,
mirtazapine, or a TCA
For outpatients, we recommend
sertraline, escitalopram, or
bupropion first-line
We do not recommend other
agents as first-line for
outpatients because of greater
side effects, inferior
performance in head-to-head
comparisons, and in some cases,
unavailability in the United
States
If no response to initial
treatment, we offer more
specific switches and
augmentations: one can switch
to one of the initial options not
previously tried, to a dual action
agent, to transcranial magnetic
stimulation, or to S-
adenosylmethionine/ St. John’s
wort, or augment with selected
evidenced nutrients such as L-
methylfolate, light therapy,
second-generation
antipsychotics (aripiprazole,
quetiapine, or risperidone),
bupropion, mirtazapine, lithium,
or T3
Florida Best
Practice
Psychotherapeutic
Medication
Guidelines for
Adults with
Major Depressive
Disorder34
2017 Do not distinguish between
inpatient and outpatient
treatment of depression
For initial treatment of
depression, recommend an SSRI
(without stating preference of
one agent over another within
this class), an SNRI (without
stating preference of one agent
over another within this class),
bupropion, mirtazapine, or
vortioxetine
For inpatients with severe
melancholic depression, we
recommend venlafaxine,
mirtazapine, or a TCA
For outpatients, we recommend
sertraline, escitalopram, or
bupropion first-line
We do not recommend SNRIs or
mirtazapine first-line for
outpatients because of greater
side effects
We do not recommend
vortioxetine because of lack of
robust evidence thus far
We provide different
We provide different
recommendations for commonly
seen comorbid conditions
PAPHSS, Psychopharmacology Algorithm Project at the Harvard South Shore Program; SNRI, serotonin-
norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; T3, triiodothyronine; TCA,
tricyclic antidepressant.
Strengths of the present algorithm include simplifying the switching and
augmentation options to those that have the best evidence for efficacy and the
lowest risk of the more problematic side effects, and that are the most cost-
effective. We also give more weight than other algorithms to patient preferences
at key points where the evidence supporting what to do next is not that
definitive. Finally, we consider the impact of severity, key specifiers, and
important comorbidities on medication choice.
DISCUSSION
Some physicians do not welcome the appearance of medication treatment
algorithms and are reluctant to follow them, no matter how evidence-supported
and peer-reviewed the algorithms may be. 190 Such physicians have more faith in
the quick, intuitive decision-making process generally known as the art of
medicine. Faith in this art is part of the culture of medicine and has deep
historical roots. This art is initially conveyed by more experienced mentors and
is then refined by personal experience as the emerging practitioner makes his or
her own mistakes. As Groupman 191 has noted, however, we do not want airline
pilots to learn from their mistakes; we want them to make the right decision
every time. Even the expert mentors, if we judge by studies in other fields (e.g.,
engineering), make more errors using their art and experience than would be
made by following algorithms devised a priori by other experts in the field. 192 ,
193 Unfortunately for patients, the health care system continues to be built on a
foundation of mistakes followed by “corrective action plans.”191 Following
standardized care driven by evidence-supported algorithms, however, is a model
that has produced superior and cost-effective outcomes with illnesses such as
diabetes, pneumonia, and heart disease, 194 and the aggregate evidence of their
use to improve depression outcomes seems comparable.21 , 22 , 195 A more detailed
review, by PAPHSS authors, of issues related to the value of following
evidence-supported psychopharmacology algorithms has been published
previously. 196
A limitation in the value of the proposed medication treatment sequences is
that the quantity and quality of evidence supporting each recommendation varies
considerably. The funding sources may include industry (which adds potential
bias in favor of the sponsor’s product), government, or both in differing ratios.
It is important for prescribers to remember that all available antidepressants
work by similar mechanisms. It is therefore not surprising that STAR*D found
that after patients have failed a couple of trials, the odds of responding become
much lower, and any remissions are likely to have a high risk of not being
maintained. This algorithm offers an organized and efficient approach to early
medication selection from among the best supported and safest options available,
while also taking in account that medical and other comorbidities might be the
primary problem (with the depression secondary).
Our mission as medical providers is to provide patients with an understanding
of the existing evidence, including an analysis of risks and benefits, and to help
them make an informed decision about what treatments to try. This
noncommercial, evidence-informed informational heuristic, which includes
specific opportunities for patients to contribute to decision making, can be used
by clinicians to guide such discussions.
Declaration of interest: The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of the article.
We would like to thank Benjamin Gonzalez, MD, for work on an initial draft;
Ronald Pies, MD, for his helpful review; and Rachel Meyen, MD, for
researching the evidence on geriatric depression.
REFERENCES
1. World Health Organization. The global burden of disease: 2004 update. Geneva: WHO,
2008.
2. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity
of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry
2005;62:617–27.
3. Olfson M, Blanco C, Marcus SC. Treatment of adult depression in the United States. JAMA Intern
Med 2016;176:1482–91.
4. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant
trials and its influence on apparent efficacy. N Engl J Med 2008;358:252–60.
5. Kirsch I. Antidepressant drugs ‘work,’ but they are not clinically effective. Br J Hosp Med (Lond)
2008;69:359.
6. Kirsch I, Johnson BT. Moving beyond depression: how full is the glass? BMJ 2008;336:629–30.
7. Fountoulakis KN, Moller HJ. Efficacy of antidepressants: a re-analysis and re-interpretation of the
Kirsch data. Int J Neuropsychopharmacol 2011;14:405–12.
Moller HJ. Isn’t the efficacy of antidepressants clinically relevant? A critical comment on the results of
8.
Moller HJ. Isn’t the efficacy of antidepressants clinically relevant? A critical comment on the results of
the metaanalysis by Kirsch et al. Eur Arch Psychiatry Clin Neurosci 2008;258:451–5.
9. Parker G. Antidepressants on trial: how valid is the evidence? Br J Psychiatry 2009;194:1–3 .
10. Zimmerman M. The FDA’s failure to address the lack of generalisability of antidepressant efficacy
trials in product labelling. Br J Psychiatry 2016;208:512–4.
11. Denton WH, Carmody TJ, Rush AJ, et al. Dyadic discord at baseline is associated with lack of
remission in the acute treatment of chronic depression. Psychol Med 2010;40:415–24.
12. Jain R, Maletic V, McIntyre RS. Diagnosing and treating patients with mixed features. J Clin
Psychiatry 2017;78:1091–102.
13. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders
(ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry 2013;170:1249–
62.
14. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious
versus nonanxious depression: a STAR*D report. Am J Psychiatry 2008;165:342–51.
15. Davies SJ, Jackson PR, Potokar J, Nutt DJ. Treatment of anxiety and depressive disorders in patients
with cardiovascular disease. BMJ 2004;328:939–43.
16. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed
outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry
2006;163:1905–17.
17. Zimmerman M, Thongy T. How often do SSRIs and other new-generation antidepressants lose their
effect during continuation treatment? Evidence suggesting the rate of true tachyphylaxis during
continuation treatment is low. J Clin Psychiatry 2007;68:1271–6.
18. O’Donnell M. A sceptic’s medical dictionary. London: BMJ, 1997.
19. Osser DN, Patterson RD. Algorithms for the pharmacotherapy of depression, parts one and two. Dir
Psychiatry 1998;18: 303–34.
20. Hripcsak G, Ryan PB, Duke JD, et al. Characterizing treatment pathways at scale using the OHDSI
network. Proc Natl Acad Sci U S A 2016;113:7329–36.
21. Adli M, Wiethoff K, Baghai TC, et al. How effective is algorithm-guided treatment for depressed
inpatients? Results from the randomized controlled multicenter German Algorithm Project 3 trial. Int
J Neuropsychopharmacol 2017;20: 721–30.
22. Trivedi MH, Rush AJ, Crismon ML, et al. Clinical results for patients with major depressive disorder
in the Texas Medication Algorithm Project. Arch Gen Psychiatry 2004;61:669–80.
23. Nakagawa A, Mitsuda D, Sado M, et al. Effectiveness of supplementary cognitive-behavioral therapy
for pharmacotherapy-resistant depression: a randomized controlled trial. J Clin Psychiatry
2017;78:1126–35.
24. Davidson JR, Zhang W, Connor KM, et al. A psychopharmacological treatment algorithm for
generalised anxiety disorder (GAD). J Psychopharmacol 2010;24:3–26.
25. Mohammad O, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore
Program: an algorithm for acute mania. Harv Rev Psychiatry 2014;22:274–94.
26. Ansari A, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore
Program: an update on bipolar depression. Harv Rev Psychiatry 2010;18:36–55.
Bajor LA, Ticlea AN, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South
27.
Bajor LA, Ticlea AN, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South
Shore Program: an update on posttraumatic stress disorder. Harv Rev Psychiatry 2011;19:240–58.
28. Hamoda HM, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: an update on psychotic depression. Harv Rev Psychiatry 2008;16:235–47.
29. Osser DN, Roudsari MJ, Manschreck T. The Psychopharmacology Algorithm Project at the Harvard
South Shore Program: an update on schizophrenia. Harv Rev Psychiatry 2013;21:18–40.
30. Osser DN. A systematic approach to the classification and pharmacotherapy of nonpsychotic major
depression and dysthymia. J Clin Psychopharmacol 1993;13:133–44.
31. Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the
Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin
Psychiatry 1999;60:142–56.
32. Bauer M, Pfennig A, Severus E, et al. World Federation of Societies of Biological Psychiatry
(WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on
the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry
2013;14:334–85 .
33. Kennedy SH, Lam RW, McIntyre RS, et al. Canadian Network for Mood and Anxiety Treatments
(CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder:
section 3. Pharmacological treatments. Can J Psychiatry 2016;61:540–60.
34. McIntyre RS, Suppes T, Tandon R, Ostacher M. Florida Best Practice Psychotherapeutic Medication
Guidelines for adults with major depressive disorder. J Clin Psychiatry 2017;78: 703–13.
35. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed.
Arlington, VA: American Psychiatric Publishing, 2013.
36. Trivedi MH, Thase ME, Fava M, et al. Adjunctive aripiprazole in major depressive disorder: analysis
of efficacy and safety in patients with anxious and atypical features. J Clin Psychiatry 2008;69:1928–
36.
37. Carney RM, Freedland KE. Treatment-resistant depression and mortality after acute coronary
syndrome. Am J Psychiatry 2009;166:410–7.
38. Glassman AH, O’Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients
with acute MI or unstable angina. JAMA 2002;288:701–9.
39. Kang HJ, Bae KY, Kim SW, et al. Associations between serotonergic genes and escitalopram
treatment responses in patients with depressive disorder and acute coronary syndrome: the
EsDEPACS Study. Psychiatry Investig 2016;13:157–60.
40. Walther CP, Shah AA, Winkelmayer WC. Treating depression in patients with advanced CKD:
beyond the generalizability frontier. JAMA 2017;318:1873–4.
42. Vieweg WV, Hasnain M, Howland RH, et al. Citalopram, QTc interval prolongation, and torsade de
pointes. How should we apply the recent FDA ruling? Am J Med 2012;125:859–68.
43. Paton C, Ferrier IN. SSRIs and gastrointestinal bleeding. BMJ 2005;331:529–30.
44. Na KS, Jung HY, Cho SJ, Cho SE. Can we recommend mirtazapine and bupropion for patients at risk
for bleeding? A systematic review and meta-analysis. J Affect Disord 2018; 225:221–6.
45. Mead GE, Hsieh CF, Lee R, et al. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery.
Cochrane Database Syst Rev 2012;11:CD009286.
Cochrane Database Syst Rev 2012;11:CD009286.
46. Picker L, Van Den Eede F, Dumont G, Moorkens G, Sabbe BG. Antidepressants and the risk of
hyponatremia: a class-by-class review of literature. Psychosomatics 2014;55:536–47.
47. Thorlund K, Druyts E,Wu P, Balijepalli C, Keohane D, Mills E. Comparative efficacy and safety of
selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors in older
adults: a network meta-analysis. J Am Geriatr Soc 2015;63: 1002–9.
48. Naples JG, Kotlarczyk MP, Perera S, Greenspan SL, Hanlon JT. Non-tricyclic and non-selective
serotonin reuptake inhibitor antidepressants and recurrent falls in frail older women. Am J Geriatr
Psychiatry 2016;24:1221–7.
49. Kellner CH, Husain MM, Knapp RG, et al. Right unilateral ultrabrief pulse ECT in geriatric
depression: phase 1 of the PRIDE study. Am J Psychiatry 2016;173:1101–9.
50. Fenske JN, Petersen K. Obsessive-compulsive disorder: diagnosis and management. Am Fam
Physician 2015;92:896–903.
51. Lavretsky H, Reinlieb M, St Cyr N, Siddarth P, Ercoli LM, Senturk D. Citalopram, methylphenidate,
or their combination in geriatric depression: a randomized, double-blind, placebo-controlled trial. Am
J Psychiatry 2015;172:561–9.
52. Bennett HA, Einarson A, Taddio A, Koren G, Einarson TR. Prevalence of depression during
pregnancy: systematic review. Obstet Gynecol 2004;103:698–709.
53. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women
who maintain or discontinue antidepressant treatment. JAMA 2006;295: 499–507.
54. Addis A, Koren G. Safety of fluoxetine during the first trimester of pregnancy: a meta-analytical
review of epidemiological studies. Psychol Med 2000;30:89–94.
55. Kieler H, Artama M, Engeland A, et al. Selective serotonin reuptake inhibitors during pregnancy and
risk of persistent pulmonary hypertension in the newborn: population based cohort study from the
five Nordic countries. BMJ 2012;344:d8012 .
56. Brown AS, Gyllenberg D, Malm H, et al. Association of selective serotonin reuptake inhibitor
exposure during pregnancy with speech, scholastic, and motor disorders in offspring. JAMA
Psychiatry 2016;73:1163–70.
57. Reefhuis J, Devine O, Friedman JM, Louik C, Honein MA; National Birth Defects Prevention Study.
Specific SSRIs and birth defects: Bayesian analysis to interpret new data in the context of previous
reports. BMJ 2015;351:h3190.
58. Coryell W. A medication for depression with mixed features. Am J Psychiatry 2016;173:315–6.
59. Suppes T, Silva R, Cucchiaro J, et al. Lurasidone for the treatment of major depressive disorder with
mixed features: a randomized, double-blind, placebo-controlled study. Am J Psychiatry
2016;173:400–7.
60. Thase ME, Demyttenaere K, Earley WR, Gustafsson U, Udd M, Eriksson H. Extended release
quetiapine fumarate in major depressive disorder: analysis in patients with anxious depression.
Depress Anxiety 2012;29:574–86.
61. Pringsheim T, Gardner D, Patten SB. Adjunctive treatment with quetiapine for major depressive
disorder: are the benefits of treatment worth the risks? BMJ 2015;350:h569.
62. Anderson IM. SSRIs versus tricyclic antidepressants in depressed inpatients: a meta-analysis of
efficacy and tolerability. Depress Anxiety 1998;7 suppl 1:11–7.
Guelfi JD, Ansseau M, Timmerman L, Kørsgaard S; MirtazapineVenlafaxine Study Group.
63. Guelfi JD, Ansseau M, Timmerman L, Kørsgaard S; MirtazapineVenlafaxine Study Group.
Mirtazapine versus venlafaxine in hospitalized severely depressed patients with melancholic features.
J Clin Psychopharmacol 2001;21:425–31.
64. Husain MM, Rush AJ, Fink M, et al. Speed of response and remission in major depressive disorder
with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report. J
Clin Psychiatry 2004;65:485–91.
65. Schulze-Rauschenbach SC, Harms U, Schlaepfer TE, Maier W, Falkai P, Wagner M. Distinctive
neurocognitive effects of repetitive transcranial magnetic stimulation and electroconvulsive therapy
in major depression. Br J Psychiatry 2005;186: 410–6.
66. Sackeim HA, Prudic J, Devanand DP, et al. A prospective, randomized, double-blind comparison of
bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen
Psychiatry 2000;57:425–34.
67. McCall WV, Reboussin DM, Weiner RD, Sackeim HA. Titrated moderately suprathreshold vs. fixed
high-dose right unilateral electroconvulsive therapy: acute antidepressant and cognitive effects. Arch
Gen Psychiatry 2000;57:438–44.
68. Kho KH, Zwinderman AH, Blansjaar BA. Predictors for the efficacy of electroconvulsive therapy:
chart review of a naturalistic study. J Clin Psychiatry 2005;66:894–9.
69. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the
treatment of mood disorders. JAMA Psychiatry 2017;74:399–405.
70. Wilkinson ST, Sanacora G. Considerations on the off-label use of ketamine asa treatment for mood
disorders. JAMA 2017;318: 793–4.
71. Wilkinson ST, Toprak M, Turner MS, Levine SP, Katz RB, Sanacora G. A survey of the clinical, off-
label use of ketamine as a treatment for psychiatric disorders. Am J Psychiatry 2017;174:695–6.
72. Bjerre J, Fontenay C. Ketamine in melancholic depression. Ugeskr Laeger 2010;172:460–1.
73. Marder SR, Gitlin MJ. A cruel irony for clinicians who treat depression. Am J Psychiatry
2017;174:409–10.
74. White N, Litovitz T, Clancy C. Suicidal antidepressant overdoses: a comparative analysis by
antidepressant type. J Med Toxicol 2008;4:238–50.
75. Benkert O, Grunder G, Wetzel H, Hackett D. A randomized, double-blind comparison of a rapidly
escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia. J
Psychiatr Res 1996;30:441–51.
76. Guelfi JD, White C, Hackett D, Guichoux JY, Magni G. Effectiveness of venlafaxine in patients
hospitalized for major depression and melancholia. J Clin Psychiatry 1995;56: 450–8.
77. Connolly KR, Thase ME. If at first you don’t succeed: a review of the evidence for antidepressant
augmentation, combination and switching strategies. Drugs 2011;71:43–64 .
78. Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive
disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry 2007;68:
935–40.
79. Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of
refractory depression. A meta-analysis. Arch Gen Psychiatry 1996;53:842–8.
80. Altshuler LL, Bauer M, Frye MA, et al. Does thyroid supplementation accelerate tricyclic
antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry
2001;158:1617–22.
2001;158:1617–22.
81. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation
following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry
2006;163:1519–30; quiz 665.
82. Carvalho AF, Cavalcante JL, Castelo MS, Lima MC. Augmentation strategies for treatment-resistant
depression: a literature review. J Clin Pharm Ther 2007;32:415–28.
83. Kirino E. Escitalopram for the management of major depressive disorder: a review of its efficacy,
safety, and patient acceptability. Patient Prefer Adherence 2012;6:853–61.
84. Carlat D. Evidence-based somatic treatment of depression in adults. Psychiatr Clin North Am
2012;35:131–42.
85. Garnock-Jones KP, McCormack PL. Escitalopram: a review of its use in the management of major
depressive disorder in adults. CNS Drugs 2010;24:769–96.
86. Sanchez C, Reines EH, Montgomery SA. A comparative review of escitalopram, paroxetine, and
sertraline: are they all alike? Int Clin Psychopharmacol 2014;29:185–96.
87. Rosenbluth M, Macqueen G, McIntyre RS, et al. The Canadian Network for Mood and Anxiety
Treatments (CANMAT) task force recommendations for the management of patients with mood
disorders and comorbid personality disorders. Ann Clin Psychiatry 2012;24:56–68.
88. McIntyre RS, Alsuwaidan M, Goldstein BI, et al. The Canadian Network for Mood and Anxiety
Treatments (CANMAT) task force recommendations for the management of patients with mood
disorders and comorbid metabolic disorders. Ann Clin Psychiatry 2012;24:69–81.
89. Ramasubbu R, Taylor VH, Samaan Z, et al. The Canadian Network for Mood and Anxiety
Treatments (CANMAT) task force recommendations for the management of patients with mood
disorders and select comorbid medical conditions. Ann Clin Psychiatry 2012;24:91–109.
90. Cleare A, Pariante CM, Young AH, et al. Evidence-based guidelines for treating depressive disorders
with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines.
J Psychopharmacol 2015;29:459–525.
91. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-
generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009;373:746–58.
92. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21
antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic
review and network meta-analysis. Lancet 2018;391:1357–66.
93. Sung SC, Haley CL, Wisniewski SR, et al. The impact of chronic depression on acute and long-term
outcomes in a randomized trial comparing selective serotonin reuptake inhibitor monotherapy versus
each of 2 different antidepressant medication combinations. J Clin Psychiatry 2012;73:967–76.
94. Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based guidelines for treating depressive
disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology
guidelines. J Psychopharmacol 2008;22:343–96.
95. Zimmerman M, Posternak MA, Attiullah N, et al. Why isn’t bupropion the most frequently
prescribed antidepressant? J Clin Psychiatry 2005;66:603–10.
96. Trivedi MH, Rush AJ, Carmody TJ, et al. Do bupropion SR and sertraline differ in their effects on
anxiety in depressed patients? J Clin Psychiatry 2001;62:776–81.
97. Dunner DL, Zisook S, Billow AA, Batey SR, Johnston JA, Ascher JA. A prospective safety
surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry
surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry
1998;59:366–73.
98. Tripp AC. Bupropion, a brief history of seizure risk. Gen Hosp Psychiatry 2010;32:216–7 .
99. Mohamed S, Johnson GR, Chen P, et al. Effect of antidepressant switching vs. augmentation on
remission among patients with major depressive disorder unresponsive to antidepressant treatment:
the VAST-D randomized clinical trial. JAMA 2017; 318:132–45.
100. Gandhi TK, Weingart SN, Borus J, et al. Adverse drug events in ambulatory care. N Engl J Med
2003;348:1556–64.
101. Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants: a meta-
analysis. J Clin Psychopharmacol 2009;29:259–66.
102. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction
associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish
Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry
2001;62 suppl 3:10–21.
103. Fava M, Nurnberg HG, Seidman SN, et al. Efficacy and safety of sildenafil in men with
serotonergic antidepressant-associated erectile dysfunction: results from a randomized, double-
blind, placebo-controlled trial. J Clin Psychiatry 2006;67:240–6.
104. Moon CA, Laws D, Stott PC, Hayes G. Efficacy and tolerability of controlled-release trazodone in
depression: a large multicentre study in general practice. Curr Med Res Opin 1990;12:160–8.
105. Frampton JE. Vortioxetine: a review in cognitive dysfunction in depression. Drugs 2016;76:1675–
82.
106. McIntyre RS, Florea I, Tonnoir B, Loft H, Lam RW, Christensen MC. Efficacy of vortioxetine on
cognitive functioning in working patients with major depressive disorder. J Clin Psychiatry
2017;78:115–21.
107. Spielmans GI. Duloxetine does not relieve painful physical symptoms in depression: a meta-
analysis. Psychother Psychosom 2008;77:12–6.
108. Gebhardt S, Heinzel-Gutenbrunner M, Konig U. Pain relief in depressive disorders: a meta-analysis
of the effects of antidepressants. J Clin Psychopharmacol 2016;36:658–68.
109. Leong C, Alessi-Severini S, Enns MW, et al. Cerebrovascular, cardiovascular, and mortality events
in new users of selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake
inhibitors: a propensity score-matched population-based study. J Clin Psychopharmacol
2017;37:332–40.
110. Safer DJ. Raising the minimum effective dose of serotonin reuptake inhibitor antidepressants:
adverse drug events. J Clin Psychopharmacol 2016;36:483–91.
111. Uher R, Mors O, Rietschel M, et al. Early and delayed onset of response to antidepressants in
individual trajectories of change during treatment of major depression: a secondary analysis of data
from the Genome-Based Therapeutic Drugs for Depression (GENDEP) study. J Clin Psychiatry
2011;72:1478–84.
112. Nelson JC. Treatment of antidepressant nonresponders: augmentation or switch? J Clin Psychiatry
1998;59 suppl 15: 35–41.
113. Gaynes BN, Dusetzina SB, Ellis AR, et al. Treating depression after initial treatment failure:
directly comparing switch and augmenting strategies in STAR*D. J Clin Psychopharmacol
2012;32:114–9.
114. Quitkin FM, McGrath PJ, Stewart JW, et al. Remission rates with 3 consecutive antidepressant
trials: effectiveness for depressed outpatients. J Clin Psychiatry 2005;66:670–6.
115. Papakostas GI, Fava M, Thase ME. Treatment of SSRI-resistant depression: a meta-analysis
comparing within-versus across-class switches. Biol Psychiatry 2008;63:699–704.
116. Ruhe HG, Huyser J, Swinkels JA, Schene AH. Switching antidepressants after a first selective
serotonin reuptake inhibitor in major depressive disorder: a systematic review. J Clin Psychiatry
2006;67:1836–55.
117. Souery D, Serretti A, Calati R, et al. Switching antidepressant class does not improve response or
remission in treatmentresistant depression. J Clin Psychopharmacol 2011;31:512–6.
118. Bschor T, Baethge C. No evidence for switching the antidepressant: systematic review and meta-
analysis of RCTs of a common therapeutic strategy. Acta Psychiatr Scand 2010;121:174–9.
119. Bauer M, Tharmanathan P, Volz HP, Moeller HJ, Freemantle N. The effect of venlafaxine
compared with other antidepressants and placebo in the treatment of major depression: a
metaanalysis. Eur Arch Psychiatry Clin Neurosci 2009;259:172–85 .
120. Smith D, Dempster C, Glanville J, Freemantle N, Anderson I. Efficacy and tolerability of
venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a
meta-analysis. Br J Psychiatry 2002;180:396–404.
121. Rudolph RL, Feiger AD. A double-blind, randomized, placebo-controlled trial of once-daily
venlafaxine extended release (XR) and fluoxetine for the treatment of depression. J Affect Disord
1999;56:171–81.
122. Leinonen E, Skarstein J, Behnke K, Agren H, Helsdingen JT. Efficacy and tolerability of
mirtazapine versus citalopram: a double-blind, randomized study in patients with major depressive
disorder. Nordic Antidepressant Study Group. Int Clin Psychopharmacol 1999;14:329–37.
123. Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressants in the acute-
phase treatment of adults with major depression: systematic review and meta-analysis. J Clin
Psychiatry 2008;69:1404–15.
124. Schutter DJ, van Honk J. A framework for targeting alternative brain regions with repetitive
transcranial magnetic stimulation in the treatment of depression. J Psychiatry Neurosci 2005;30:
91–7.
125. Seminowicz DA, Mayberg HS, McIntosh AR, et al. Limbic-frontal circuitry in major depression: a
path modeling metanalysis. Neuroimage 2004;22:409–18.
126. Eranti S, Mogg A, Pluck G, et al. A randomized, controlled trial with 6-month follow-up of
repetitive transcranial magnetic stimulation and electroconvulsive therapy for severe depression.
Am J Psychiatry 2007;164:73–81.
127. O’Reardon JP, Cristancho P, Pilania P, Bapatla KB, Chuai S, Peshek AD. Patients with a major
depressive episode responding to treatment with repetitive transcranial magnetic stimulation
(rTMS) are resistant to the effects of rapid tryptophan depletion. Depress Anxiety 2007;24:537–44.
128. Sharma A, Gerbarg P, Bottiglieri T, et al. S-adenosylmethionine (SAMe) for neuropsychiatric
disorders: a clinician-oriented review of research. J Clin Psychiatry 2017;78:e656-e67.
129. Linde K, Berner MM, Kriston L. St John’s wort for major depression. Cochrane Database Syst Rev
2008;(4):CD000448.
130. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy for SSRI-
resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J
resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J
Psychiatry 2012;169:1267–74.
131. Berk M, Dean OM, Cotton SM, et al. The efficacy of adjunctive N-acetylcysteine in major
depressive disorder: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry
2014;75:628–36.
132. Gertsik L, Poland RE, Bresee C, Rapaport MH. Omega-3 fatty acid augmentation of citalopram
treatment for patients with major depressive disorder. J Clin Psychopharmacol 2012;32:61–4.
133. Perera S, Eisen R, Bhatt M, et al. Light therapy for nonseasonal depression: systematic review and
meta-analysis. BJPsych Open 2016;2:116–26.
134. Sarris J, Murphy J, Mischoulon D, et al. Adjunctive nutraceuticals for depression: a systematic
review and meta-analyses. Am J Psychiatry 2016;173:575–87.
135. Jefferson JW. Folate for depression: fabulous facilitator or fantastic flop? Psychopharm Rev
2007;42:75–82.
136. Lam RW, Levitt AJ, Levitan RD, et al. Efficacy of bright light treatment, fluoxetine, and the
combination in patients with nonseasonal major depressive disorder: a randomized clinical trial.
JAMA Psychiatry 2016;73:56–63.
137. Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in
major depression. J Clin Psychiatry 1999;60:256–9.
138. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a
meta-analysis of placebocontrolled randomized trials. Am J Psychiatry 2009;166: 980–91.
139. Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC. Adjunctive atypical
antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life,
and safety outcomes. PLoS Med 2013;10: e1001403.
140. Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) study. Psychiatr Clin North Am 2003;26: 457–94, x
.
141. Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant
augmentation with mirtazapine. Biol Psychiatry 2002;51:183–8.
142. Carpenter LL, Jocic Z, Hall JM, Rasmussen SA, Price LH. Mirtazapine augmentation in the
treatment of refractory depression. J Clin Psychiatry 1999;60:45–9.
143. Atmaca M, Korkmaz S, Topuz M, Mermi O. Mirtazapine augmentation for selective serotonin
reuptake inhibitor-induced sexual dysfunction: a retrospective investigation. Psychiatry Investig
2011;8:55–7.
144. Ivanova JI, Birnbaum HG, Kidolezi Y, Subramanian G, Khan SA, Stensland MD. Direct and
indirect costs of employees with treatment-resistant and non-treatment-resistant major depressive
disorder. Curr Med Res Opin 2010;26:2475–84.
145. Pae CU, Tharwani H, Marks DM, Masand PS, Patkar AA. Atypical depression: a comprehensive
review. CNS Drugs 2009;23:1023–37.
146. Joyce PR, Mulder RT, Luty SE, et al. Patterns and predictors of remission, response and recovery
in major depression treated with fluoxetine or nortriptyline. Aust N Z J Psychiatry 2002; 36:384–
91.
147. Sogaard J, Lane R, Latimer P, et al. A 12-week study comparing moclobemide and sertraline in the
treatment of outpatients with atypical depression. J Psychopharmacol 1999; 13:406–14.
treatment of outpatients with atypical depression. J Psychopharmacol 1999; 13:406–14.
148. Henkel V, Mergl R, Allgaier AK, Kohnen R, Moller HJ, Hegerl U. Treatment of depression with
atypical features: a meta-analytic approach. Psychiatry Res 2006;141:89–101.
149. Stewart JW, Tricamo E, McGrath PJ, Quitkin FM. Prophylactic efficacy of phenelzine and
imipramine in chronic atypical depression: likelihood of recurrence on discontinuation after 6
months’ remission. Am J Psychiatry 1997;154:31–6.
150. Rabkin J, Quitkin F, Harrison W, Tricamo E, McGrath P. Adverse reactions to monoamine oxidase
inhibitors. Part I. A comparative study. J Clin Psychopharmacol 1984;4:270–8.
151. Patkar AA, Pae CU, Masand PS. Transdermal selegiline: the new generation of monoamine
oxidase inhibitors. CNS Spectr 2006;11:363–75.
152. Rapaport MH, Thase ME. Translating the evidence on atypical depression into clinical practice. J
Clin Psychiatry 2007; 68:e11.
153. Stahl SM. Prescriber’s guide: Stahl’s essential psychopharmacology. 6th ed. Cambridge:
Cambridge University Press, 2017:663.
154. Asnis GM, Henderson MA. EMSAM (deprenyl patch): how a promising antidepressant was
underutilized. Neuropsychiatr Dis Treat 2014;10:1911–23.
155.
Becker ME, Hertzberg MA, Moore SD, Dennis MF, Bukenya DS, Beckham JC. A placebo-
controlled trial of bupropion SR in the treatment of chronic posttraumatic stress disorder. J Clin
Psychopharmacol 2007;27:193–7.
156. Fava M. Lessons learned from the VA Augmentation and Switching Treatments for Improving
Depression Outcomes (VAST-D) study. JAMA 2017;318:126–8.
157. Baldomero EB, Ubago JG, Cercos CL, Ruiloba JV, Calvo CG, Lopez RP. Venlafaxine extended
release versus conventional antidepressants in the remission of depressive disorders after previous
antidepressant failure: ARGOS study. Depress Anxiety 2005;22:68–76.
158. Thase ME, Rush AJ, Howland RH, et al. Double-blind switch study of imipramine or sertraline
treatment of antidepressant resistant chronic depression. Arch Gen Psychiatry 2002;59: 233–9.
159. Blier P, Ward HE, Tremblay P, Laberge L, Hebert C, Bergeron R. Combination of antidepressant
medications from treatment initiation for major depressive disorder: a double-blind randomized
study. Am J Psychiatry 2010;167:281–8.
160. Rasmussen KG, Mueller M, Knapp RG, et al. Antidepressant medication treatment failure does not
predict lower remission with ECT for major depressive disorder: a report from the Consortium for
Research in Electroconvulsive Therapy. J Clin Psychiatry 2007;68:1701–6.
161. Dombrovski AY, Mulsant BH, Haskett RF, Prudic J, Begley AE, Sackeim HA. Predictors of
remission after electroconvulsive therapy in unipolar major depression. J Clin Psychiatry
2005;66:1043–9.
162. Briley M, Moret C. Treatment of comorbid pain with serotonin norepinephrine reuptake inhibitors.
CNS Spectr 2008;13: 22–6 .
163. Philipp M, Fickinger M. Psychotropic drugs in the management of chronic pain syndromes.
Pharmacopsychiatry 1993;26: 221–34.
164. Rintala DH, Holmes SA, Courtade D, Fiess RN, Tastard LV, Loubser PG. Comparison of the
effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal
cord injury. Arch Phys Med Rehabil 2007;88:1547–60.
Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain
165.
Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain
treatment: an evidence-based proposal. Pain 2005;118:289–305.
166. Bech P, Gormsen L, Loldrup D, Lunde M. The clinical effect of clomipramine in chronic
idiopathic pain disorder revisited using the Spielberger State Anxiety Symptom Scale (SSASS) as
outcome scale. J Affect Disord 2009;119:43–51.
167. Perahia DG, Pritchett YL, Desaiah D, Raskin J. Efficacy of duloxetine in painful symptoms: an
analgesic or antidepressant effect? Int Clin Psychopharmacol 2006;21:311–7.
168. Raskin J, Pritchett YL, Wang F, et al. A double-blind, randomized multicenter trial comparing
duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med
2005;6:346–56.
169. Arnold LM, Pritchett YL, D’Souza DN, Kajdasz DK, Iyengar S, Wernicke JF. Duloxetine for the
treatment of fibromyalgia in women: pooled results from two randomized, placebo-controlled
clinical trials. J Womens Health (Larchmt) 2007;16:1145–56.
170. Brecht S, Courtecuisse C, Debieuvre C, et al. Efficacy and safety of duloxetine 60 mg once daily in
the treatment of pain in patients with major depressive disorder and at least moderate pain of
unknown etiology: a randomized controlled trial. J Clin Psychiatry 2007;68:1707–16.
171. Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for
painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a
range of doses. Diabetes Care 2008;31: 1448–54.
172. Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane
Database Syst Rev 2011;(3):CD005452.
173. Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and
fibromyalgia in adults. Cochrane Database Syst Rev 2011;(3):CD007938.
174. Bloch MH, McGuire J, Landeros-Weisenberger A, Leckman JF, Pittenger C. Meta-analysis of the
dose-response relationship of SSRI in obsessive-compulsive disorder. Mol Psychiatry 2010;15:
850–5.
176. Tollefson GD, Rampey AHJr, Potvin JH, et al. A multicenter investigation of fixed-dose fluoxetine
in the treatment of obsessive-compulsive disorder. Arch Gen Psychiatry 1994;51: 559–67.
177. Veale D, Miles S, Smallcombe N, Ghezai H, Goldacre B, Hodsoll J. Atypical antipsychotic
augmentation in SSRI treatment refractory obsessive-compulsive disorder: a systematic review and
meta-analysis. BMC Psychiatry 2014;14:317.
178. Wilens TE, Morrison NR, Prince J. An update on the pharmacotherapy of attention-
deficit/hyperactivity disorder in adults. Expert Rev Neurother 2011;11:1443–65.
179. Nuijten M, Blanken P, van de Wetering B, Nuijen B, van den Brink W, Hendriks VM. Sustained-
release dexamfetamine in the treatment of chronic cocaine-dependent patients on heroin-assisted
treatment: a randomised, double-blind, placebo-controlled trial. Lancet 2016;387:2226–34.
180. McIntyre RS, Lee Y, Zhou AJ, et al. The efficacy of psychostimulants in major depressive
episodes: a systematic review and meta-analysis. J Clin Psychopharmacol 2017;37:412–8.
181. Rosler M, Retz W, Fischer R, et al. Twenty-four-week treatment with extended release
methylphenidate improves emotional symptoms in adult ADHD. World J Biol Psychiatry
2010;11:709–18.
182. Wernicke JF, Adler L, Spencer T, et al. Changes in symptoms and adverse events after
discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder:
a prospective, placebo-controlled assessment. J Clin Psychopharmacol 2004;24:30–5.
183. Wilens TE, Haight BR, Horrigan JP, et al. Bupropion XL in adults with attention-
deficit/hyperactivity disorder: a randomized, placebo-controlled study. Biol Psychiatry 2005;57:
793–801 .
184. Wilens TE, Biederman J, Mick E, Spencer TJ. A systematic assessment of tricyclic antidepressants
in the treatment of adult attention-deficit hyperactivity disorder. J Nerv Ment Dis 1995;183:48–50.
185. Hornig-Rohan M, Amsterdam JD. Venlafaxine versus stimulant therapy in patients with dual
diagnosis ADD and depression. Prog Neuropsychopharmacol Biol Psychiatry 2002;26: 585–9.
186. Adler LA, Resnick S, Kunz M, Devinsky O. Open-label trial of venlafaxine in adults with attention
deficit disorder. Psychopharmacol Bull 1995;31:785–8.
187. Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with
nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry 192.
2013;170:1003–10.
188. De Jong J, Wauben P, Huijbrechts I, Oolders H, Haffmans J. 193. Doxazosin treatment for
posttraumatic stress disorder. J Clin Psychopharmacol 2010;30:84–5.
189. Aaronson ST, Sears P, Ruvuna F, et al. A 5-year observational study of patients with treatment-
resistant depression treated 194. with vagus nerve stimulation or treatment as usual: comparison of
response, remission, and suicidality. Am J Psychiatry 195. 2017;174:640–8.
190. Avorn J. The psychology of clinical decision making—implications for medication use. N Engl J
Med 2018;378:689–91.
191. Groopman J. How doctors think. Boston: Houghton Mifflin, 2007.
193. Dawes RM. The robust beauty of improper linear models in decision making. In: Kahneman D,
Slovic P, Tversky A, eds. Judgment under uncertainty: heuristics and biases. New York:
Cambridge University Press, 1983:391–407.
194. Mullaney TJ. Doctors wielding data. Bus Week 2005;21 Nov: 94,98.
195. Adli M, Bauer M, Rush AJ. Algorithms and collaborative-care systems for depression: are they
effective and why? A systematic review. Biol Psychiatry 2006;59:1029–38.
196. Osser D, Patterson R. On the value of evidence-based psychopharmacology algorithms. Bull Clin
Psychopharmacol 2013;23: 1–5.
NOTE: There have been a few changes in this text that corrected errors in the
original publication. The changes can be obtained from the author upon request.
From Harvard Medical School and VA Boston Healthcare System, Brockton Division, Brockton, MA.
Original manuscript received 4 December 2017, accepted for publication subject to revision 4 February
2017; revised manuscript received 4 March 2017.
Correspondence: Christoforos Iraklis Giakoumatos, MD, VA Boston Healthcare System, 940 Belmont St.,
Brockton, MA 02301. Email: cigiakoumatos@gmail.com
he major depression algorithm was published less than 1 year ago, and
there have not been significant changes in the recommendations,
although there have been some new studies that add to the evidence
base supporting basic and specific recommendations. There have also been
developments with ketamine and particularly its S-enantiomer
“esketamine” that require discussion. The published algorithm did propose
a role for intravenous ketamine for severely ill inpatients with melancholia
if electroconvulsive therapy (ECT) is ineffective or refused. Another
development is the release and marketing of the ™GeneSight genetic test
for predicting antidepressant response.
Esketamine for Treatment-Resistant Depression?
Esketamine in the form of a nasal spray was approved by the U.S. Food and
Drug Administration (FDA) as an augmentation of antidepressants for
treatment-resistant depression (TRD) in June of 2019. It is expensive, with
a retail price of $7000–$10,600 for the labeled initial 2-month treatment
course. 1 The history of studies leading to this approval is complicated. 2
There was a need to balance concerns about potential harms, including
abuse potential (ketamine was known on the street as “Special K” because
of its dissociative effects), hypertension (transient increases of 40 mm Hg
can occur), risk of suicide, and sedation. The FDA approved it with a Risk
Evaluation and Mitigation Strategy (REMS) requiring that it be given only
in major clinical centers where the patient can be observed for 2 hours after
each administration. It was tested and approved as an augmentation of an
antidepressant, because it was considered unethical to treat patients with a
serious illness like TRD without a potentially effective treatment on board.
TRD has many definitions. In our algorithm, it is defined as failure to
respond satisfactorily to two adequate trials of antidepressant therapy
(either successive monotherapies or a single antidepressant followed by an
evidence-supported augmentation trial). In the esketamine studies, TRD
was defined as two adequate trials (one of those was observed
prospectively). There were many exclusion criteria: psychosis, bipolar
disorder, personality disorders, moderate or severe substance use disorders
within the past 6 months or a positive recent screen, and obsessive-
compulsive disorder. Some of the excluded depressed patients could be
covered by the algorithms in this book for bipolar depression and psychotic
depression.
A commentary on the esketamine studies leading to FDA approval by
Alan Schatzberg in the American Journal of Psychiatry is telling and had
more questions than answers. 3 Although easier to administer than
intravenous ketamine, the efficacy of esketamine in some of the studies was
marginal. It was unclear how long it should be prescribed (in addition to the
antidepressant) and what to do if effectiveness was lost. There were some
suggestions that patients can relapse rapidly, and might become suicidal.
Significant concern was also expressed about the mechanism of action: Is it
an opiate receptor-mediated effect and will abusability issues become more
and more evident as we gain more experience with esketamine? 4 The 12-
week maintenance followed by discontinuation trial recently published was
somewhat reassuring in that regard, 5 but the patients enrolled mostly had
only one or two previous antidepressant trials, and the antidepressants to
which the esketamine was added were suboptimally dosed. Thus, it is not
clear if a higher dose of the antidepressants or another augmentation
strategy would have been as effective, according to a comment by Steven
Dubovsky in the New England Journal of Medicine Journal Watch
Psychiatry newsletter, December 2019.
Another concern regarding abuse potential is whether depressed patients,
when they no longer have access to ketamine or esketamine, might turn to
opiates or other abusable drugs or illegal ketamine. 6 Evidently, the
registries that have been set up do not capture this information.
In conclusion, regarding esketamine, it does not appear to be ready to
replace any of our favored switches or augmentations for the second or
even the third trial in the algorithm. The evidence-base is rapidly evolving
and should be followed closely, but at this time esketamine seems to belong
in the algorithm only at the end after at least several reasonably conducted
antidepressant trials have been completed.
Table 1 : Comorbidities and other features in major
depression and how they affect the algorithm
The last item in this table is depression with anxious distress. We noted that
in STAR*D and other studies, this is a common comorbidity and it is
associated with poorer response to antidepressants and most augmenters.
Sedating second-generation or “atypical” antipsychotics such as quetiapine
can be effective as augmenters in this diagnostic situation, but they bring a
significant side-effect burden. Aripiprazole, which is less sedating, is
another option. We failed to mention the option of adding a
benzodiazepine. They have their own burden of side effects of course, and
they were not utilized in STAR*D, but there is an older literature
suggesting that they may enhance depression outcome in some patients. In
a meta-analysis published in 2001, of 9 studies involving 697 subjects, 7 the
rate of response of depression (response = 50% reduction in rating scale
scores) with an added benzodiazepine was 63% versus 38% with the
antidepressant alone. Number needed to treat (NNT) was 4. These were all
short-term studies of 4–8 weeks so the long-term risks of the combination
could not be known, but they certainly might include dependence on the
benzodiazepine and accident proneness.
Node 4B: If Response to the First Antidepressant Trial Is
Unsatisfactory, Try One of These
Four options for switching and four options for augmenting were offered.
No clear differences in efficacy could be discerned from the evidence base,
so the choice would be heavily influenced by what side effects and costs
would be involved for the individual patient. Patient preference has always
been important, but was even more so at this step in the algorithm. To
reiterate, the switching choices were (1) to a different agent from the Node
4 first-line choices (sertraline, escitalopram, or bupropion); (2) to a dual-
action agent (venlafaxine or mirtazapine); (3) to repetitive transcranial
magnetic stimulation (rTMS); or (4) to S-adenosylmethionine or St. John’s
wort. The augmentation options were (1) omega-3 fatty acid, L-
methylfolate, N-acetylcysteine, or bright light therapy; (2) aripiprazole,
quetiapine, or risperidone; (3) an antidepressant (bupropion or mirtazapine);
or (4) lithium or triiodothyronine (T3).
A new study compared two augmentations head-to-head in a fairly large
open-label trial. A total of 104 patients with severe (Hamilton Depression
Rating of 24 or more) major depression (16% inpatients) who had failed to
respond to a 10-week trial of imipramine at therapeutic levels were
randomized to add-on lithium versus addition of citalopram. 8 About 21%
remitted with the lithium compared with 40% with the citalopram over the
next 10 weeks, which was a significant difference and had an NNT of 5.
Although the order of combining the imipramine and citalopram is reversed
from what it would be if one were following the algorithm, the study does
suggest that the combination of a selective serotonin reuptake inhibitor
(SSRI) and a tricyclic antidepressant is an evidenced option (superior to
lithium addition in this study, even though lithium augmentation of tricyclic
antidepressants is reasonably evidenced 9 ) and could be a third choice
added to the bupropion and mirtazapine group. Tricyclics do, however,
introduce more side effects than the other two antidepressants.
Node 5B: TRD Without Comorbidities and Without Atypical
Features
At this point in the algorithm, the patient has had two adequate
antidepressant trials. It was proposed that the prescriber consider some of
the eight options for switches and augmentations not yet tried that were
offered for the second trial at Node 4B (plus, a few other choices were
added). As noted earlier, one of those eight options was rTMS, which is
FDA approved after one failed antidepressant trial but not after two failed
trials. Many clinicians think rTMS is an evidenced treatment for TRD, but
actually the evidence of success with it after two or more failed trials is
mostly uncontrolled. There is one large study in civilian patients with a
moderate level of treatment resistance (1–4 previous trials, mean of 1.5
trials), which found that 14% receiving rTMS remitted compared to 5%
getting sham treatment (statistically significant, NNT of 11). 10 Therefore,
although not a particularly impressive option, rTMS was left in the
algorithm as an option to consider at Node 5B. However, a new large study
of rTMS in U.S. veterans with about the same moderate level of TRD (at
least two failed trials) did not find an advantage of rTMS over sham. A total
of 164 participants were randomized and 41% remitted with rTMS and 37%
with sham (NNT = 25). 11 The reasons for the overall higher rate of
remission in the veteran population are difficult to explain; perhaps the
complex procedures in both groups had a high placebo effect in this group.
Nevertheless, it seemed that the rTMS had at best a very minor impact on
their TRD. The authors speculated that advances in the techniques of
administering rTMS could have produced better results if the study was to
be repeated with those techniques, but a letter to the editor sharply
disagreed with concluding the article with that speculation.1 Further study is
needed before giving TMS greater prominence in the algorithm.
It was noted earlier that, in addition to reconsidering the eight switch and
augmentation options offered after failure on the first trial, several
additional options were added at this point. They were switching to a
tricyclic antidepressant, using a combination of venlafaxine and
mirtazapine, and ECT. A newly published study from Barcelona, Spain,
enhances the evidence for a switch to a tricyclic. Navarro and colleagues
developed a sample of 112 patients (90% outpatients) with moderate
treatment resistance but with significant severity (Hamilton Depression
Ratings of 21 or more) whose last trial was with venlafaxine 225–300 mg
daily for 10 weeks. 13 These subjects were randomized (open label) to have
mirtazapine added to their venlafaxine versus switching to imipramine with
dose adjusted with plasma levels. A total of 71% responded to the
imipramine, whereas 39% responded to the mirtazapine addition (NNT = 3
favoring imipramine).
The GeneSight Genetic Test and Other Pharmacogenomic
Testing Strategies
In a multicenter randomized trial of this amalgam of 59 genetic tests related
to the pharmacogenetics of drug metabolism and pharmacodynamics of 38
medications, the use of the test to select treatment was compared with
“treatment as usual” by primary care and psychiatric clinicians. 14 A total of
1541 patients participated. There was no difference in rating scale measures
of depression (the primary outcome measure) but secondary outcomes of
improvement and remission slightly favored the GeneSight group (NNT of
16 for improvement, 20 for remission). These are differences that are not
clinically meaningful. Also, clinicians were not blinded and could have
communicated group assignments some of the time, and the study was
funded by GeneSight. With all due respect for the clinical acumen and
experience of the practitioners in the study, their treatment as usual may not
necessarily be evidence supported. These genomic products need to
compare their results with the results by clinicians endeavoring to utilize
the evidence base as closely as possible, employing algorithms based on the
evidence such as the one in this book. 15 None of the studies have done that.
Another difficulty is the lack of transparency in these genomic products.
There is no reasoning offered for why the test is predicting a particular
drug. Indeed, their algorithm of how the computer mixes and matches the
gene results to make a prediction is proprietary and a secret. It would seem
that clinicians should not cease efforts to stay up-to-date and to practice in
accord with the best evidence rather than letting the decisions be made by
reasoning that is blinded to the prescriber and patient using costly tests like
GeneSight.
REFERENCES
1. Wilkinson ST, Howard DH, Busch SH. Psychiatric practice patterns and barriers to the adoption
of esketamine. JAMA 2019;322:1039–40.
2. Kim J, Farchione T, Potter A, Chen Q, Temple R. Esketamine for treatment-resistant depression
—first FDA-approved antidepressant in a new class. N Engl J Med 2019;381:1–4.
3. Schatzberg AF. A word to the wise about intranasal esketamine. Am J Psychiatry 2019;176:422–
4.
4. George MS. Is there really nothing new under the sun? Is low-dose ketamine a fast-acting
antidepressant simply because it is an opioid? Am J Psychiatry 2018;175:1157–8.
5. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant
treatment for relapse prevention in patients with treatment-resistant depression: a randomized
clinical trial. JAMA Psychiatry 2019;76:893–903.
6. McShane R, Baldwin DS, McAllister-Williams RH, et al. Esketamine and the need for a new
type of registry for drugs with abuse potential. Am J Psychiatry 2019;176:966.
7. Furukawa TA, Streiner DL, Young LT. Is antidepressant-benzodiazepine combination therapy
clinically more useful? A meta-analytic study. J Affect Disord 2001;65:173–7.
8. Navarro V, Boulahfa I, Obach A, et al. Lithium augmentation versus citalopram combination in
imipramine-resistant major depression: a 10-week randomized open-label study. J Clin
Psychopharmacol 2019;39:254–7.
9. Thase ME. Therapeutic alternatives for difficult-to-treat depression: a narrative review of the
state of the evidence. CNS Spectr 2004;9:808–16, 18–21.
10. George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic
stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch
Gen Psychiatry 2010;67:507–16.
11. Yesavage JA, Fairchild JK, Mi Z, et al. Effect of repetitive transcranial magnetic stimulation
on treatment-resistant major depression in US veterans: a randomized clinical trial. JAMA
Psychiatry 2018;75:884–93.
12. Chow ZR. Sham treatment is as effective for treatment-resistant depression as repetitive
transcranial magnetic stimulation. JAMA Psychiatry 2019;76:99.
13. Navarro V, Boulahfa I, Obach A, et al. Switching to imipramine versus add-on mirtazapine in
venlafaxine-resistant major depression: a 10-week randomized open study. J Clin
Psychopharmacol 2019;39:63–6.
14. Greden JF, Parikh SV, Rothschild AJ, et al. Impact of pharmacogenomics on clinical
outcomes in major depressive disorder in the GUIDED trial: a large, patient- and rater-blinded,
outcomes in major depressive disorder in the GUIDED trial: a large, patient- and rater-blinded,
randomized, controlled study. J Psychiatr Res 2019;111:59–67.
15. Zubenko GS, Sommer BR, Cohen BM. On the marketing and use of pharmacogenetic tests for
psychiatric treatment. JAMA Psychiatry 2018;75:769–70.
The Psychopharmacology Algorithm Project at
the Harvard South Shore Program: 2012
Update on Psychotic Depression
Michael Tang , DO 1 and David N. Osser, MD 2
Abstract: The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: 2012 Update on Psychotic Depression
Background: The Psychopharmacology Algorithm Project at the Harvard South Shore
Program (PAPHSS) has published evidence-supported algorithms for the
pharmacological treatment of major depressive disorder with psychotic features
(psychotic depression) in 1998 and 2008. This article is an update for the 2008
algorithm.
Method: Using similar methodology as with the 2008 update, PubMed and EMBASE
searches were conducted to identity relevant literature in the English language from
November 2007 through July 2012. Articles were evaluated for quality of the data and
for whether they provided additional evidence support for previous recommendations
or prompted changes to the prior algorithm.
Results: Minor changes were made to the algorithm: most prior recommendations
were upheld. The most effective treatment for hospitalized, severe psychotic depression
patients remains electroconvulsive therapy (ECT). The combination of an
antidepressant (tricyclic [TCA], selective serotonin reuptake inhibitor [SSRI], or
serotonin-norepinephrine reuptake inhibitor [SNRI]) plus an antipsychotic continues to
be the preferred pharmacological modality when ECT is an unavailable/deferred
option. Since the last update, new evidence tends to support using venlafaxine ER, a
SNRI, as the first choice antidepressant. Regarding the antipsychotic, both olanzapine
and quetiapine have new data demonstrating efficacy. Nevertheless, it is suggested that
it may be reasonable to try other atypical antipsychotics with more benign safety
profiles (e.g. ziprasidone, aripiprazole) as the first choice antipsychotic. New data also
suggest at least four months of maintenance therapy is effective. If the first
antidepressant-antipsychotic combination produces an unsatisfactory outcome, and
ECT is still not acceptable or appropriate, the second pharmacotherapy trial can be
with a change in the antidepressant, as was recommended in the 2008 algorithm. After
two trials of combination therapy have failed (and, again, ECT is not an option), the
algorithm continues to recommend augmentation with lithium. Limited evidence also
suggests consideration of a switch to clozapine monotherapy. Augmentation with
methylphenidate is a newly mentioned possible option based on very small evidence.
When combination therapy is deferred, evidence suggests monotherapy with a TCA
may be more effective than an SNRI or SSRI. However, safety issues and possible
increased risk of psychosis exacerbation are unfavorable factors for TCA monotherapy.
ECT or addition of an antipsychotic should be reconsidered if antidepressant
monotherapy failed.
Conclusion: This heuristic further refines the previous PAPHSS analysis of the
available evidence for pharmacological treatment of psychotic depression. The validity
of the conclusions is limited by the quality and quantity of the literature available: the
number of head-to-head prospective trials in psychotic depression is still relatively
small. However, this algorithm may serve as a guide for clinicians in the management
of psychotic depression.
INTRODUCTION
The pharmacological management of psychotic depression has varied
among clinicians, and debate regarding the optimum approach is
ongoing. The Psychopharmacology Algorithm Project at the Harvard
South Shore Program (PAPHSS) created and published evidence-
supported heuristics for the use of medication in psychotic depression
in 1998 and 2008 ( 1 , 2 ). This article serves as an update to the 2008
algorithm.
It is estimated that psychotic depression occurs in 14%–18% of all
patients with depressive episodes ( 3 , 4 ), and in approximately 25%
of patients hospitalized for major depressive disorder ( 5 ). However,
there is evidence of diagnostic instability when patients are followed
longitudinally. In a 10-year prospective study by Ruggero and
colleagues ( 6 ), 80 subjects initially diagnosed with psychotic
depression by the DSM-IV criteria were followed. Only 36 (45%)
retained the original diagnosis at year 10, while 11 (14%) were
diagnosed with bipolar disorder and 33 (41%) had a non-mood
disorder at year 10. In another study, Tohen and colleagues conducted
a two-year follow up of 56 patients with first-episode psychotic
depression ( 7 ). Seven dropped out of the study, 29 (59%) retained
their initial diagnosis, and the other 20 changed to a diagnosis of either
bipolar disorder (14/20) or schizoaffective disorder (6/20). Given such
statistics, clinicians should remember that initial diagnosis is only
provisional, and the subsequent course may result in a change in
diagnosis and in the indicated psychopharmacology.
METHODS
This algorithm update is one of several recently published by the
PAPHSS (1 , 8 – 11 ) and available in condensed format for access on
smart phone devices on the website www.psychopharm.mobi . The
methods of producing these algorithms have been described in the
previous publications. For this psychotic depression update, the
authors utilized similar methodology to the 2008 update, in which
PubMed and EMBASE searches were conducted to identify relevant
studies, meta-analyses, practice guidelines, and reviews in English
from November 2007 through July, 2012. Articles were evaluated for
the quality of the evidence, and whether they either added support for
previous conclusions of the PAPHSS algorithm or called for
reconsideration or change of recommendations.
The algorithm is depicted in Figure 1 . It focuses on
psychopharmacological treatment of psychotic depression and does
not address psychotherapy treatment options. Arabic numerals refer to
“nodes” in the algorithm flowchart, and each node is reviewed below
with discussion of the pertinent evidence and its limitations .
Figure 1: Flowchart of the Algorithm for Psychotic Depression
Norepinephrine Reuptake Inhibitor; TCA: Tricyclic Antidepressant. *Patients with psychotic
depression are at a higher risk of suicide/overdose
NODE 1: IF SEVERELY ILL, HAVE YOU
CONSIDERED ELECTROCONVULSIVE THERAPY?
The algorithm starts with questioning the patient’s appropriateness for
electroconvulsive therapy (ECT) as the initial treatment. Consistent
with the 2008 algorithm, ECT is still to be considered for hospitalized,
severely ill patients, as it may be the most effective treatment for
psychotic depression. However, the supporting data are all from
uncontrolled studies. In an observational study by Petrides and
colleagues, 77 subjects with psychotic depression receiving bilateral
ECT achieved a remission rate of 95%, based on the 24-item Hamilton
Depression Rating Scale (HAM-D-24) versus 83% in nonpsychotic
depressed patients; (n=176), p < .01 ( 12 ). In a chart review
comparing 14 patients receiving ECT and 12 unmatched patients
receiving antidepressant plus antipsychotic combination, 86% of ECT
patients received a favorable overall response as compared to 42% of
patients in the combination group (p< 0.05) ( 13 ). This study had a
small sample size, and ECT was compared to different combinations
with varying doses and treatment periods.
Other uncontrolled studies found ECT to have better response rates
than pharmacological management. Olfson and colleagues found that
ECT is more rapidly effective than pharmacotherapy, shortens hospital
stays, and reduces treatment costs if initiated within five days of
admission ( 14 ).
However, ECT still remains to be compared randomly and
prospectively in acute treatment with any medication regimen, and the
duration of ECT effect still remains unclear ( 15 ).
Although this algorithm mainly focuses on acute management of
psychotic depression, it is worth noting a new maintenance treatment
study by Navarro and colleagues that reflects positively on the role of
ECT ( 16 ). It was a 2-year randomized, single-blind study of patients
age 60 or greater initially treated with ECT and nortriptyline, followed
by either nortriptyline monotherapy (n=16) or ECT plus nortriptyline
(n=17). The nortriptyline monotherapy group also was given 6 weeks
of risperidone up to 2 mg daily. Results showed 5/17 patients on
nortriptyline monotherapy did not have a recurrence, as compared to
11/16 in the ECT plus nortriptyline group (p=0.009). Both groups had
4 dropouts. Limitations to the study included its small sample size and
the inclusion of only older subjects. Also, it would have been of
interest to have a comparison group of patients maintained on
combined antidepressant plus antipsychotic.
Despite its apparent effectiveness, ECT has several problems
including its limited availability and its side effects, most notably
memory impairment. Also, some studies have also reported a high
relapse rate in psychotic depression after a good response to ECT ( 17
, 18 ). In addition, patients and families may refuse ECT treatment, or
patients may not be good candidates because of comorbid medical
conditions.
NODE 2: HAVE YOU TRIED (2A) TRICYCLIC
ANTIDEPRESSANT PLUS ANTIPSYCHOTIC, (2B)
SELECTIVE SEROTONIN REUPTAKE INHIBITOR
PLUS ANTIPSYCHOTIC, OR (2C) SEROTONIN
NOREPINEPHRINE REUPTAKE INHIBITOR PLUS
ANTIPSYCHOTIC?
When the patient has a milder presentation, refuses ECT, or is not a
suitable candidate for ECT, pharmacological management is
recommended by the 2010 American Psychiatric Association (APA)
Practice Guideline ( 19 ) and the 2009 British National Institute for
Clinical Excellence (NICE) guideline ( 20 ). The 2008 PAPHSS
algorithm (1 ), the APA practice guideline, and a recent meta-analysis
by Farahani et al ( 21 ) suggest that psychotic depression typically
responds better to combination therapy with an antidepressant plus an
antipsychotic than to monotherapy with either antidepressant or
antipsychotic. The most recent update (2009) of the Cochrane
collaboration meta-analysis on psychotic depression ( 22 ), however,
continues to suggest that antidepressant monotherapy should be the
initial offering and then combination antidepressant/antipsychotic
therapy if the patient is not responding to antidepressant alone. They
emphasize the potential for adverse effects associated with
combination therapy. In this algorithm update, combination therapy
still continues to be the first-line recommendation. We will evaluate
the evidence related to these different opinions.
Node 2A: The Combination of a Tricyclic Antidepressant and an
Antipsychotic As described in the 2008 version of the PAPHSS
algorithm (1 ), below are some key studies pertinent to the issue of
whether tricyclic antidepressant (TCA) and antipsychotic combination
has a better treatment response as compared with TCA monotherapy.
In 1985, Spiker and colleagues conducted what may be considered
the landmark pharmacotherapy study for psychotic depression with 51
delusional depression patients ( 23 ). Delusional depression is
somewhat different from the current DSM-IV concept of psychotic
depression, as was described in the previous algorithm paper (1 ).
Patients were randomized for six weeks to either amitriptyline plus
perphenazine combination therapy (n=18), amitriptyline monotherapy
(n=17), or perphenazine monotherapy (n=16). Results showed
combination therapy to have a 78% response rate as determined by the
17-item Hamilton Depression Rating Scale (HAM-D-17), as compared
to 41% for amitriptyline monotherapy and 19% for perphenazine
monotherapy (p<0.01). Limitations to the study included small sample
size, the absence of a placebo group, and the fact that after taking into
account several dropouts, the intent-to-treat analysis did not show a
statistically significant benefit of combination therapy over
antidepressant alone.
Anton and Burch ( 24 ) studied a similar comparison employing 38
inpatient subjects given either amitriptyline plus perphenazine or
amoxapine alone for a 4-week period. Response rates (defined as
>50% reduction in HAM-D-17) were 81% for combination therapy
and 71% for monotherapy, a non-significant difference. 76% of
patients on amitriptyline plus perphenazine had an improvement on
the Brief Psychiatric Rating Scale (BPRS) of more than 50%,
compared to 59% of the patients on amoxapine. This difference was
also non-significant. Limitations to the study included its single-blind
design, small sample size, and lack of placebo control. Importantly,
the failure of combination therapy to produce more than a slight
numerical advantage over amoxapine could be because amoxapine is
actually a combination treatment: its main metabolite has dopamine
receptor blocking properties and is probably an antipsychotic (1 ).
In another study with 35 delusionally depressed patients given
desipramine plus perphenazine or plus haloperidol, Nelson and
colleagues concluded from their results that both the TCA and the
antipsychotic contributed independently to the clinical benefit ( 25 ).
Responders had an average haloperidol dose of 12 mg/d versus
nonresponders having a daily dose of 6 mg (p<.04). Perphenazine
responders had an average dose over 48 mg daily. The number of
responders when desipramine plasma levels were less than 100 ng/ml
was 1 of 8 patients, compared to 15 of 23 patients when the levels
were over 100 ng/ml (p<.05).
In a randomized double-blind trial by Mulsant and colleagues ( 26 ),
52 elderly patients (mean age=72) were initially started on
nortriptyline monotherapy for a two week period This was followed by
addition of either perphenazine (n=17) or placebo (n=19) for two more
weeks. Response was defined as a HAM-D-17 score of less than 10
and remission of psychotic symptoms on the BPRS. Results showed
44% responding during initial nortriptyline monotherapy treatment. In
the remaining period (with each group having 3 dropouts), response
was seen in 50% (n=7) of the nortriptyline plus perphenazine group,
and 44% (n=7) in the nortriptyline plus placebo group—a
nonsignificant difference. Limitations of the study included small
sample size and a population of elderly and demented patients that
might have reduced response rates.
In their meta-analysis of the question of combination therapy versus
TCA monotherapy, the Cochrane review considered only two of these
four studies: Spiker et al and Mulsant et al. They found no significant
advantage for the combination (relative risk ratio = 1.44; 95%
confidence interval, 0.86–2.41; p=0.16). However, these two studies
had small sample sizes, dissimilar patient populations (average age of
72 versus average age of 44), and different methodologies (e.g. –
timing of initiating combination therapy). In the 2008 PAPHSS
algorithm, it was noted that even with the limitation to these two
studies, the numerical advantage for combination treatment appeared
large enough to be clinically significant.
Node 2B: The Combination of a Selective Serotonin Reuptake
Inhibitor and an Antipsychotic Selective serotonin reuptake inhibitors
(SSRIs) have displaced TCAs in the treatment of depression in usual
practice because of their greater safety. However, some evidence
supports the notion that TCAs are superior in efficacy, especially in
men and in patients with more severe depression ( 27 , 28 ). In
psychotic depression, unfortunately, head-to-head prospective
comparisons between an SSRI plus an antipsychotic versus a TCA
plus an antipsychotic still have not been done. Below, we briefly
review some studies indirectly pertinent to these issues that were
discussed in the 2008 algorithm and one new clinical trial.
SSRIs have been combined with both typical and atypical
antipsychotics so we will discuss these combinations separately.
SSRIs and typical antipsychotics Two small studies examined the
combination of an SSRI and a typical antipsychotic.
The first was conducted by Rothschild and colleagues and included
30 patients (meeting DSM-III-R criteria for psychotic depression)
treated with a combination of fluoxetine and perphenazine ( 29 ). 73%
of the patients (23/30) had a reduction of HAM-D-17 and BPRS
scores of 50% or more after five weeks. Study limitations include
open-label design, small sample size, and lack of a placebo control
group. Of note, 7/30 of patients carried bipolar diagnoses. The second
study was conducted by Wolfersdorf and colleagues with 14 patients
treated with paroxetine and either zotepine or haloperidol, or both ( 30
). 3/4 patients receiving combined paroxetine plus haloperidol had a
50% or more reduction in HAM-D-24. Limitations to the study were
its tiny sample size, non-blind design, lack of placebo control, and
short 3-week treatment period.
SSRIs and atypical antipsychotics Rothschild and colleagues ( 31 )
evaluated fluoxetine and olanzapine in two multisite, double-blind,
randomized controlled trials (RCTs), with 124 inpatients in trial 1, and
125 inpatients in trial 2. Patients diagnosed with psychotic depression
(meeting DSM-IV criteria) were randomized into three groups
(placebo, olanzapine plus placebo, and olanzapine plus fluoxetine) and
treated for an eight-week period. Response was defined as ≥50%
decrease from baseline HAM-D-24. Results from trial 1 showed the
combination group (n=22) having a significantly higher response rate
(64%) than the placebo (28%: n=50; p=.004) or olanzapine (35%:
n=43; p=.027) groups. However, trial 2 showed no significant
differences in response among treatment groups (combination 48%;
n=23, placebo 32%; n=44: p=.20, and olanzapine 36%; n=47: p=.35).
Notably, olanzapine alone was not different from placebo in either
study, but the 36% response rate seems higher than the 19% response
rate to perphenazine monotherapy in the landmark Spiker et al study
(23 ). This may be attributed to the possibility that less ill patients
would be admitted to the Rothchild et al studies that had a placebo
control than to one with all active treatment arms. A limitation of the
study was its lack of a fluoxetine monotherapy group. Hence, it did not
offer an opportunity to evaluate combination therapy vs. SSRI
monotherapy (See Node 7).
Although it did not duplicate the results in trial 1, trial 2 actually
had a trend that was possibly clinically significant in favor of
combination treatment. The small sample sizes in the combination
groups were due to the randomization schedule: the investigators only
intended to use the combination group as an “exploratory pilot arm.”
The primary goal in these industry-sponsored trials was to evaluate
olanzapine monotherapy for psychotic depression, and in that respect
the results were disappointing.
Since the 2008 update, Meyers, Rothschild, and others published
the “STOP-PD” study, a 12 week, double-blind RCT comparing
olanzapine (15-20 mg/d) plus sertraline (150-200 mg/d) versus
olanzapine plus placebo for psychotic depression ( 32 ). 259 patients
were followed with remission as the primary outcome measure.
Patients were evaluated weekly for the first 6 weeks, followed by
every other week until week 12. Remission was defined as a HAM-D-
24 score ≤ 10 at 2 consecutive assessments and absence of delusions at
the second assessment. Results showed the combination produced
significantly more remissions (odds ratio 1.28, 95% CI 1.12-1.47,
p<0.001) than olanzapine alone. 41.9% (54/129) of patients with
combination therapy were in remission during their last assessment
compared with 23.9% (31/130) in patients on olanzapine (p=0.002).
As in Rothschild and colleagues’ earlier study with olanzapine, this
study again lacked an antidepressant monotherapy arm, and it had a
high attrition rate (42%).
Recently, the authors of this study published an evaluation of the
impact of previous medication treatment before study entry ( 33 ).
They found that if the patient had a prior failed adequate
antidepressant monotherapy trial (n=35) and then received
combination therapy in the trial, only 20% responded. By contrast, the
19 patients with no previous treatment who were put on the
combination had a 63% response (12/19) vs. 33% response (4/12) if
they were put on olanzapine alone. This suggests, despite the small
numbers, that in this patient population failure to respond to SSRI
monotherapy was associated with a guarded prognosis for adding an
antipsychotic. For the treatment-naïve patients, the combination was
superior.
In summary regarding the use of SSRIs, the combination of an SSRI
plus a typical or an atypical antipsychotic is clearly effective compared
with placebo or antipsychotic monotherapy, but there have been no
direct comparisons of the combination with SSRI monotherapy. Thus,
if an SSRI is chosen as the antidepressant, confidence that
combination therapy will be superior to antidepressant monotherapy
may be somewhat less than if a TCA is chosen.
Node 2C: The Combination of a Serotonin-Norepinephrine
Reuptake Inhibitor and an Antipsychotic Since the 2008 update, the
first double-blind RCT involving a serotonin-norepinephrine reuptake
inhibitor (SNRI) antidepressant (venlafaxine ER) has been published.
In this trial, a TCA (imipramine), venlafaxine ER, and a combination
of venlafaxine ER plus quetiapine were compared ( 34 ). 122 patients
were randomized for a 7 week period. Venlafaxine ER dose was 375
mg daily, imipramine was dosed to produce a plasma level of 200- 300
ng/ml of imipramine + desipramine, and the combination involved
venlafaxine ER at 375 mg daily and quetiapine at 600 mg daily.
Response was defined as greater than a 50% decrease in the HAM-D-
17 score and a final score of less than 15. Remission rates (HAM-D-17
< 8) were also examined. The results showed a 66% (27/41) response
rate to the combination, 52% (22/42) in the imipramine group, and
33% (13/39) in the venlafaxine ER group. Combination therapy was
shown to be more effective than venlafaxine alone (with adjusted odds
ratio of 4.02, 95% confidence interval at 1.56-10.32), but there was no
significant difference in response when compared with the imipramine
group (adjusted odds ratio at 1.76, 95% CI 0.72-4.30). In remission
comparisons, 42% (17/41) occurred in the combination group, 21%
(9/42) in imipramine monotherapy, and 28% (11/39) in venlafaxine
monotherapy. The combination was statistically superior only to the
imipramine. In linear mixed models analysis, the mean score decrease
of HAM-D was numerically (but not statistically significantly) greater
with imipramine compared to venlafaxine.
Limitations to the study included lack of a placebo group, remission
comparisons done as a post hoc secondary outcome measure, and
small sample size. Nevertheless, this study suggests that an SNRI plus
antipsychotic combination can be more effective than an SNRI or
TCA alone. The study did not provide data on how an SNRI plus an
antipsychotic would compare to a TCA or an SSRI plus an
antipsychotic.
Nodes 2A, 2B, & 2C: Conclusions Despite the limitations of the data,
the authors still find sufficient support to conclude that the
combination of an antidepressant and antipsychotic is the first-line
psychopharmacological treatment for psychotic depression. However:
which antidepressants are preferred?
Antidepressant preference: TCA, SSRI, or SNRI? As noted, there are
still no head-to-head comparisons of a TCA, SSRI, and SNRI in
combination therapy. In our prior update, we presented a detailed
effort to make a comparison based on indirect evidence and concluded
there was a slight basis for preferring a TCA over an SSRI for
effectiveness but a stronger basis to prefer an SSRI for safety
including overdose risk (1 ). We now have some data with an SNRI
(venlafaxine ER) in psychotic depression (34 ). It worked well in
combination with an antipsychotic, separating from monotherapy with
a TCA and an SNRI on either response or remission. When compared
in monotherapy with a TCA, the different trends on response and
(secondarily) remission made it difficult to have a preference. Safety
concerns would favor venlafaxine over a TCA. In conclusion,
venlafaxine has become our first choice for the antidepressant to be
used in combination therapy.
There is no evidence to support the favoring of other antidepressant
types (e.g. bupropion, mirtazapine, monoamine oxidase inhibitors) in
psychotic depression.
Antipsychotic preference No direct comparisons are available to test
the relative efficacy and safety of different typical and atypical
antipsychotics. Our previous analysis of the indirect evidence failed to
find any basis for any preference based on effectiveness (1 ). Since the
previous update, as we have noted, quetiapine and olanzapine have
new RCTs and both were shown to be effective choices for
combination therapy. Quetiapine has more efficacy than olanzapine
and other atypical antipsychotics for some other depressive disorders
such as bipolar depression (8 ). This suggests it might be favored (for
effectiveness) for psychotic depression.
Regarding safety issues, typical antipsychotics have an increased
risk of tardive dyskinesia when compared to atypical antipsychotics
especially in mood-disordered psychotic patients ( 35 ). Atypical
antipsychotics often produce weight gain and related metabolic
problems, particularly olanzapine ( 36 ). Interestingly, Rothschild’s
group ( 37 ) evaluated the weight gain of 118 patients from their
olanzapine and sertraline STOP-PD study, looking for risk factors.
Age had a significant negative association with weight gain (p=0.01)
even after controlling for differences in cumulative olanzapine dose
and baseline body mass index. Each 10-year increase in age was
associated with a decrease in mean weight gain over 12 weeks of
approximately 0.6 kg (p=0.01). The results suggest that olanzapine-
induced weight gain is more of a concern in younger patients.
Quetiapine causes weight gain as well, second only to olanzapine in
a study in antipsychotic-naïve young patients ( 38 ). It also has a new
package insert warning in 2011 regarding QTc prolongation and now
must receive extra safety monitoring for this and may not be combined
with at least 12 specified medications (to which should be added
citalopram which has had a similar warning since September, 2011)
Given that olanzapine and quetiapine are both effective in psychotic
depression combination treatment despite their different
pharmacodynamic properties (e.g. olanzapine is strongly bound to the
dopamine type 2 receptor and quetiapine is loosely bound), it may be
reasonable to consider other atypical antipsychotics with a more
benign safety profile even if their efficacy has not been as well-
demonstrated. Ziprasidone (40-160 mg/d) was combined with
sertraline (100-200 mg/d) in 19 psychotic depression patients open-
label for 4 weeks. 17 completed the study. Patients improved
significantly on the HAM-D-21, BPRS, and other rating scales ( 39 ).
There was no weight gain or prolactin increase, but QTc increased by
a mean of 15 ms (p=0.04). Aripiprazole was combined with
escitalopram in an open-label, 7-week trial ( 40 ). Response rate on the
13 completers was 63% with response defined as a 50% drop in the
HAM-D-17 and no psychosis. Risperidone was combined with an
antidepressant in 11 patients as part of an investigation in a
heterogeneous population most of whom had psychotic depression and
the results seemed promising ( 41 ).
Continuation of combination therapy after the acute phase Wijkstra
and colleagues recently addressed this question in a 4-month follow up
study of their comparison of acute treatment with venlafaxine,
imipramine, and combined venlafaxine and quetiapine ( 42 ). 59
responders (20 patients from imipramine group, 13 from the
venlafaxine group, and 26 from the combination group) had their
HAM-D-17 measured during open-label follow-up for 4 months. Six
dropped out, but 86% (51 of 59) maintained their response: 16/17
(94%) of imipramine patients, 12/12 (100%) on venlafaxine, and
23/24 (96%) on the combination (p=1.0). This study suggests that
continuation of treatment with an initially effective medication
regimen for at least 4 months is highly recommended.
In an older naturalistic follow-up study, 78 patients who had
remitted on combination therapy had a high rate of relapse if they went
off their antipsychotics ( 43 ). Patients were on the antipsychotics for a
mean of 5.0 months but relapsed in a mean of 2.0 months after
antipsychotic dosage reduction or discontinuation. Another study in
older patients, however, found no differences in relapse rate with
antipsychotic discontinuation (17 ). During a 6-month observation
period, 7 of 28 subjects relapsed: 5 of 15 while on combination
therapy compared with 2 of 13 on monotherapy (p=0.4). A recent two-
year follow-up study of patients receiving naturalistic treatment after
their first diagnosis of psychotic depression found that 45%
experienced new episodes (7 ). It is unclear if this is because
suboptimal treatment was prescribed, patients became non-adherent,
or because of confounding changes in diagnosis over time.
In conclusion, this algorithm addresses acute management, and
maintenance therapy data are limited. However, the most recent study
suggests at least 4 months of maintenance is effective. One should
particularly consider the long-term metabolic side effects associated
with maintaining the antipsychotic that has received the most study,
i.e. olanzapine. If metabolic side effects are significant, it may be
worth trying to change to a different antipsychotic or seeing if it can
be discontinued.
NODE 3: HAVE YOU TRIED SWITCHING THE
ANTIDEPRESSANT IF A FIRST COMBINATION
TRIAL HAS FAILED?
If the patient has had, and failed, an SSRI plus antipsychotic
combination, one may consider switching the antidepressant to
venlafaxine ER or to a TCA. As noted, this is based on very limited
evidence – but it seems there is a little more rationale for this
compared with the other option of switching the antipsychotic. If the
patient initially failed on venlafaxine plus antipsychotic, close
consideration of the conflicting monotherapy data from the Wijkstra et
al study (34 ) suggests it is possible that they might do better on a
TCA.
If the patient’s initial treatment happened to have been with a TCA
plus antipsychotic, there is minor evidence to suggest that a switch to
an SSRI or SNRI as the antidepressant might be advantageous. In one
study, eight patients with prior failure on full-dose TCA and typical
antipsychotic combination therapy showed a 62% (5/8) response rate
after being switched to SSRI plus antipsychotic therapy (29 ).
Blumberger et al found that even after failure on an adequate trial of
various (unspecified) combinations of antidepressants and
antipsychotics (n=13), 25% then responded to the combination of
sertraline plus olanzapine, and (surprisingly) 40% of 11 patients
responded when assigned to olanzapine monotherapy even though that
was not a good treatment for treatment-naïve patients in their study
(33 ). Possibly the diagnoses of these 11 patients were incorrect and
they actually had a primary psychotic disorder (6 ,7 ).
Thus, though this evidence is very limited, switching
antidepressants seems to have some chance of success and it is
proposed that this be the next intervention in Node 3.
Reconsideration of ECT should also occur here given its
effectiveness in non-responsive patients ( 44 ).
NODE 4: IF TWO COMBINATION TRIALS FAILED,
AGAIN RECONSIDER ECT
ECT is probably the treatment of choice after two failed combination
trials with different antidepressants. As noted earlier, Blumberger and
colleagues found that prior failure to respond to adequate
antidepressant courses is associated with poor outcomes with
olanzapine and sertraline combination therapy even under research
conditions (33 ). In a study with 15 inpatients with psychotic
depression (DSM-III criteria), 8/9 patients who were not responsive to
TCA plus antipsychotic combination showed excellent clinical
response after ECT ( 45 ). In Spiker and colleagues’ 1985 study, all six
patients failing combination therapy responded well with ECT (23 ).
NODE 5: DID TWO COMBINATIONS AND ECT ALL
FAIL OR WAS ECT UNAVAILABLE OR
UNACCEPTABLE?
Some evidence is available to support augmentation therapy with
lithium in this situation. Lithium was used to augment a TCA plus
antipsychotic combination in a 20-patient case series, and 40% had
partial or marked response ( 46 ). In another augmentation series with
6 unresponsive patients to TCA plus antipsychotic combination, 3/6
had dramatic response and 2/6 had gradual response with lithium ( 47
). Rothschild et al’s early study had 3/8 patients responding to lithium
augmentation after failing fluoxetine and perphenazine (29 ). Finally,
since the last algorithm update, Birkenhager and colleagues reported
on the open-label addition of lithium for 4 weeks to 15 non-responding
patients from their venlafaxine/imipramine/quetiapine study ( 48 ).
They were kept on their blinded initial medications. Nine patients
(60%) had sustained remission. Five of the 15 patients were on
combination therapy but unfortunately their results were not reported
separately.
NODE 6: DID TWO COMBINATIONS AND LITHIUM
AUGMENTATION FAIL?
ECT is still considered the best option at the point if not yet tried.
Clozapine may be considered based on evidence derived from case
series and case reports. Three patients with refractory psychotic
depression, not responding to ECT, had clozapine initiated ( 49 ).
There was improvement in both psychotic and mood symptoms
(response was delayed for 1 patient), and no relapses occurred over a
4-6 year follow up period.
In a case report, a female patient’s initial BPRS score of 62 dropped
to 39 after 4 weeks of clozapine, and to 21 after four months ( 50 ).
Another case report described similar results with a female patient
whose mood symptoms responded well and psychotic symptoms
remitted after receiving clozapine ( 51 ).
Since the 2008 update, a new report of an augmentation strategy
involving the addition of methylphenidate has appeared. This adds to
an old report from over 40 years ago ( 52 , 53 ). In the new case, there
was a good effect in a female patient with psychotic depression who
had failed on venlafaxine plus olanzapine combination. The patient’s
family had refused ECT. Her psychosis remitted with a Clinical
Global Impression score of 3 and HAM-D score of 8 after 4 days, and
she had no recurrence at 2-year follow up.
NODE 7: TCA, SNRI, OR SSRI MONOTHERAPY?
Sometimes monotherapy with an antidepressant will be preferred (e.g.
– due to side effect concerns with antipsychotics). If so, which one
should be selected?
Node 7A: TCA Monotherapy? TCAs seem to be effective for many
cases of psychotic depression. A meta-analysis found TCAs to be
superior to placebo ( 54 ) and to antipsychotic monotherapy (22 ).
Some evidence suggests TCAs would be preferred over SSRIs. Van
Den Borek and colleagues conducted an RCT in depressed patients
showing that imipramine at a plasma level of imipramine +
desipramine of 192-521 ng/ml was more effective than fluvoxamine at
150-1800 mg daily ( 55 ). Cochrane analysis of the psychotic
depression patients in this study ( 56 ) found that 64% (16/25) of
patients on imipramine had 50% reduction in HAM-D, as compared
30% (7/23) on fluvoxamine (p=0.03).
In another RCT of depressed patients by Brujin and colleagues,
imipramine was shown to be more effective than mirtazapine ( 57 ).
Cochrane review’s analysis of the psychotic depression patients in this
study (56 ) showed that 9/15 patients (60%) on imipramine achieved a
50% reduction in HAM-D scores, as compared to 3/15 patients (20%)
in the mirtazapine group (p=0.05).
As discussed earlier, the recent RCT comparing the TCA
imipramine head-to-head with venlafaxine is hard to interpret because
of conflicting data on response and remission (34 ).
Amoxapine as mentioned earlier has strong typical antipsychotic
properties from its metabolite 7-hydroxy amoxapine (24 ). This
product is therefore not recommended due to its possible associated
risks for tardive dyskinesia.
Node 7B: An SSRI/SNRI? Studies suggesting effectiveness of SSRI
or SNRI monotherapy are discussed below. Fluvoxamine ( 58 ),
sertraline ( 59 ), paroxetine (59 ), and venlafaxine (34 , 60 ) all have
some evidence.
Zanardi and colleagues conducted a double-blind controlled 6-week
study comparing the responses of 66 patients with psychotic
depression (DSM-III-R) to sertraline (n=24) and paroxetine (n=22) (59
). The HAM-D-21 and the Dimensions of Delusional Experience
Rating Scale (DDERS) were utilized for response assessment. 75% of
sertraline patients and 46% of paroxetine patients responded, but the
difference was not statistically significant (p=0.16). Limitations to the
study include lack of placebo group, high dropout rate (41%) in the
paroxetine group, and enrollment of 14 bipolar patients.
Case studies and case series have described the use of fluvoxamine
monotherapy (58 ). In a recent case study a female patient was initially
treated with fluvoxamine and risperidone for 1 year followed by
fluvoxamine monotherapy maintenance for 2 years ( 61 ). At this
point, she was switched to sertraline but then developed delusions. Her
symptoms resolved after switching back to fluvoxamine. In a case
series, 5 patients treated with fluvoxamine all showed reduction in
HAM-D and BPRS scores ( 62 ).
Zanardi and colleagues conducted another 6-week RCT with 28
inpatients with DSM-IV psychotic depression (60 ). Subjects received
either 300 mg of fluvoxamine or 300 mg of venlafaxine. 79% of the
fluvoxamine group (n=11) and 58% of the venlafaxine (n=7) showed
response with a reduction in HAM-D-21 score to ≤ 8 and DDRS score
of 0. No statistically significant difference was found between the two
drugs (p=0.40). Limitations to the study included small sample size,
lack of placebo control, and enrollment of 6 bipolar patients.
Kantrowitz and colleagues examined the risk for psychosis
exacerbation with TCA and serotonergic antidepressant monotherapy
in a systemic review on psychotic depression ( 63 ). Of the 20 studies
reviewed, patients assigned to a tricyclic antidepressant were more
likely to experience psychosis exacerbation (8/78) than patients on
serotonergic antidepressants (1/93), p=0.01. 6/6 patients treated with
MAOIs experienced psychosis exacerbation.
In conclusion, there may be some efficacy for SSRI or venlafaxine
monotherapy, but the evidence appears slightly stronger for TCA
monotherapy. However, TCAs have the previously noted safety issues
and there may also be some increased risk of psychosis exacerbation
with TCA monotherapy. The strongest evidence supports initial use of
combination therapy with an antidepressant and an antipsychotic, if
ECT is not used.
FINAL COMMENTS
This update to the 2008 PAPHSS algorithm further refines the
previous analysis of the available evidence for pharmacological
treatment of psychotic depression. However, the validity of the
conclusions are limited by the quality and quantity of studies and
evidence available. Head-to-head prospective trials in psychotic
depression are still relatively few in number. Yet, the alternative to
relying as best as possible on this evidence-base would be to make
decisions solely on the individual practitioner’s clinical experience.
This can be an unreliable basis for decision-making ( 64 ). Andreescu
and colleagues in 2007 found that only 57% of 100 patients with
psychotic depression received at least one combination of an
antidepressant and an antipsychotic, and only 5% received a full dose
of the antipsychotic ( 65 ). Mulsant and colleagues showed similar
results in 1997, when 4% of 53 patients received adequate
combination therapy ( 66 ). Therefore, this algorithm update hopes to
inform clinicians about the evidence available for the
psychopharmacology of psychotic depression. It organizes that
evidence in a systematic manner, but it is flexible enough in its
recommendations to leave ample opportunity to add individual
judgment based on clinical experience.
REFERENCES
1. Hamoda HM, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South
Shore Program: an update on psychotic depression. Harv Rev Psychiatry. 2008;16:235-47.
2. Osser DN, Patterson RD. Algorithms for the pharmacotherapy of depression: Part One
Directions in Psychiatry. 1998;18:303-18.
3. Johnson J, Jowarth E, Weissman MM. The validity of major depression with psychotic features
based on a community study Arch Gen Psychiatry. 1991;48:1075-81.
4. Ohayon MM, Schatzberg AF. Prevalence of depressive episodes with psychotic features in the
general population. Am J Psychiatry. 2002;159:1855-61.
5. Coryell W, Lavori P, Endicott J, Keller M, VanEerdewegh M. Outcome in schizoaffective,
psychotic, and nonpsychotic depression. Course during a six- to 24-month follow-up. Arch Gen
psychotic, and nonpsychotic depression. Course during a six- to 24-month follow-up. Arch Gen
Psychiatry. 1984;41:787-91.
6. Ruggero CJ, Kotov R, Carlson GA, Tanenberg-Karant M, Gonzalez DA, Bromet EJ. Diagnostic
consistency of major depression with psychosis across 10 years. J Clin Psychiatry.
2011;72:1207-13 .
7. Tohen M, Khalsa HM, Salvatore P, Vieta E, Ravichandran C, Baldessarini RJ. Two-year
outcomes in first-episode psychotic depression the McLean-Harvard First-Episode Project. J
Affect Disord. 2012;136:1-8.
8. Ansari A, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore
Program: an update on bipolar depression. Harv Rev Psychiatry. 2010;18:36-55.
9. Bajor LA, Ticlea AN, Osser DN. The Psychopharmacology Algorithm Project at the Harvard
South Shore Program: an update on posttraumatic stress disorder. Harv Rev Psychiatry.
2011;19:240-58.
10. Osser DN, Dunlop LR. The Psychopharmacology Algorithm Project at the Harvard South
Shore Program: an update on generalized social anxiety disorder. Psychopharm Review.
2010;45:91-8.
11. Osser DN, Jalali-Roudsari M, Manschreck T. The Psychopharmacology Algorithm Project at
the Harvard South Shore Program: an update on schizophrenia. Harv Rev Psychiatry.
2013;21:in press.
12. Petrides G, Fink M, Husain MM, Knapp RG, Rush AJ, Mueller M, et al. ECT remission rates
in psychotic versus nonpsychotic depressed patients: a report from CORE. J ECT.
2001;17:244-53.
13. Perry P, Morgan D, Smith R, Tsuang M. Treatment of unipolar depression accompanied by
delusions. J Affect Disord. 1982;4:195- 200.
14. Olfson M, Marcus S, Sackeim HA, Thompson J, Pincus HA. Use of ECT for the inpatient
treatment of recurrent major depression. Am J Psychiatry. 1998;155:22-9.
15. Keller J, Schatzberg AF, Maj M. Current issues in the classification of psychotic major
depression. Schizophr Bull. 2007;33:877-85.
16. Navarro V, Gasto C, Torres X, Masana G, Penades R, Guarch J, et al.
Continuation/maintenance treatment with nortriptyline versus combined nortriptyline and ECT
in late-life psychotic depression: a two-year randomized study. Am J Geriatr Psychiatry.
2008;16:498-505.
17. Meyers BS, Klimstra SA, Gabriele M, Hamilton M, Kakuma T, Tirumalasetti F, et al.
Continuation treatment of delusional depression in older adults. American Journal of Geriatric
Psychiatry. 2001;9:415-22.
18. Sackeim HA, Haskett RF, Mulsant BH, Thase ME, Mann JJ, Pettinati HM, et al. Continuation
pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a
randomized controlled trial. JAMA. 2001;285:1299-307.
19. American Psychiatric Association. Practice guideline for the treatment of patients with major
depressive disorder, third edition. Am J Psychiatry. 2010;167:1-118.
20. National Collaborating Centre for Mental Health. The treatment and management of
depression in adults: NICE clinical guideline 90. London; Leicester, UK: Gaskell and the
British Psychological Society, 2009.
21. Farahani A, Correll CU. Are antipsychotics or antidepressants needed for psychotic
depression? A systematic review and meta-analysis of trials comparing antidepressant or
antipsychotic monotherapy with combination treatment. J Clin Psychiatry. 2012;73:486-96.
23. Spiker DG, Weiss JC, Dealy RS, Griffin SJ, Hanin I, Neil JF, et al. The pharmacological
treatment of delusional depression. Am J Psychiatry. 1985;142:430-6.
24. Anton R, Burch E. Amoxapine vs amitriptyline combined with perphenazine in the treatment
of psychotic depression. Am J Psychiatry. 1990;147:1203-8.
25. Nelson JC, Price L, Jatlow P. Neuroleptic dose and desipramine concentration during
combined treatment of unipolar delusional depression. Am J Psychiatry. 1986;143:1151-4.
26. Mulsant BH, Sweet RA, Rosen J, Pollock BG, Zubenko GS, Flynn T, et al. A double-blind
randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in
the treatment of psychotic depression in late life. J Clin Psychiatry. 2001;62:597- 604.
27. Anderson IM. SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis
of efficacy and tolerability. Depress Anxiety. 1998;7 Suppl 1:11-7.
28. Vermeiden M, van den Broek WW, Mulder PG, Birkenhager TK. Influence of gender and
menopausal status on antidepressant treatment response in depressed inpatients. J
Psychopharmacol. 2010;24:497-502 .
29. Rothschild AJ, Samson JA, Bessette MP, Carter-Campbell JT. Efficacy of the combination of
fluoxetine and perphenazine in the treatment of psychotic depression. J Clin Psychiatry.
1993;54:338- 42.
30. Wolfersdorf M, Barg T, Konig F, Leibfarth M, Grunewald I. Paroxetine as antidepressant in
combined antidepressant-neuroleptic therapy in delusional depression: observation of clinical
use. Pharmacopsychiatry. 1995;28:56-60.
31. Rothschild AJ, Williamson DJ, Tohen MF, Schatzberg A, Andersen SW, Van Campen LE, et
al. A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for
major depression with psychotic features. J Clin Psychopharmacol. 2004;24:365-73.
32. Meyers BS, Flint AJ, Rothschild AJ, Mulsant BH, Whyte EM, Peasley-Miklus C, et al. A
double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus
placebo for psychotic depression: the study of pharmacotherapy of psychotic depression
(STOP-PD). Arch Gen Psychiatry. 2009;66:838-47.
33. Blumberger DM, Mulsant BH, Emeremni C, Houck P, Andreescu C, Mazumdar S, et al.
Impact of prior pharmacotherapy on remission of psychotic depression in a randomized
controlled trial. J Psychiatr Res. 2011;45:896-901.
34. Wijkstra J, Burger H, van den Broek WW, Birkenhager TK, Janzing JG, Boks MP, et al.
Treatment of unipolar psychotic depression: a randomized, double-blind study comparing
imipramine, venlafaxine, and venlafaxine plus quetiapine. Acta Psychiatr Scand.
2010;121:190-200.
35. Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-
generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry.
2004;161:414-25.
Chiu CC, Chen KP, Liu HC, Lu ML. The early effect of olanzapine and risperidone on insulin
36.
Chiu CC, Chen KP, Liu HC, Lu ML. The early effect of olanzapine and risperidone on insulin
secretion in atypical-naive schizophrenic patients. J Clin Psychopharmacol. 2006;26:504-7.
37. Smith E, Rothschild AJ, Heo M, Peasley-Miklus C, Caswell M, Papademetriou E, et al.
Weight gain during olanzapine treatment for psychotic depression: effects of dose and age. Int
Clin Psychopharmacol. 2008;23:130-7.
38. Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK. Cardiometabolic
risk of second-generation antipsychotic medications during first-time use in children and
adolescents. JAMA. 2009;302:1765-73.
39. Moeller O, Evers S, Deckert J, Baune BT, Dannlowski U, Nguyen DH, et al. The impact of
ziprasidone in combination with sertraline on visually-evoked event-related potentials in
depressed patients with psychotic features. Prog Neuropsychopharmacol Biol Psychiatry.
2007;31:1440-3.
40. Matthews JD, Siefert C, Dording C, Denninger JW, Park L, van Nieuwenhuizen AO, et al. An
open study of aripiprazole and escitalopram for psychotic major depressive disorder. J Clin
Psychopharmacol. 2009;29:73-6.
41. Goto M, Yoshimura R, Kakihara S, Shinkai K, Yamada Y, Kaji K, et al. Risperidone in the
treatment of psychotic depression. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:701-
7.
42. Wijkstra J, Burger H, van den Broek WW, Birkenhager TK, Janzing JG, Boks MP, et al. Long-
term response to successful acute pharmacological treatment of psychotic depression. J Affect
Disord. 2010;123:238-42.
43. Aronson T, Shukla S, Hoff A. Continuation therapy after ECT for delusional depression: a
naturalistic study of prophylactic treatments and relapse. Convulsive Therapy. 1987;3:251-9.
44. Schatzberg AF, Rothschild AF. Psychotic (delusional) major depression: should it be included
as a distinct syndrome in DSM- IV? Am J Psychiatry. 1992;149:733-45.
45. Khan A, Cohen S, Stowell M, Capwell R, Avery D, Dunner DL. Treatment options in severe
psychotic depression. Convulsive Therapy. 1987;3:93-9.
46. Price LH, Charney DS, Heninger GR. Variability of response to lithium augmentation in
refractory depression. Am J Psychiatry. 1986;143:1387-92.
47. Price L, Conwell Y, Nelson JC. Lithium augmentation of combined neuroleptic-tricyclic
treatment in delusional depression. Am J Psychiatry. 1983;140:318-22.
48. Birkenhager TK, van den Broek WW, Wijkstra J, Bruijn JA, van Os E, Boks M, et al.
Treatment of unipolar psychotic depression: an open study of lithium addition in refractory
psychotic depression. J Clin Psychopharmacol. 2009;29:513-5 .
49. Ranjan R, Meltzer HY. Acute and long-term effectiveness of clozapine in treatment-resistant
psychotic depression. Biol Psychiatry. 1996;40:253-8.
50. Jeyapaul P, Vieweg R. A case study evaluating the use of clozapine in depression with
psychotic features. Ann Gen Psychiatry. 2006;5:20.
51. Dassa D, Kaladjian A, Azorin JM, Giudicelli S. Clozapine in the treatment of psychotic
refractory depression. British Journal of Psychiatry. 1993;163:822-4.
52. Huang CC, Shiah IS, Chen HK, Mao WC, Yeh YW. Adjunctive use of methylphenidate in the
treatment of psychotic unipolar depression. Clin Neuropharmacol. 2008;31:245-7.
53. Wharton R, Perel J, Dayton P, Malitz S. A potential clinical use for methylphenidate with
tricyclic antidepressants. Am J Psychiatry. 1971;127:1619-25.
tricyclic antidepressants. Am J Psychiatry. 1971;127:1619-25.
54. Khan A, Noonan C, Healey W. Is a single tricyclic antidepressant trial an active treatment for
psychotic depression? Progress in Neuro-Psychopharmacology and Biological Psychiatry.
1991;15:765-70.
55. van den Broek WW, Birkenhager TK, Mulder PG, Bruijn JA, Moleman P. A double-blind
randomized study comparing imipramine with fluvoxamine in depressed inpatients.
Psychopharmacology (Berl). 2004;175:481-6.
56. Wijkstra J, Lijmer J, Balk F, Geddes J, Nolen WA. Pharmacological treatment for psychotic
depression. The Cochrane Database of Systematic Reviews, 2004: Art. No.:CD004044.pub2.
DOI:10.1002/14651858.CD004044.pub2.
57. Bruijn JA, Moleman P, Mulder PG, van den Broek WW, van Hulst AM, van der Mast RC, et
al. A double-blind, fixed blood-level study comparing mirtazapine with imipramine in
depressed in-patients. Psychopharmacology (Berl). 1996;127:231-7.
58. Gatti F, Bellini L, Gasperini M, Perez J, Zanardi R, Smeraldi E. Fluvoxamine alone in the
treatment of delusional depression. Am J Psychiatry. 1996;153:414-6.
59. Zanardi R, Franchini L, Gasperini M, Perez J, Smeraldi E. Double- blind controlled trial of
sertraline versus paroxetine in the treatment of delusional depression. Am J Psychiatry.
1996;153:1631-3.
60. Zanardi R, Franchini L, Serretti A, Perez J, Smeraldi E. Venlafaxine versus fluvoxamine in the
treatment of delusional depression: a pilot double-blind controlled study. J Clin Psychiatry.
2000;61:26-9.
61. Kishimoto A, Todani A, Miura J, Kitagaki T, Hashimoto K. The opposite effects of
fluvoxamine and sertraline in the treatment of psychotic major depression: a case report. Ann
Gen Psychiatry. 2010;9:23.
62. Furuse T, Hashimoto K. Fluvoxamine monotherapy for psychotic depression: the potential role
of sigma-1 receptors. Ann Gen Psychiatry.2009;8:26.
63. Kantrowitz JT, Tampi RR. Risk of psychosis exacerbation by tricyclic antidepressants in
unipolar Major Depressive Disorder with psychotic features. J Affect Disord. 2008;106:27279-
84.
64. Osser DN. Why physicians do not follow some algorithms and guidelines. Drug Benefit
Trends. 2009;21:345-54.
65. Andreescu C, Mulsant BH, Peasley-Miklus C, Rothschild AJ, Flint AJ, Heo M, et al. Persisting
low use of antipsychotics in the treatment of major depressive disorder with psychotic features.
J Clin Psychiatry. 2007;68:194-200.
66. Mulsant BH, Haskett RF, Prudic J, Thase ME, Malone KM, Mann JJ, et al. Low use of
neuroleptic drugs in the treatment of psychotic major depression. Am J Psychiatry.
1997;154:559-61.
1 DO, Harvard Medical School; VA Boston Healthcare System, Brockton Division, Brockton,
MA
2 MD, Harvard Medical School; VA Boston Healthcare System, Brockton Division, Brockton,
MA
Address reprint requests to: David N. Osser, MD, VA Boston Healthcare System, Brockton
Division, 940 Belmont Street, Brockton, MA 02301
Phone: 774-826-1650
Fax: 774-826-1655
E-mail address: David.Osser@va.gov
Date of acceptance: 9 Aralık 2012 / December 9, 2012
Declaration of interest:
M.T., D.N.O.: The authors reported no conflict of interest related to this article.
mailto:David.Osser@va.gov
I
UPDATE
PSYCHOTIC DEPRESSION ALGORITHM
n the seven years since the publication of the last version of this
algorithm, the recommendations and flowchart remain the same. There
have been no new studies that seem to change the overall sequences of
the nodes. However, there have been some studies adding support to what
was proposed in the 2012 algorithm.
The importance of correctly diagnosing and treating psychotic depression
in the most evidence-supported way was reinforced by a recent meta-
analysis of 20 relevant studies finding the rate of suicide attempts is more
than double the rate in nonpsychotic depressed patients ( 1 ). This was true
in all age groups, and was not associated with any particular features of the
episodes, such as severity, presence or absence of hallucinations, cognitive
dysfunction, or physical or psychiatric comorbidity. Completed suicide was
also greater in the psychotic depression group, with an odds ratio of 1.7 (if
an outlying large study was excluded) ( 2 ).
NODE 2B: FIRST-LINE TREATMENT WITH A
COMBINATION OF AN SSRI ANTIDEPRESSANT AND
AN ANTIPSYCHOTIC
At this node, the authors considered the evidence supporting the
combination of a selective serotonin reuptake inhibitor (SSRI) as the
antidepressant, and an antipsychotic. The evidence with different
antipsychotics was reviewed. In the STOP-PD study, sertraline was the
SSRI and olanzapine was the antipsychotic, and this combination was
compared with olanzapine alone ( 3 ). Consistent with other studies of
antidepressant/antipsychotic combinations, the remission rate on the
combination was superior to antipsychotic monotherapy, with an odds ratio
(OR) of 1.3. A new study called STOP-PD II was published in 2019 ( 4 ).
This new trial was sponsored by the National Institute of Mental Health,
whereas STOP-PD was sponsored by the manufacturer of olanzapine,
which explains the selection of this particularly side-effect prone second-
generation antipsychotic (SGA) and the design of the study which focused
on finding how effective olanzapine could be as a monotherapy. In STOP-
PD II, the purpose was to see if patients remitting on the combination of
sertraline and olanzapine could be maintained on the antidepressant alone
without the olanzapine versus staying on the combination, for 9 months.
In STOP-PD II, 269 subjects (mostly inpatients, aged 18–85) were
recruited from 4 centers and treated open-label with sertraline (150–200
mg) plus olanzapine (15–20 mg). Those who were remitted or near-remitted
for 8 weeks were randomized to stay on their combination or have their
olanzapine tapered off over 4 weeks using identical-appearing placebos.
The relapse rate on the combination was 20% compared with 55% on the
sertraline plus placebo, which was an impressive number-needed-to-treat of
2.8. Almost all of the relapses occurred within the first 2 months. On the
downside for the combination, patients gained an additional (mean of) 6 lb
on olanzapine versus 3 lb on placebo. Patients had already gained a mean of
12 lb in the open-label phase involving the olanzapine. This study adds
strong support for the algorithm’s recommendation of using a combination
of an antipsychotic and an antidepressant for psychotic depression, and
further suggests it should be continued for at least 4 months before any
thought of trying to taper off the antipsychotic.
An editorial advises that clinicians consider using a less hazardous SGA
than olanzapine, for example aripiprazole ( 5 ), even though the quantity of
evidence available from studies is greatest with olanzapine. The use of
another SGA might reduce the incentive to taper and eliminate the
antipsychotic beyond 4 months. This was also the suggestion in the 2012
algorithm. If the patient had suicidal ideation when depressed, one should
be particularly reluctant to remove the antipsychotic. The editorial author
also points out that patients with hallucinations were excluded from STOP-
PD II, though they are allowed in the DSM-IV and -V criteria for psychotic
depression; this slightly reduces the applicability of the results.
The study did not include bipolar depressed patients, and the treatment
approach should be different. The editorial suggests that lithium can be just
as effective as antipsychotics for such patients (5 ). See the chapter in this
book on the algorithm for bipolar depression, which is in accord with that
view.
et al. Psychotic (delusional) depression and suicidal attempts: a systematic review and meta-
analysis. Acta Psychiatr Scand. 2018;137:18-29.
analysis. Acta Psychiatr Scand. 2018;137:18-29.
2. Gournellis R, Tournikioti K, Touloumi G, Thomadakis C, Michalopoulou PG, Michopoulos I, et
al. Psychotic (delusional) depression and completed suicide: a systematic review and meta-
analysis. Ann Gen Psychiatry. 2018;17:39.
3. Meyers BS, Flint AJ, Rothschild AJ, Mulsant BH, Whyte EM, Peasley-Miklus C, et al. A
double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo
for psychotic depression: the study of pharmacotherapy of psychotic depression (STOP-PD).
Arch Gen Psychiatry. 2009;66:838-47.
4. Flint AJ, Meyers BS, Rothschild AJ, Whyte EM, Alexopoulos GS, Rudorfer MV, et al. Effect of
continuing olanzapine vs placebo on relapse among patients with psychotic depression in
remission: the STOP-PD II randomized clinical trial. JAMA. 2019;322:622-31.
5. Coryell WH. Maintenance treatment for psychotic depressive disorders: progress and remaining
challenges. JAMA. 2019;322:615-7.
T
The Psychopharmacology Algorithm Project at the
Harvard South Shore Program: An Update on
Schizophrenia
David N. Osser, MD, Mohsen Jalali Roudsari, MD, and Theo
Manschreck, MD
This article is an update of the algorithm for schizophrenia from the Psychopharmacology Algorithm
Project at the Harvard South Shore Program. A literature review was conducted focusing on new
data since the last published version (1999–2001). The first-line treatment recommendation for new-
onset schizophrenia is with amisulpride, aripiprazole, risperidone, or ziprasidone for four to six
weeks. In some settings the trial could be shorter, considering that evidence of clear improvement
with antipsychotics usually occurs within the first two weeks. If the trial of the first antipsychotic
cannot be completed due to intolerance, try another until one of the four is tolerated and given an
adequate trial. There should be evidence of bioavailability. If the response to this adequate trial is
unsatisfactory, try a second monotherapy. If the response to this second adequate trial is also
unsatisfactory, and if at least one of the first two trials was with risperidone, olanzapine, or a first-
generation (typical) antipsychotic, then clozapine is recommended for the third trial. If neither trial
was with any these three options, a third trial prior to clozapine should occur, using one of those
three. If the response to monotherapy with clozapine (with dose adjusted by using plasma levels) is
unsatisfactory, consider adding risperidone, lamotrigine, or ECT. Beyond that point, there is little
solid evidence to support further psychopharmacological treatment choices, though we do review
possible options.
he evolution of clinical therapeutics in schizophrenia challenges clinicians to
remain current and evidence based in their psychopharmacological practices.
New medicines have been added to the array of available antipsychotic
drugs, and the older medications have been the subject of new studies and meta-
analyses of their comparative efficacy and safety. Heightened awareness of side
effects associated with long-term administration of medications suggests an
increased need for advance planning for individuals at risk for a shortened life
span from these complications. Also, there is increasing evidence that integrative
approaches, utilizing psychosocial and cognitive-behavioral techniques to
augment drug treatment, hold promise to produce better outcomes. For example,
psychoeducation interventions, cognitive-behavioral therapy, and, more recently,
cognitive-rehabilitation 1 protocols have demonstrated significant advances in
helping patients. However, success with nonpharmacological strategies relies
fundamentally on the effectiveness and tolerability of medication treatment.
Psychiatrists consequently need to have both broad knowledge about adjunctive
and supplemental therapeutics and expertise concerning the complex issues of
drug treatment.
In this article, we present a newly updated algorithm to guide clinicians in the
pharmacological dimension of care for patients with schizophrenia. This version
is part of our ongoing series of revisions of a schizophrenia
psychopharmacology algorithm, first published in 1988. 2 – 7 It has also been
influenced by the schizophrenia algorithm of the International
Psychopharmacology Algorithm Project (2005–06, at www.ipap.org ), for which
one of the authors (DNO) was a co-chair. We have integrated newer, more
extensive evidence with these earlier efforts, but the present algorithm differs
substantially in focus, design, and complexity from its predecessors. It is
intended to stand alone as an interpretation of that evidence and does not require
reference to previous versions.
METHODS
This algorithm is one of several being developed by the Psychopharmacology
Algorithm Project at the Harvard South Shore Program (PAPHSS). The latest
methods have been described in recent PAPHSS publications. 8 – 11 Literature
searches were conducted using PubMed and other databases, focusing on new
randomized, controlled trials (RCTs) published since the last version about ten
years ago. We also examined systematic reviews of pertinent clinical issues as
well as other published guidelines and algorithms. This algorithm begins with an
approach to newly diagnosed individuals with schizophrenia and then suggests
strategies to counter unsatisfactory treatment responses. The primary target of
interest for the algorithm is positive symptoms, although we discuss
management of persistent negative, cognitive, and other symptoms. For each
decision point or node, we specify strategies that appear to accord with the best
evidence. Since schizophrenia is a chronic illness, and patients are likely to
require medications indefinitely, recommendations prioritize use of medications
with demonstrated effectiveness but also those with the most acceptable long-
term side effects. The authors favored putting greater emphasis on choice of an
antipsychotic with a milder long-term side-effect profile for the first
http://www.ipap.org
antipsychotic trial. Thereafter, for the next trial and those beyond, we placed
greater emphasis on efficacy (while still heightening awareness of the toxicities
of some of those agents).
All hierarchical and other clinical recommendations are the result of full
agreement by the three authors. In addition, the peer review process that
followed submission of this article was an important part of the validation
assessment for this algorithm (and other PAPHSS algorithms): if the reasoning,
based on the evidence interpretations provided, was plausible to all reviewers,
then it was retained. When there were differences of opinion on any particular
issue, adjustments were made or further exploration of relevant evidence was
done until consensus was achieved or the authors could present a stronger
argument in support of their position.
The algorithm is built around questions that might be asked by a
psychopharmacology consultant equipped with knowledge of the evidence base.
The consultant responds to questions either with another question or with an
appraisal of evidence pertinent to the optimal treatment of the clinical scenario at
hand. Then, recommendations are made that are derived from this appraisal.
FLOWCHART OF THE ALGORITHM
The algorithm appears in Figure 1 . Each numbered node reflects a decision
point in treatment. The questions and rationale for recommendations at each
node will be presented below .
Figure 1. Flowchart for the algorithm for schizophrenia. ECT, electroconvulsive therapy; FGA, first-
generation antipsychotic; O3FA, omega-3 fatty acid; SGA, second-generation antipsychotic.
At the threshold, accurate diagnosis is essential for the application of
evidence-based psychopharmacology. Characterization of possible comorbid
conditions is also critical, including both medical and psychiatric diseases. 12 , 13
The presence of these comorbidities may influence response to medication and
may alter treatment selection in the algorithm. Table 1 summarizes common
comorbid considerations in patients with schizophrenia and how they may
influence the algorithm.
Table 1 | Comorbidity and Other Features in Schizophrenia, and How
They Affect the Algorithm
Comorbid
conditions
Evidence considerations Recommendations
Suicidality 14 – 16 Clozapine reduced suicidal symptoms
and behavior more than olanzapine in
the InterSePT study.
Benzodiazepine use was associated
with increased mortality from suicide
in schizophrenia.
For schizophrenia patients with active
suicidal thoughts or behaviors,
consider clozapine earlier (e.g., at
Node 2) even if the patient is not
treatment resistant.
Avoid benzodiazepines.
Hostile, aggressive
behavior 17 – 19
Clozapine was more effective for
improving aggressive behavior than
olanzapine, risperidone, and
haloperidol.
Olanzapine seems to be the next best.
Consider clozapine for persistent
hostility and violent behavior even if
the patient is not treatment resistant.
The small early-efficacy advantage
for olanzapine over the others must be
weighed against its longterm adverse
effects.
Agitation requiring
rapid management
20 – 25
IM lorazepam, IM haloperidol, and
IM SGAs are superior to placebo in
controlling agitation in schizophrenia.
Combination of lorazepam and
haloperidol seemed more beneficial
than either haloperidol or lorazepam
alone.
IM SGAs have a significantly lower
risk of acute EPS compared to
haloperidol when used without
lorazepam or antiparkinson agents.
However, this risk difference
becomes insignificant when adding an
anticholinergic agent or lorazepam.
Note: patients prefer oral agents.
IM haloperidol plus lorazepam is still
the treatment of choice for efficacy
and for rapid, cost-effective treatment
of severe agitation in schizophrenia.
Oral PRN antipsychotics are often
used but are usually unnecessary for
less severe agitation. 26
Note: patients prefer oral agents.
Secondary negative
symptoms (i.e., due
to underlying causes
such as positive
symptoms, EPS, or
depression) 27
FGAs and SGAs vary in their ability
to cause secondary negative
symptoms. 28
Treat positive symptoms (e.g.,
paranoia producing asocial behavior)
with standard algorithm.
Treat EPS with appropriate agents, or
change to antipsychotic with lower
EPS risk.
Manage sedation by eliminating, if
possible, unnecessary sedatives.
Primary negative
symptoms (i.e.,
“deficit” symptoms,
including enduring
decrease in
motivation,
decreased affective
intensity and
emotional range,
and paucity of
communication)27
Primary negative symptoms respond
poorly to all antipsychotics, even
clozapine. 29
The evidence base suggests some
efficacy for adding antidepressants in
some patients. 30 ’ 31
Possible experimental treatments for
primary negative symptoms include
memantine, d-serine, sarcosine,
selegiline, 32 dehydroepiandrosterone,
33 ginkgo biloba, and minocycline. 35
Might try adding SSRI, mirtazapine,
trazodone, or fluvoxamine to FGAs or
risperidone; efficacy even less clear
for these additions to other SGAs,
including clozapine.
Use caution if combining clozapine
with fluvoxamine, fluoxetine, or
paroxetine, due to pharmacokinetic
interactions.
Citalopram increases clozapine levels
and prolongs QTc at doses above 40
mg daily, as noted in package insert
warnings.
Major depression 36
– 38
Overall, the literature is limited.
Several studies found no efficacy for
adding antidepressants to FGAs.
Older studies did find improvement in
depression in patients with “post-
psychotic depression” who received a
tricyclic added to ongoing treatment.
Imipramine showed a positive effect
versus placebo in a maintenance trial.
SGAs may be more effective than
classical neuroleptics in treating
comorbid depression. 39
FGAs may cause more secondary
depressive and negative symptoms.
First, ensure antipsychotic
compliance and dose optimization.
Treat post-psychotic depression with
an antidepressant. Consider a tricyclic
if an SSRI fails. Consider
pharmacokinetic and
pharmacodynamic interactions if
antidepressants are added.
An SSRI may be effective in mildly
depressed older patients with chronic
illness. 40
Treatment of
women of child-
bearing potential 41
– 52
Although the safety of antipsychotics
in pregnancy has not been clearly
established (due to many limitations
in the studies), the wide use of FGAs
over several decades suggests that
Prescribe as few drugs as possible.
Use the lowest effective dose of the
drugs with lowest risk.
During the first trimester of
– 52 over several decades suggests that
teratogenic risks are small.
Both FGAs and SGAs seem to be
associated with an increased risk of
perinatal complications. Some FGAs
are associated with neonatal
dyskinesias or neonatal jaundice. The
SGAs that cause weight gain appear
to increase risk of gestational
metabolic complications, including
diabetes and babies large for
gestational age.
Olanzapine may be associated with
low and high birth weight and with a
small risk of malformations, including
hip dysplasia, meningocele,
ankyloblepharon, and neural tube
defects.
Clozapine may be associated with
increased risk of neonatal seizures but
seems to show no increased risk of
congenital malformations. The FDA
has given it a B rating for pregnancy
safety.
During the first trimester of
pregnanacy, try to avoid all drugs.
Adjust doses as pregnancy
progresses: blood volume expands
30% in third trimester; plasma level
monitoring is helpful.
FGAs may still be preferred over
SGAs in pregnancy; however, when
pregnancy occurs during
antipsychotic treatment, it is usually
best to continue the existing therapy
to avoid exposure to multiple agents.
Consider the risk of relapse or
withdrawal when switching
medications or changing doses.
Anticholinergic drugs should not be
prescribed to pregnant women except
for acute, short-term needs.
Depot antipsychotics should not be
routinely used in pregnancy, as
infants may show extrapyramidal
symptoms for several months.
Active substance
abuse or
dependence 53 – 55
Substance abuse or dependence
occurs in approximately 50%-70% of
patients with schizophrenia.
Active substance abuse is associated
with poorer outcome with
antipsychotic treatment.
Tobacco-dependence rates may be as
high as 90%; this addiction increases
risk of cardiac death in schizophrenia
patients 12-fold.
The hydrocarbons in tobacco smoke
(but not the nicotine) induce
metabolism of clozapine (strongly)
and olanzapine at the P450 1A2
enzyme. 56
Benzodiazepines are associated with
higher risk for mortality in
schizophrenia.16
Almost no studies of medication use
have been done in patients actively
using substances other than tobacco;
hence, this algorithm may not be
applicable to them. Treatment of the
substance misuse, insofar as possible,
is therefore a high priority.
Clozapine levels must be monitored
when smokers start or stop smoking.
Naltrexone may be helpful for
alcohol-abusing schizophrenia
patients. 57
Bupropion is effective for smoking
cessation, 58 as is varenicline. 59
Avoid benzodiazepines.
Cardiac disease or
presence of QTc-
In a meta-analysis of 15 studies
comparing six SGAs for their effect
Consider aripiprazole as the
antipsychotic to use in these patients.
presence of QTc-
prolonging drugs 60
comparing six SGAs for their effect
on QTc prolongation, only
aripiprazole had significantly less
effect than other antipsychotics.
A seventh SGA, quetiapine, had five
relevant studies, but the manufacturer
refused to provide authors with QTc
data. In 2011, however, the quetiapine
package insert was amended with new
QTc prolongation warnings and
requirements for monitoring.
FGAs—especially thioridazine,
pimozide, and parenteral haloperidol
—also prolong QTc.
antipsychotic to use in these patients.
Older patients 61 Elderly patients with schizophrenia
have greater risk of EPS, metabolic
syndrome, and tardive dyskinesia
(from FGAs).
Antipsychotics probably increase
cerebrovascular events in this age
group, especially if there is comorbid
dementia or a history of stroke.
Use antipsychotics with great caution
and close monitoring, especially if
there is comorbid dementia.
Behavioral symptoms and mild
depression may respond to addition of
NODE 1: FIRST EPISODE/FIRST TRIAL
Having reviewed these preliminary considerations related to diagnosis and
comorbidity, we turn to an analysis of the evidence base for selecting the initial
antipsychotic for the patient with new-onset schizophrenia.
Crossley and colleagues 63 performed a meta-analysis of 15 RCTs comparing
first-generation, or typical, antipsychotics (FGAs) and second-generation, or
atypical, antipsychotics (SGAs) in early psychosis and found no differences in
acute efficacy. In comparison to FGAs, however, SGAs appear to show greater
long-term advantages, such as increased time to relapse, better treatment
retention, and greater probability of staying in remission. 64 – 68 Four studies in
first-episode patients suggest that FGAs are less effective than SGAs in
preventing a second episode. 69 SGAs also have a lower incidence of drug-
induced movement disorders and tardive dyskinesia.64 , 65 , 68 , 70 – 73 FGAs are
associated with higher use of adjunctive anticholinergic medications in these
studies, which present an increased risk of adverse cognitive and peripheral
anticholinergic effects. 74 While helping with the secondary negative symptoms
due to extrapyramidal side effects, anticholinergics may also blunt the
antipsychotic effect of FGAs on positive symptoms. 75 Even very low doses of
haloperidol (1.7 mg) in first-episode patients were associated with a high
incidence of tardive dyskinesia at one year (12%). 76 Not all studies confirm this
risk difference between FGAs and SGAs, 77 however, and earlier studies,
reviewed by Correll and colleagues in 2004, 71 may have been flawed by the use
of high doses of haloperidol or by biases in study design associated with industry
sponsorship. Nevertheless, given the direction of the preponderance of data cited
above, we favor SGAs over FGAs for first-line, Node 1 use in this algorithm.
Some differences among SGAs influence their selection for use in first-onset
patients. We focus on differences in side effects and ability to prevent future
episodes. Both are important considerations in view of the long-term nature of
this illness and the need to minimize both the serious medical morbidity from
long-term use and the harm caused by exacerbations and relapses. Unfortunately,
no SGAs are optimal in both respects. Four SGAs, on balance, appear slightly
more advantageous, at least if properly dosed and monitored: amisulpride,
aripiprazole, risperidone, and ziprasidone.63 , 68 , 78 , 79 We will explain the
reasoning supporting these choices and the problems with other options.
It is proposed, in agreement with others, 80 that olanzapine not be used for
first-episode patients. Olanzapine, compared to other antipsychotics, is
associated with much greater weight gain and other metabolic side effects in
these patients.68 , 78 , 79 , 81 Weight gain is almost twice as high as with quetiapine
and risperidone,78 which are considered to have intermediate risk for weight
gain. The risks of glucose dysregulation and insulin resistance are also high with
olanzapine—and occur early even in the absence of weight gain—placing the
patient at risk for diabetes. 82 Risperidone is associated with less change in serum
triglycerides and HDL cholesterol level than olanzapine and quetiapine.78 In the
open-label European First-Episode Schizophrenia Trial, Kahn and colleagues68
reported, regarding glucose regulation, that amisulpride, haloperidol, olanzapine,
quetiapine, and ziprasidone can all disturb fasting glucose status in first-episode
patients. Nevertheless, there were significant differences in weight gain. After
one year of treatment, ziprasidone was associated with a mean weight gain of 10
pounds, compared to 16 pounds for haloperidol, 21 for amisulpride, 23 for
quetiapine, and 31 for olanzapine (p < .0001). In two other RCTs with first-
episode patients, olanzapine produced significantly more metabolic problems
than haloperidol. 67 , 83
Quetiapine induces fewer movement disorders than other SGAs (especially
compared to olanzapine, risperidone, and ziprasidone). It also induces less
prolactin elevation than risperidone. It is associated, however, with higher
weight gain and associated problems than risperidone and ziprasidone: in the
CAFE study of early psychosis, 50% of patients on quetiapine experienced more
than 7% increase in body weight at one year, second only to olanzapine with
80% of patients. 84 A recent concern is noted in a new package insert warning for
quetiapine in July 2011 regarding QTc elevation; it suggests that the product
should not be combined with a list of 12 specified medications. The list should
also include citalopram because it has a similar QTc warning issued in
September 2011. In an analysis of the evidence base on different antipsychotics
time to rehospitalization or relapse after initiations, quetiapine seemed the least
likely, or among the least, to maintain patients in an improved state. 85 For
example, in an open-label, four-year maintenance study of 674 patients who had
responded to quetiapine in several acute treatment protocols, 92% discontinued
from all causes, most of them within three months. 86 Almost half of the
withdrawals were due to lack of efficacy. For these reasons (side effects, poor
maintenance effectiveness), quetiapine should not be among the recommended
Node 1 antipsychotics.
The recommended list includes risperidone . As will be discussed in Node 2,
it may be one of the more effective antipsychotics in patients having acute
exacerbations of recurrent illness, 87 , 88 and it is also one that may have a
relatively rapid effect in the inpatient setting.7 In a study of patients having first
exposure to an SGA in an eight-week RCT, risperidone was not different from
olanzapine and was superior to quetiapine. 89 Side-effect issues include higher
risk than olanzapine, quetiapine, ziprasidone, and even low-dose haloperidol of
inducing prolactin elevation in first-episode psychosis. 66 , 78 Prolactin elevation
is one of several factors associated with (but it may not be a cause of) sexual
dysfunction in males, 90 , 91 and it causes menstrual dysfunction, gynecomastia,
galactorrhea, and increases risk of osteoporosis.90 , 91 Sexual dysfunction and loss
of libido occurred in patients with higher levels of pathology and in association
with most antipsychotics in the European First-Episode Schizophrenia Trial.90 , 91
Investigation into these problems in this patient group could include evaluation
for hypogonadism, which can be a consequence of hyperprolactinemia. When
present, and if the risk of relapse from switching to a different antipsychotic is
considered unacceptable, testosterone replacement could be helpful. 92
Extrapyramidal side effects are greater with risperidone than other SGAs,
especially if excessive doses are used (e.g., over 2 mg in a first-onset patient, or
over 4 mg in a patient with previous exposure to antipsychotics with strong D2
receptor-blocking properties). In summary, risperidone is highly effective but
has important side effects. However, long-term risperidone side effects may be
more easily managed or are generally not as serious as those of olanzapine or
quetiapine.
Limited data are available concerning aripiprazole in first-episode patients.
Komossa and colleagues, 93 in a systematic review comparing aripiprazole and
other antipsychotics for schizophrenia, reported that aripiprazole may be less
effective than olanzapine but more tolerable in terms of metabolic effects and
sedation. Though aripiprazole is associated with little weight gain in chronic
schizophrenia patients, its use in children and adolescents who have not
previously been exposed to antipsychotics is associated with considerable weight
gain. 94 In a study by Correll and colleagues,94 after a median of 11 weeks,
youths aged 4 to 19 with various diagnoses gained a mean of 10 pounds on
aripiprazole, though that was less than the 12 pounds on risperidone, 13 pounds
on quetiapine, and 19 pounds on olanzapine. No evidence indicates any
difference in efficacy for aripipazole compared to risperidone, but the former has
a more favorable profile in terms of dystonia, lipid and prolactin increases, and
QTc prolongation. Aripiprazole is the safest SGA with respect to QTc
prolongation,60 which may be one of the long-term risk factors for sudden
cardiac death with antipsychotics. 95
In a Cochrane systematic review, Komossa and colleagues 96 reported that
ziprasidone may be slightly less efficacious than amisulpride, olanzapine, and
risperidone. It was also more likely to be discontinued than olanzapine and
risperidone. In a recent double-blind study by Grootens and colleagues in
patients with recent-onset schizophrenia, 97 however, it was found that
ziprasidone and olanzapine have comparable therapeutic efficacy but that they
differ in their side-effect profiles. Ziprasidone was associated with lower levels
of triglycerides, cholesterol, and transaminases, whereas these parameters
increased in the olanzapine group. Other studies support the finding that
ziprasidone has probably the lowest tendency of any SGA to induce weight gain
and associated metabolic problems such as triglyceride increase.68 However,
ziprasidone prolongs QTc to a greater extent than haloperidol, olanzapine,
quetiapine, and risperidone, 98 although the evidence is not uniform. Ziprasidone
needs to be administered at 80 mg twice daily with a 500 kcal meal to ensure
optimal, reliable bioavailability. 99 Suboptimal dosing protocols in older studies
and in usual clinical practice may account for some of the relatively poor
effectiveness outcomes with ziprasidone.
Komossa and colleagues, 100 in another Cochrane review, compared
amisulpride (not available in the United States) to olanzapine, risperidone, and
ziprasidone in treating schizophrenia. They found that amisulpride was similar in
effectiveness to olanzapine and risperidone and more effective than ziprasidone.
Amisulpride induced less weight gain than risperidone and olanzapine, and less
of an increase in glucose than olanzapine. No difference in cardiac effects and
extrapyramidal symptoms was found with amisulpride compared to olanzapine,
risperidone, and ziprasidone. In the European First-Episode Schizophrenia Trial,
amisulpride was second in effectiveness only to olanzapine in the primary
outcome measure of all-cause discontinuation rate at one year.68 Olanzapine had
a 33% discontinuation rate, whereas it was 40% with amisulpride, 45% with
ziprasidone, 53% with quetiapine, and 63% with haloperidol. All SGAs were
significantly better than haloperidol.
Some newer antipsychotics, though not included in our Node 1 recommended
list, should be discussed. Iloperidone 101 has recently been approved for treating
acute schizophrenia in adult patients. Although iloperidone has a low incidence
of extrapyramidal symptoms, it is associated with more weight gain than
risperidone. Additionally, there are concerns with QTc prolongation that appears
to be dose-related and similar to those associated with ziprasidone. Twice-daily
administration may be a disadvantage for some patients. Studies are needed with
first-episode psychotic patients and to compare iloperidone to other SGAs.
Asenapine is a new antipsychotic, approved in 2009, for sublingual
administration at a recommended dose of 5 mg twice daily. 102 The unusual mode
of administration and the lack of data in first-episode patients render it
inappropriate for Node 1 (see also the discussion in Node 2).
Lurasidone 103 is a new atypical antipsychotic that was approved in the United
States for treatment of schizophrenia in October 2010. It may be as effective as
aripiprazole, quetiapine, and ziprasidone in treating schizophrenia but seems less
effective than olanzapine. 104 , 105 Lurasidone has a relatively well-tolerated side-
effect profile with low liability for extrapyramidal symptoms, no significant QTc
prolongation, once-daily administration (with 350 kcal of food, optimally at
mealtime), and a benign metabolic profile (weight, lipids, and glucose).
Lurasidone may be more beneficial than ziprasidone for treating cognitive
deficits, 120 but comparison with other antipsychotics has not been reported. 106
Lurasidone may have the potential to replace ziprasidone on our preferred list for
Node 1, but more research and clinical experience are needed to be more
confident about where to position it in the algorithm. No studies in first-onset
patients have been reported.
As for the dosing of antipsychotics in first-episode patients, the use of lower-
than-usual doses is especially important to reduce the incidence and severity of
adverse effects and to improve treatment acceptability. 107 – 110 Since
antipsychotic side effects can have a lasting negative impact on attitudes toward
antipsychotic treatment and adherence, efforts to minimize them are especially
important. 111 For example, risperidone provided no greater antipsychotic
benefits at doses of 4 mg or higher in first-onset patients but was associated with
more neurocognitive side effects and motor impairment.107 , 109 , 110 An exception
to this suggestion for lower-than-usual dosing is quetiapine, which is not
effective in first-onset patients when used in doses lower than those used in
multiepisode schizophrenia.78
Summary: Node 1 Recommendations
For selection of antipsychotics as first-line treatment for first-episode
schizophrenia—taking into account short- and long-term efficacy, side effects,
and tolerability—amisulpride, aripiprazole, risperidone, and ziprasidone can be
selected as the best first choices. However, if minimizing risk for weight gain is
a strong priority, it may be reasonable to consider ziprasidone first, even though
no head-to-head comparisons have been reported in this population. Because of
its high long-term safety risks, olanzapine is not recommended as a Node 1
treatment. Quetiapine also presents significant problems with weight gain and
metabolic side effects, and has the poorest record for maintenance treatment. For
these reasons we also do not recommend quetiapine as a Node 1 treatment.
We do not encourage the use of FGAs as first-line treatment, because of the
risk of movement disorders and tardive dyskinesia,80 and because of inferior
results compared to SGAs in preventing a second episode.69
Node 1a: Intolerance or Inadequate Trial of a Node 1
Antipsychotic?
Before considering a patient a poor responder and moving on to Node 2, it is
important to determine whether the Node 1 antipsychotic has been given an
adequate trial. A four- to six-week trial on an adequate antipsychotic dose
represents a reasonable trial for most patients. Leucht and colleagues 112 found
that for multiepisode patients, if the patient does not achieve a 25% reduction in
symptoms in the first two weeks, outcome is likely to be poor at four weeks.
Gallego and colleagues, 113 however, found that in first-episode patients, early
symptom response was not a good predictor and that more time is often needed
for an adequate trial. In this study of 112 subjects, 40% responded by week 8,
and 65% by week 16.113
As for adequate dosing, FGAs can be in the range of 300–1000 mg
chlorpromazine equivalents,80 and suggested doses of SGAs can be 2–6 mg for
risperidone, 114 10–20 mg for olanzapine 115 (though perhaps preferably, at least
16 mg), 116 10–15 mg of aripiprazole,116 300–750 mg for quetiapine,80 and 160
mg for ziprasidone 117 (80 mg twice daily with a 500 kcal meal).99
When response is unsatisfactory—despite having optimized the dose (as
allowed by side effects) and duration of trial, considered reports of adherence by
patient and caretakers, and assessed for the presence of any known enzyme
inducers or substance abuse—consider checking the antipsychotic plasma
concentration. Aripiprazole, clozapine, haloperidol, olanzapine, and ziprasidone
are among the antipsychotics with available assays.52 In the absence of side
effects, and if the plasma level is well below the range seen in patients on typical
doses, suspect poor adherence or rapid metabolism. If the patient reports severe
side effects that are not objectively apparent, a plasma level will help in
assessing whether those are a somatization or nocebo effect. At times, unusual
objectively observed side effects are worth evaluating with a plasma level: a low
or zero level will suggest they are caused by something else.
Aripiprazole plasma level data are especially useful, with a suggested optimal
range between 150 and 210 ng/ml. 118 Growing evidence suggests that the range
for olanzapine is 20–40 ng/ml, with no greater benefit and significant toxicity
associated with levels above 80 ng/ml. 119 , 120 Other possible ranges, less well
delineated, include amisulpride at 200–320 ng/ml 121 and risperidone at 20–60
ng/ml.52 Quetiapine levels are so variable that they do not seem useful at this
time. 122
If the problem is determined to be nonadherence, and it is not due to
intolerance of side effects, consider using a long-acting injectable antipsychotic
(LAI). In some cases, the use of an LAI may be necessary to complete an
adequate trial at Node 1. The role of LAIs in managing schizophrenia has been
investigated in new studies, to which we now turn.
Poorly Adherent Patients: The Role of Long-Acting Injectable
Poorly Adherent Patients: The Role of Long-Acting Injectable
Antipsychotics
Nonadherence to medication is one of the major problems in treating patients
with schizophrenia, and LAIs are an intervention that has been thought to
improve adherence. It has been argued, however, that the data actually suggest
that LAIs may not be significantly superior to oral antipsychotics unless the
patient is committed to accepting this form of treatment. Supporting this
assertion is the study by Olfson and colleagues 123 of patients in the California
Medicaid program. In this real-world, observational study— which may have
important external validity—2695 marginally adherent patients were evaluated
before, during, and after initiating treatment with fluphenazine decanoate,
haloperidol decanoate, or LAI risperidone microspheres. The authors found that
very few of these patients continued to take their LAI for six months
(haloperidol, 9.7%; fluphenazine, 5.4%; and risperidone 2.6%; p < .0001). It was
speculated that the particularly poor outcome with risperidone LAI may have
reflected formulary restrictions in some outpatient settings. Rosenheck and
colleagues, 124 however, also found disappointing results with LAI risperidone in
another observational study of 369 U.S. veterans with unstable schizophrenia or
schizoaffective disorder. Risperidone LAI was not superior to oral antipsychotics
in the rate of rehospitalization in this study. It was also associated with more
extrapyramidal effects and local injection-site pain.
Tiihonen and colleagues 125 examined the risk of rehospitalization and drug
discontinuation in schizophrenia patients from Finland who had been
hospitalized for the first time. They showed that the risk of rehospitalization for
patients receiving depot medications was about one-third of that for patients
receiving oral formulations of the same compounds (adjusted hazard ratio =
0.36; 95% confidence interval [CI], 0.17–0.75). Their patient sample may have
been relatively unrepresentative, however, of more underresourced populations
such as the U.S. public sector patients in the Olfson and colleagues study.123
Leucht and colleagues 126 recently published a meta-analysis of controlled
comparisons of LAIs and oral formulations in more chronic populations and
concluded that LAIs are better in reducing relapse. Again, though, the patient
samples in these mostly industry-sponsored RCTs were free of major
comorbidity, able to cooperate with complex study procedures, and otherwise
“clean” compared to the more difficult populations in underfunded public
programs.
There are currently six LAIs of FGAs in international use, including
flupenthixol, fluphenazine, haloperidol, perphenazine, pipotiazine, and
zuclopenthixol. Among SGAs, olanzapine, risperidone, and paliperidone have
LAI formulations. We will comment briefly on some pertinent issues regarding
the use of some of these LAIs.
FGA LAIs might be expected to give rise to acute extrapyramidal symptoms,
tardive dyskinesia, and symptoms related to hyperprolactinemia. 127 , 128 The
frequency of movement disorders and tardive dyskinesia with FGA LAIs is
similar to that seen with oral FGAs. 129 Fluphenazine decanoate and haloperidol
decanoate may be associated with a relatively higher rate of movement disorders
compared to other LAIs, but perhaps with a lower risk of causing weight gain.128
Risperidone LAI has some advantage over FGAs concerning risk of
movement disorders. However, it is associated with increased plasma prolactin
similar to, albeit somewhat lower in magnitude than, that seen with oral
risperidone.128 Risperidone LAI is affected by delayed release:128 it takes about
3–6 weeks from the first injection of risperidone to produce a therapeutic plasma
level.52 Though often impractical, supplementation with oral risperidone during
this crossover period appears essential to get optimal results. 130 A recent RCT
found that patients stabilized on FGA LAIs had more treatment discontinuations
when randomized to six months of risperidone LAI (31%) compared to staying
on their original FGA LAI (10%). 131 Risperidone patients gained significantly
more weight but had no difference in new-onset extrapyramidal side effects.
Paliperidone palmitate is the LAI associated with paliperidone, the major
active metabolite of risperidone. It may be initiated with two weekly injections
to achieve therapeutic concentration rapidly, and unlike risperidone LAI, it does
not require supplementation with oral antipsychotics. Subsequent injections
occur at four-week intervals, an advantage over the two-week interval with
risperidone LAI. The tolerability and safety of paliperidone palmitate was
generally similar to risperidone LAI. 132 , 133
LAI olanzapine is similar to oral olanzapine both in effectiveness and in
adverse effects,128 , 129 , 134 with the exception of a new side effect: post-injection
delirium/sedation syndrome (incidence = 1.4% of patients treated), which
involves sedation, confusion, dizziness, dysarthria, somnolence, and possible
unconsciousness.128 , 134 , 135 This syndrome results from occasional inadvertent
intravascular injection of olanzapine. Patients must be observed for three hours
after each injection, and medical referral must be immediately available. All
patients have recovered, but some have required up to three days of
hospitalization.
In conclusion, LAIs may not have a marked benefit over oral medications,
especially in chronically ill, poorly-compliant patients. We do not recommend
their routine use in the algorithm, but they may have a role in evaluating acute
antipsychotic efficacy if poor results are clearly due to nonadherence. Evidence
does suggest that their initiation early in the course of schizophrenia in relatively
cooperative patients may improve long-term outcome.125 This effect may be due
to their prevention of covert nonadherence.127 When presenting treatment options
for the first or second antipsychotic trial to the patient, we think it reasonable to
include a discussion of the LAIs as an approach that could reduce early
rehospitalization and relapse. LAIs should be discussed in a way that tries to
overcome the stigma associated with the idea of receiving medication by
injection. Before recommending and selecting an LAI, however, it is also
important to be aware of any systems-related barriers that may impede follow-up
care with LAIs. 136 Community care systems will vary in the availability of
nurses to give injections and of funding and reliable monitoring processes.
If an LAI is chosen, haloperidol decanoate and paliperidone palmitate are
advantageous because of their four-week periods of effectiveness.123 , 125 Cost
considerations strongly favor the former option at this time. The least effective
appears to be risperidone LAI, perhaps because of its delayed release.
Additional Issues for the Node 1 Trial
Some clinicians might consider raising doses above the recommended ranges
when patients fail to respond well to usual doses at Node 1 despite adequate time
and blood levels sufficient to demonstrate bioavailability. No significant clinical
evidence, however, supports this strategy.80 Higher doses are not associated with
greater improvement with aripiprazole, quetiapine, risperidone, or olanzapine,
and they often result in increased side effects.114 , 119 , 137 , 138 Administering a
different antipsychotic is a preferable approach.
Intolerance of the side effects of the antipsychotic can cause poor adherence
and early discontinuation.52 If the patient discontinues a trial prematurely despite
dosage adjustment or other management strategies (e.g., changing the time of
dosing, or stopping or reducing other medications that may be contributing to the
side effect), then Node 1 has not been completed, and another trial should occur
with one of the recommended agents.
Akathisia is an antipsychotic-induced adverse effect that particularly affects
adherence. The first adjustment should be to reduce the dose if possible. If that
fails, it seems reasonable to try to treat the akathisia. 139 See Text Box 1 for a
review of treatment options. It should be noted, however, that akathisia was
found to be a predictor of, or marker for, patients who will have poor outcome
from FGA therapy despite usual treatment efforts. 140 It is unclear if the same is
true with akathisia from SGAs.
Text Box 1 | Antipsychotic-Induced Akathisia in Schizophrenia
Evidence Considerations Recommendations
Akathisia is a feeling of discomfort, often a tingling
sensation, especially in the legs, relieved somewhat by motor
activity. 141
At its extreme, it may precipitate aggressive, violent, and
suicidal behaviors. 142 , 143
To diagnose, ask patient to cease moving and to describe
subjective sensations, if any. Differentiate psychotic
agitation, anxiety, drug withdrawal syndromes, some
neurological disorders, or tardive dyskinesia. 144 Akathisia
can be misdiagnosed as psychotic agitation, which may lead
to an inappropriate increase in antipsychotic therapy.144 , 145
Akathisia has been found to occur at antipsychotic doses that
produce full occupancy of striatal D2 receptors. 146
However, this full occupancy has no mechanistic
implications for akathisia; other neurotransmitter systems
(norepinephrine, serotonin) likely contribute to its
pathophysiology. 147 – 149
The development of akathisia may be a possible predictor of
an unsatisfactory response to a neuroleptic.140 Even if the
dose is raised (after treating the akathisia), the antipsychotic
response may still be unsatisfactory. 150 It is unclear if these
findings apply to the akathisia-like symptoms associated
with some SGAs.
Start with smaller dose, and increase
the dose gradually, particularly in drug-
naive patients.139 Consider beta-
adrenergic antagonists139 , 148 —for
example, propranolol.
Consider benzodiazepines139 —for
example, clonazepam, lorazepam, or
diazepam (especially if associated with
anxiety).
Consider antimuscarinic agents139 , 147
, 151 , 152 —for example, benztropine
(particularly if akathisia is associated
with parkinsonism). However, the
evidence base for their use is weak.139
There are other possible options for
treatment-resistant akathisia:
trazodone, 153 cyproheptadine,148
mirtazapine,149 zolmitriptan, 154 and
vitamin B6. 155
NODE 2: UNSATISFACTORY RESPONSE TO AN
ADEQUATE TRIAL OF A NODE 1
ANTIPSYCHOTIC?
Relatively limited evidence is available to guide selection of the next
antipsychotic after failure of the first adequate antipsychotic trial. We will
review some of that evidence.
In 2006, Mc Cue and colleagues,88 in an open-label randomized prospective
trial (n = 327), compared five SGAs and haloperidol in newly admitted, acutely
ill patients with schizophrenia, schizoaffective disorder, or schizophreniform
disorder. This real-world effectiveness study employed the somewhat
unorthodox and perhaps bias-prone primary outcome measure of whether the
patients were able to be discharged from inpatient care within three weeks. The
results were that three medications did significantly better than three others:
olanzapine (mean dose = 19 mg; 92% discharged), haloperidol (16 mg; 89%),
and risperidone (5.2 mg; 88%) did the best, whereas aripiprazole (22 mg; 64%),
quetiapine (650 mg; 63%), and ziprasidone (150 mg; 64%) were significantly
less effective on this measure. Dosing was robust for all six medications. This
study suggests that there may be important differences in the effectiveness of
antipsychotics in the acute inpatient setting. These findings are not inconsistent
with those of an often cited meta-analysis by Leucht and colleagues28 of
primarily industry-sponsored trials comparing different antipsychotics, except
for its finding that haloperidol, an FGA, was as effective as the better SGAs.
However, the differences in favor of the better options were sharper in the data
from McCue and colleagues88 than in the meta-analysis.28
Suzuki and colleagues,89 in a randomized, open-label study, evaluated the
effectiveness of sequential switch among three SGAs. Japanese patients (n = 78)
who had never had a full trial of any SGA were randomized to robust doses of
olanzapine, risperidone, or quetiapine for up to eight weeks. Then, unsatisfactory
responders to this trial were randomized to one of the other two antipsychotics
for up to eight more weeks. Poor responders after the second trial were given the
third antipsychotic. The study found that 50% (n = 39) of the patients responded
to the first round of antipsychotic therapy. Olanzapine and risperidone were not
different in their response rates, and both were superior to quetiapine. Among
first-round nonresponders, 38% (n = 14) responded to the second randomized
SGA trial. Quetiapine was the most effective second-line option, with a
surprisingly good response rate of 60%. Only two patients responded in the third
trial. Suzuki and colleagues concluded that after failure on an initial trial with an
SGA, a second trial is a reasonable strategy, but that after two failed trials, a
third trial has minimal chance of success. If patients received either olanzapine
or risperidone first, the findings did not support favoring risperidone or
olanzapine over quetiapine as a second choice. If patients received quetiapine
first, the findings suggest a switch to either olanzapine or risperidone.
As noted earlier, ziprasidone, which was not included in the above study, has
generally not fared well in comparisons to other antipsychotics: a Cochrane
analysis of 11 comparative trials in established, as opposed to first-onset,
patients concluded that ziprasidone was not as effective as other antipsychotics.96
These results may be due in part to the failure to employ optimal administration
parameters: 160 mg daily117 (which is at the high end of the recommended range)
in two doses, taken with 500 kcal meals. 156 Even if these conditions can be met,
ziprasidone may still not be the best choice for Node 2.
In a similarly designed, randomized, open-label, eight-week study—also from
Japan, and involving newly admitted, acutely ill psychotic patients—olanzapine
and risperidone were again significantly superior to aripiprazole and quetiapine
in the outcome as measured by time to discontinuation.87
Overall, these data, which are derived from studies with good external
validity, support the proposition that if the Node 1 trial was not with one of the
proposed more effective SGAs (olanzapine, risperidone, or an FGA), a second
trial should involve one of these. The success of perphenazine in Phase 1 of the
Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), compared
to the SGAs olanzapine, risperidone, quetiapine, and ziprasidone, has convinced
some clinicians that perphenazine is now the FGA of choice over the more
traditional haloperidol. 157 In this context, it is worth noting that bioavailability of
perphenazine can also be assessed with plasma levels. The proposed optimal
range is 1–3 ng/ml, with levels above that producing no additional benefit and
perhaps greater probability of side effects. 158 , 159
Therapeutic drug monitoring with haloperidol has a long and complicated
history. 160 Haloperidol was once thought, based on six early studies, to have a
curvilinear plasma level/response relationship (i.e., a therapeutic window), with
a proposed therapeutic range of 5–15 ng/ml. Subsequent efforts to confirm this
range have had mixed results. 161 Haloperidol levels remain at least as useful as
other antipsychotic levels for confirming compliance and bioavailabity. The
consensus is that levels higher than 15 ng/ml bring no additional benefit,160 but
the lower limit is probably lower than 5 ng/ml for patients experiencing first
exposure to strong D2 receptor–occupying FGAs. Attention might also be paid
to the presence of parkinsonian side effects (cogwheeling, akinesia), which, if
present, indicate greater than 75% D2 occupancy and suggest that no matter how
low (or high) the plasma level, raising the dose would be of little advantage. 6 By
the same token, the absence of parkinsonism suggests lower striatal D2
occupancy and potential value to raising the dose.
Lurasidone, one of the newer SGAs, was discussed earlier as a potential Node
1 antipsychotic because of some advantages over ziprasidone. We do not favor
it, however, as a Node 2 choice. In the only randomized comparison (n = 478)
with any of the antipsychotics that performed better in the effectiveness studies
reviewed above,87 – 89 lurasidone at either dose (40 or 120 mg) appeared inferior
to olanzapine 15 mg105 —despite the study’s sponsorship by the manufacturer of
lurasidone.
In 2006, Stroup and colleagues, 162 in phase 2T of the CATIE study, examined
patients (n = 444) who had failed their first SGA and then were randomized to a
different SGA. Patients who switched to olanzapine or risperidone did better
than those switched to quetiapine or ziprasidone. However, a methodological
issue with CATIE is that a high proportion of the patients who did better on
olanzapine in the second trial had been on olanzapine before entering the study.
163 This limitation was not present in the study by Suzuki and colleagues,89 which
did not find an advantage to olanzapine or risperidone for the second trial.
It is unclear at this time if asenapine is a reasonable option for Node 2.
Placebo-controlled RCTs with haloperidol and risperidone have been published
showing comparable efficacy. Since the haloperidol trial excluded patients who
had a history of failing on another antipsychotic, the patients would not be
comparable to Node 2 patients. 164 Three unpublished trials in over 1000 patients
involved comparison with olanzapine, and in two of them asenapine was
described as less effective than olanzapine. 165 Thus, the potential categorization
of asenapine as one of the more effective antipsychotics awaits the publication of
more of its trials and more extensive clinical experience.102 On September 30,
2011, the U.S. Food and Drug Administration added a warning because of 52
cases of allergic reactions, 19 of which resulted in emergency room visits or
hospitalization.
Summary: Node 2 Recommendations
Some evidence supports trying a carefully selected second antipsychotic. If not
tried before, an FGA, olanzapine, or risperidone is recommended. If one of these
was tried in Node 1, any antipsychotic except clozapine may be selected for
Node 2.
If olanzapine is selected, consider taking steps to try to prevent weight gain or
to prevent further gain if it begins right away—that is, within early weeks of
treatment. Diet and exercise are recommended for those few patients sufficiently
motivated to make these lifestyle changes. Topiramate and metformin have been
tried, both initially and after weight gain develops. One RCT compared adding
topiramate 100 mg or placebo to 72 patients when they were started on
olanzapine. 166 Remarkably, the topiramate patients did not gain any weight,
whereas those on placebo had the usual weight gain. This study needs replication
but is promising, although topiramate has many potential side effects. Metformin
has had beneficial effects on weight and metabolic parameters. 167 , 168 Although
these studies were short term, positive results are likely to continue over time,
and metformin may have infrequent side effects. 169
Node 2a: Intolerance or Inadequate Trial of Node 2
Antipsychotic?
If the patient could not complete an adequate trial (as defined in Node 1a) of a
Node 2 option, choose another antipsychotic from the recommended options
before going to Node 3.
NODE 3: UNSATISFACTORY RESPONSE TO AN
ADEQUATE SECOND ANTIPSYCHOTIC TRIAL?
Treatment-resistant schizophrenia (TRS) denotes patients with failure to respond
to at least two adequate trials of different antipsychotics. Approximately 30%
(range 10%–45%) of schizophrenia patients meet this criterion. 170 , 171 Clozapine
is more effective than FGAs 172 – 174 and other SGAs 175 – 177 for TRS. Kane and
colleagues,172 in the first double-blind RCT in TRS, demonstrated that clozapine
(30%) was more effective than chlorpromazine (4%) in patients who had been
refractory to prior trials of FGAs, including haloperidol. Chakos and colleagues,
173 in a review and meta-analysis of subsequent randomized trials, found that
clozapine continued to be superior to FGAs in controlling symptoms in patients
with chronic schizophrenia. In Phase 2 of CATIE, McEvoy and colleagues175
compared clozapine, olanzapine, risperidone, and quetiapine in a group of
schizophrenia patients who had failed to improve after the initial trial with one
of four SGAs or perphenazine. Patients receiving clozapine were less likely to
discontinue treatment because of inadequate therapeutic response than patients
receiving any of the other SGAs.
Lewis and colleagues, 176 in the large CUtLASS RCT, compared clozapine
with amisulpride, olanzapine, quetiapine, and risperidone. Clozapine produced
significantly greater reductions in Positive and Negative Syndrome Scale total
scores than other agents (−4.93 points; CI, −8.82 to −1.05; p = .013).
Thus, the evidence appears to be substantial that clozapine is the one and only
clearly effective option for TRS as defined by failure to respond to two adequate
trials of antipsychotics as in this algorithm.80 Though six studies have compared
olanzapine in various doses to clozapine— some of which showed olanzapine’s
effectiveness to be closer than other SGAs to clozapine—these studies had
methodological problems, including low clozapine doses and small sample
sizes.80 Conley and colleagues,177 in one of those small comparison studies, used
a double-blind, crossover design with 13 patients to compare the efficacy of
clozapine (450 mg) versus high-dose olanzapine (50 mg) in well-defined TRS.
Clozapine was much more effective than olanzapine. Thirty percent of patients
responded to clozapine, the same percentage as in Kane and colleagues’ study of
TRS mentioned above,172 and no patients improved on olanzapine.177 Also, 46%
of patients dropped out in the olanzapine phase, versus none while on clozapine.
Clozapine is also more effective than haloperidol, olanzapine, and risperidone
for persistent aggressive and hostile behavior in treatment-resistant
schizophrenia 18 and is more effective than haloperidol and olanzapine for this
behavior in non-treatment-resistant schizophrenia patients.17
Clozapine is associated with reduced suicide rates in schizophrenia. There is a
threefold reduction in the risk of suicidal behaviors compared to other
antipsychotic medications. 15 In an international randomized, single-blind study
of schizophrenia and schizoaffective disorder patients at high risk for suicide (n
= 980), clozapine produced significantly fewer suicidal thoughts and actions
than those randomized to olanzapine.14 In this study, only 27% of subjects had
TRS.
Patients with TRS are often poorly compliant with antipsychotic therapy.
Adherence with clozapine, however, may be better. 178
Clozapine blood levels are useful in efforts to improve therapeutic response.
They assist with assessing unusual side effects, detecting adherence problems,
and evaluating the impact of metabolic inhibitors (e.g., fluvoxamine) and
inducers (e.g., cigarette smoke). The optimal therapeutic response usually occurs
with clozapine levels above 350–450 ng/mL. 179 – 182 Plasma levels over 600
ng/mL have been associated with increased toxicity, including seizures. 183 The
usual effective dosing range is 300–400 mg/day in divided doses. The total dose
should not exceed 900 mg/day, and single doses generally should not exceed 450
mg. If the response is unsatisfactory at 600 mg/day, a blood level should be
obtained before further increases are undertaken.56
Since clozapine is metabolized by cytochrome P450 isozymes, especially
P450 1A2, co-prescription with inhibitors and inducers of these isozymes
requires careful attention. Fluvoxamine is a strong inhibitor of the 1A2 enzyme
and can increase clozapine levels by 500%, while cigarette smoke induces 1A2-
mediated metabolism and can lower levels by over 50%.56 , 184 Citalopram has
recently been found to raise clozapine levels significantly due to an unknown
mechanism and has a new package insert warning about this effect.
If possible, benzodiazepines should be discontinued or reduced because of the
risk of respiratory depression in combination with clozapine, especially early in
the trial. 185
Clozapine is associated with adverse effects, some potentially serious and life
threatening, including agranulocytosis, seizures, myocarditis, cardiomyopathy,
constipation (which can cause obstruction and paralytic ileus), and weight
gain/metabolic syndrome. Some less serious side effects—for example, sedation,
hypersalivation, tachycardia, hypotension, dizziness, and obsessive-compulsive
symptoms—can be disruptive and result in poor adherence. Clinicians should be
familiar with the evidence for how optimally to manage these side effects. 186
Due to concerns about the adverse effects of clozapine and about the time and
effort required to perform appropriate medical monitoring, manage adverse
effects, and administer an adequate trial, this medication is underused despite its
advantages.56
Many of the adverse effects of clozapine are dose dependent and associated
with the speed of titration. Since adverse effects tend to be more common at the
beginning of the therapy, it is important to start treatment at low doses and to
increase slowly.52 The starting dose of clozapine is 12.5 mg once or twice daily.
For patients over the age of 60, 6.25 mg may be reasonable. Clozapine is
gradually titrated upward. Efforts should be made to withdraw the previous
antipsychotic gradually once effective clozapine levels are reached. Many
believe, though it has not been demonstrated in appropriately designed studies,
that optimal results occur with monotherapy. 187
NODE 4: NO OR UNSATISFACTORY
IMPROVEMENT DESPITE AN ADEQUATE
CLOZAPINE TRIAL?
Up to 30% of people with refractory schizophrenia treated with clozapine exhibit
residual positive symptoms. 188 , 189
Clozapine augmentation is a common treatment approach for patients failing
to respond to clozapine monotherapy. However, the evidence base supporting
augmentation is limited. Meta-analyses suggest small effect sizes (at best) for all
proposed options. 190 – 192
The addition of risperidone has been studied in five placebo-controlled RCTs.
193 – 197 Josiassen 196 found an advantage of risperidone over placebo
augmentation of clozapine. This study allowed doses up to 6 mg of risperidone
and was the longest trial at 12 weeks. Three other trials found no advantage for
risperidone, and one found a strong trend toward superiority of placebo, but
doses were restricted. 195 A meta-analysis showed no difference in overall
efficacy.192 Thus, the evidence for this frequently employed option is weak, but a
higher dose of risperidone for longer duration could be worth trying.
Augmentation with other antipsychotics has very limited support. In two
RCTs, the only clear impact of aripiprazole as an augmentation was to blunt the
severity of the adverse metabolic effects. 198 Recently, aripiprazole and
haloperidol were compared as clozapine augmentations in an RCT. 199 No
differences in efficacy were found, but aripiprazole had a more favorable side-
effect profile. It is difficult to draw conclusions from this study, however; a
placebo control is essential since most augmentation studies have found a large
placebo effect.
A small study of sulpiride (which is not available in the United States) found
it to be effective as an augmentation.192
Another augmentation option is lamotrigine. Tiihonen and colleagues, 200 in a
meta-analysis of five placebo-controlled RCTs of lamotrigine augmentation of
clozapine, found a small positive effect size of 0.32 by Cohen’s d. The net
benefit, however, was primarily due to one positive study, leading Sommer and
colleagues in their meta-analysis to eliminate that study as an outlier.192 In two
large, placebo-controlled RCTs (n = 429) of lamotrigine augmentation in
patients taking various antipsychotics, Goff and colleagues 201 found no
advantage for lamotrigine. However, the 63 patients who were on clozapine did
slightly better with lamotrigine. In conclusion, lamotrigine may be beneficial for
some clozapine partial responders.
The evidence supporting clozapine augmentation with electroconvulsive
therapy is weak. No RCTs have been published. However, Havaki-Kontaxaki
and colleagues, 202 in a review of the case reports of the concurrent
administration of clozapine and ECT in clozapine-resistant schizophrenia or
schizoaffective patients, found that this combined therapy appeared to be
effective and was reasonably safe. Since this option appears to have as much
merit as the well-studied, but weakly efficacious, options of risperidone and
lamotrigine, we have included it here at Node 4.
Transcranial magnetic stimulation (rTMS) has also been found to have some
efficacy for chronic auditory hallucinations in schizophrenia.80 Though financial
barriers may prevent access for many patients in public sector settings, and much
remains to be learned about parameters for optimal acute and maintenance
treatment, this treatment holds promise as a Node 4 option with potentially fewer
side effects.
Before considering these clozapine augmentations, we recommend a
reevaluation of the diagnosis, potential substance abuse, and medication
adherence. 203 Optimizing clozapine blood levels, attention to side effects, and
elimination of confounding variables such as the presence of other
antipsychotics may be important and should be considered before clozapine
augmentation.56 , 186
NODE 5: NO OR UNSATISFACTORY
IMPROVEMENT WITH CLOZAPINE
AUGMENTATION?
If there have been three failed adequate trials of antipsychotics including
clozapine, and one failed clozapine augmentation, the probability of
improvement with further psychopharmacological interventions is low.
However, unexpected positive results can occur. As noted in the flowchart in
Figure 1 , there are perhaps five approaches to consider at this point. We
comment on them in Text Box 2 , though not necessarily in order of preference.
For any particular patient, the prescribing clinician should review all five options
and determine which approach seems best. The clinician should also review the
potential psychosocial interventions and decide whether any may have been
underutilized up to this point.
Text Box 2 | Options to Consider for Treatment-Resistant Schizophrenia at
Node 5
Treatment Comments
Another of the
augmentations from Node 4
Try risperidone, lamotrigine, or electroconvulsive therapy.
Other clozapine
augmentations
Memantine. Lucena and colleagues, 204 in a small, double-blind trial of
memantine or placebo (n = 21) as augmentation in clozapine-resistant
patients, found memantine better than placebo on all outcomes, with
large effect sizes (overall improvement: ES = −2.75, p = .01; positive
symptoms: ES = −1.38). Note: no benefit has been found for
augmentation with memantine for other SGAs.204
O3FAs . Most of the interest has focused on recent use to prevent onset
of schizophrenia in high-risk youth. 205 However, in a 2002 RCT, Peet
and colleagues 206 evaluated the addition of O3FA to clozapine (n =
31), SGAs (n = 46), and FGAs (n = 36). Only patients on clozapine had
significant benefit.
Stop clozapine, and try other
single antipsychotics not
previously tried
Perhaps the best antipsychotic to try after clozapine is aripiprazole,
based on anecdotal data. 207 The theory is that the partial dopamine
agonist effect of aripiprazole will have more benefit when the patient
has not recently been treated with a strong dopamine-blocking
antipsychotic, which would have produced upregulation of these
receptors. 208 Consistent with this theory, one report described a patient
who responded well to aripiprazole after clozapine despite failing to
respond to it in a previous trial after risperidone. 209 Kane and
colleagues, 210 in an RCT, compared the efficacy and safety of
aripiprazole (high dose: 30 mg) or perphenazine (40 mg, double that
used in CATIE) in well-established, treatment-resistant schizophrenia
patients. An impressive 27% of aripiprazole- and 25% of perphenazine-
treated patients responded, as defined by a 30% decrease in rating
scores. Thus, either of these could be reasonable options at this point.
Also, consider loxapine, which has some atypical pharmacodynamic
properties 211 and some slight evidence of working when other
antipsychotics have failed. 4 , 6
Stop clozapine, and try a
combination of an FGA and
mirtazapine or, if early in
course, of an SGA and
celecoxib
The FGA/mirtazapine combination is thought to potentially duplicate
the receptor impact of clozapine. If clozapine has been tried and failed,
the likelihood of success is presumably reduced. However, if the patient
is at Node 5 because clozapine was not tolerated, this option may be
worth considering. Joffe and colleagues, 212 in a 6-week, placebo-
controlled RCT (n = 41) of mirtazapine in patients with inadequate
response to their current FGAs, found that 20% of patients (n = 4) on
mirtazapine were responders vs. 5% (n = 1) on placebo. On rating-scale
scores, the effect size was 1.0 (95% CI, 0.34–1.67). Another positive
trial was by Terevnikov. 213 Note: small trials like these can generate
higher effect sizes than larger ones. Another RCT (n = 41) did not
higher effect sizes than larger ones. Another RCT (n = 41) did not
support the use of this augmentation. 214
On the theory that inflammatory processes contribute to the
pathogenesis of schizophrenia, anti-inflammatory agents have been
tried. Aspirin (1000 mg daily) showed a small effect on positive
symptoms in an RCT. 215 In an RCT with the COX-2 inhibitor
celecoxib (400 mg daily compared to placebo, with both added to
amisulpride), Muller and colleagues 216 treated 49 patients who had
been ill for two years or less for six weeks. Significant improvements
were seen. Previous studies involving more chronically ill patients
showed no benefit from celecoxib.
Combination therapy with
non-clozapine FGAs or
SGAs
There is no good evidence that antipsychotic combination therapy not
involving clozapine offers any efficacy advantage over the use of single
antipsychotics. The evidence supporting such combinations consists
almost entirely of open-label studies and case series. 217 , 218 In a
persuasive, well-executed negative trial of combination therapy, Kane
and colleagues 219 performed a 16-week, placebo-controlled RCT (n =
323) adding aripiprazole to risperidone or quetiapine (equal numbers of
each). It could be hypothesized that, based on mechanistic speculations,
aripiprazole might be a useful adjunct to either. However, no efficacy
was demonstrated. In fact, by week 4, placebo was significantly
superior, though over the next 12 weeks this difference gradually
disappeared. Both groups improved, so ”clinical experience” would
have suggested to the observing clinicians that this augmentation was
helpful. There are few other good data, which is unfortunate,
considering how widely various combinations are used in international
practice.
COMPARISON WITH OTHER GUIDELINE AND
ALGORITHM RECOMMENDATIONS
The present algorithm for selecting psychopharmacological treatment for
schizophrenia differs in some respects from earlier versions of the PAPHSS
algorithm and from other recently published algorithms and guidelines. The
1999–2001 version of the PAPHSS algorithm recommended initial treatment of
first-onset patients with an SGA, preferably either olanzapine or risperidone, and
leaned toward risperidone because of evidence of a more rapid acute effect.6 , 7
The patient would be eligible for clozapine after receiving either of the two
preferred SGAs and one FGA. In the new version, olanzapine is no longer
preferred for first-line use, and an FGA trial is not needed before consideration
of clozapine. Table 2 lists several guidelines and algorithms published by
different groups in the last three years that have addressed a similar scope of
psychopharmacology problems to the present effort.52 , 80 , 220 , 221 We have noted
some points of contrast between their recommendations and ours.
Table 2 | Comparison with Some Other Algorithms and Guidelines
Published in the Last Three Years
Algorithm/guideline Year Comments/differences from PA algorithm
Maudsley
Prescribing
Guidelines
Algorithms52
2012 Has comprehensive discussion of antipsychotic side effects and their
management. PA focus is more on the implications of those side
effects for decisions at various points in the algorithm.
In a change from their 2009 algorithm, Maudsley decided that one of
the two antipsychotics before clozapine should be olanzapine. PA
does not find the evidence compelling that olanzapine must be one of
the two.
Evidence-Based
Pharmacotherapy of
Schizophrenia220
2011 Does not address first-episode treatment. PA suggests start first
episode with SGA other than clozapine, quetiapine, or olanzapine;
then second trial with risperidone, olanzapine, or FGA if not tried
first.
Makes no suggestions for managing resistance to clozapine. PA
reviews evidence on different clozapine-augmentation strategies and
on what to do next after stopping or not using clozapine.
Discusses combining antipsychotics as option if they have different
receptor profiles. PA finds that combining antipsychotics is not
supported by the evidence and should be the last option.
Favorable view of LAIs as “assuring” compliance. PA sees the
evidence for this view to be less convincing and does not have LAIs
in primary role.
Schizophrenia
Patient Outcomes
Research Team
(PORT)
recommendations80
2009 First episode to be treated with any antipsychotic except clozapine
and olanzapine. PA adds FGAs and quetiapine to the list of
medications not preferred.
Adequate trials defined in general terms. PA definition of adequate
trials adds bioavailability assessment, which may be assisted by a
plasma level, after dose adjustment for response and side effects.
Has no preference for second antipsychotic trial in multi-episode
patients. PA prefers risperidone, olanzapine, or FGA for second trial.
patients. PA prefers risperidone, olanzapine, or FGA for second trial.
Because the evidence was so unclear, had no recommendations for
negative symptoms, comorbid depression, or clozapine resistance.
PA endeavored to offer possibly plausible strategies.
United Kingdom’s
National Institute
for Clinical
Excellence (NICE)
Schizophrenia
Guideline221
2009 Strong emphasis on psychosocial interventions, involving patients in
medication decisions, and on cost-effectiveness of medications, but
makes no specific recommendations on medications except for
clozapine in treatment resistance. PA has many detailed
recommendations at all phases of treatment, from initial to most
treatment resistant, including many scenarios with comorbidity.
Recommends two trials, including at least one SGA, in any order,
prior to “offering” clozapine. PA recommends at least one of the
following prior to clozapine: risperidone, olanzapine, or FGA.
FGA, first-generation antipsychotic; LAI, long-acting injectable antipsychotic; PA, Psychopharmacology
Algorithm Project at the Harvard South Shore Program Algorithm; SGA, second-generation antipsychotic.
CONCLUSIONS AND FINAL COMMENT
In the quarter-century since the first iteration of this heuristic, we have seen
considerable improvement in the number and quality of treatment options for the
psychopharmacology of schizophrenia. Nevertheless, many challenges persist.
Better medications are needed with fewer side effects. Much more needs to be
learned about the pathophysiology of this chronic, disabling condition and the
comorbidities with which it often presents. Improvements in understanding
genetics, the neurobiological underpinnings of schizophrenia, and mechanisms
underlying its symptoms promise refinements in future treatments and in future
algorithms. Eventually, targeted treatments for selected symptoms in this
complex, multidimensional disorder will no doubt be developed.
Importantly, structured psychotherapies have made their mark in the world of
comprehensive care. Their purposes include emphasis on symptom remission,
efforts to educate both patients and families about the illness and its
requirements for patient-based self-management, and prioritization of the family
as the locus of care. These interventions mesh well with and complement the
advances in pharmacological treatment.
All major guidelines and algorithms for treating schizophrenia published in
the last few years propose, as do the present authors, that two monotherapy trials
with FGAs and SGAs should occur, followed, if necessary, by a trial of
clozapine, but they all also vary in how to accomplish these steps.52 , 80 , 220 , 221
We have provided information to assist with choosing what we argue is the most
evidence-supported approach as of this writing. Many clinicians deviate from the
consensus view, however, that there should be two trials and then clozapine, 222
and non-evidence-supported polypharmacy continues to be common
internationally. The recommendations provided here, if followed, offer a
reasonable path to improve psychopharmacological outcomes for patients with
schizophrenia and to reduce the time to achieve the maximum benefit obtainable
from currently available medications. The authors welcome comments regarding
readers’ experience and any other aspects of this algorithm that could lead to its
improvement in future revisions.
Declaration of interest: The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of the article.
REFERENCES
1. Eack SM, Hogarty GE, Cho RY, et al. Neuroprotective effects of cognitive enhancement therapy
against gray matter loss in early schizophrenia: results from a 2-year randomized controlled trial. Arch
Gen Psychiatry 2010;67:674–82.
2. Osser DN. Treatment resistant problems. In: Tupin JP, Shader RI, Harnett DS, eds. Clinical handbook
of psychopharmacology. New York: Jason Aronson, 1988:269–328.
3. Osser DN. A systematic approach to pharmacotherapy in patients with neuroleptic-resistant psychoses.
Hosp Community Psychiatry 1989;40:921–7.
4. Osser DN, Patterson RD. Pharmacotherapy of schizophrenia I: acute treatment. In: Soreff S, ed.
Handbook for the treatment of the seriously mentally ill. Toronto: Hogrefe & Huber, 1996:91–119.
5. Osser DN, Patterson RD. Pharmacotherapy of schizophrenia II: an algorithm for neuroleptic resistant
patients. In: Soreff S, ed. Handbook for the treatment of the seriously mentally ill. Toronto: Hogrefe &
Huber, 1996:121–55 .
6. Osser DN, Zarate CJ. Consultant for the pharmacotherapy of schizophrenia. Psychiatr Ann
1999;29:252–69.
7. Osser DN, Sigadel R. Short-term inpatient pharmacotherapy of schizophrenia. Harv Rev Psychiatry
2001;9:89–104.
8. Hamoda HM, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: an update on psychotic depression. Harv Rev Psychiatry 2008;16: 235–47.
9. Ansari A, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: an update on bipolar depression. Harv Rev Psychiatry 2010;18:36–55.
10. Osser DN, Dunlop LR. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: an update on generalized social anxiety disorder. Psychopharm Rev 2010;45:91–8.
11. Bajor L, Ticlea A, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South
Shore Program: an update on posttraumatic stress disorder. Harv Rev Psychiatry 2011;19:240–58.
Gelenberg AJ. The catatonic syndrome. Lancet 1976;1: 1339–41.
12. Gelenberg AJ. The catatonic syndrome. Lancet 1976;1: 1339–41.
13. Manschreck TC, Petri M. The paranoid syndrome. Lancet 1978;2:251–3.
14. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia:
International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003;60: 82–91.
15. Hennen J, Baldessarini RJ. Suicidal risk during treatment with clozapine: a meta-analysis. Schizophr
Res 2005;73: 139–45.
16. Tiihonen J, Suokas JT, Suvisaari JM, Haukka J, Korhonen P. Polypharmacy with antipsychotics,
antidepressants, or benzodiazepines and mortality in schizophrenia. Arch Gen Psychiatry
2012;69:476–83.
17. Krakowski MI, Czobor P, Citrome L, Bark N, Cooper TB. Atypical antipsychotic agents in the
treatment of violent patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry
2006;63:622–9.
18. Volavka J, Czobor P, Nolan K, et al. Overt aggression and psychotic symptoms in patients with
schizophrenia treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin
Psychopharmacol 2004;24:225–8.
19. Volavka J, Czobor P, Derks EM, et al. Efficacy of antipsychotic drugs against hostility in the
European First-Episode Schizophrenia Trial (EUFEST). J Clin Psychiatry 2011;72: 955–61.
20. Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam, or both for psychotic agitation? A
multicenter, prospective, double-blind, emergency department study. Am J Emerg Med
1997;15:335–40.
21. Garza-Trevino ES, Hollister LE, Overall JE, Alexander WF. Efficacy of combinations of
intramuscular antipsychotics and sedative-hypnotics for control of psychotic agitation. Am J
Psychiatry 1989;146:1598–601.
22. Breier A, Meehan K, Birkett M, et al. A double-blind, placebo-controlled dose-response comparison
of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch
Gen Psychiatry 2002;59: 441–8.
23. Andrezina R, Josiassen RC, Marcus RN, et al. Intramuscular aripiprazole for the treatment of acute
agitation in patients with schizophrenia or schizoaffective disorder: a doubleblind, placebo-controlled
comparison with intramuscular haloperidol. Psychopharmacology (Berl) 2006;188:281–92.
24. Satterthwaite TD, Wolf DH, Rosenheck RA, Gur RE, Caroff SN. A meta-analysis of the risk of acute
extrapyramidal symptoms with intramuscular antipsychotics for the treatment of agitation. J Clin
Psychiatry 2008;69:1869–79.
25. Zeller SL, Rhoades RW. Systematic reviews of assessment measures and pharmacologic treatments
for agitation. Clin Ther 2010;32:403–25.
26. Thapa PB, Palmer SL, Owen RR, Huntley AL, Clardy JA, Miller LH. P.R.N. (as-needed) orders and
exposure of psychiatric inpatients to unnecessary psychotropic medications. Psychiatr Serv
2003;54:1282–6.
27. Carpenter WT, Heinrichs DW, Wagman AMI. Deficit and nondeficit forms of schizophrenia—the
concept. Am J Psychiatry 1988;145:578–83.
28. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation
antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009;373:31–41 .
29. Buchanan RW, Breier A, Kirkpatrick B, Ball P, Carpenter WT Jr. Positive and negative symptom
response to clozapine in schizophrenic patients with and without the deficit syndrome. Am J
response to clozapine in schizophrenic patients with and without the deficit syndrome. Am J
Psychiatry 1998;155:751–60.
30. Rado JT. Treatment of negative symptoms in schizophrenia. Psychopharm Rev 2011;46:33–9.
31. Singh SP, Singh V, Kar N, Chan K. Efficacy of antidepressants in treating the negative symptoms of
chronic schizophrenia: meta-analysis. Br J Psychiatry 2010;197:174–9.
32. Bodkin JA, Siris SG, Bermanzohn PC, Hennen J, Cole JO. Double-blind, placebo-controlled,
multicenter trial of selegiline augmentation of antipsychotic medication to treat negative symptoms in
outpatients with schizophrenia. Am J Psychiatry 2005;162:388–90.
33. Strous RD, Maayan R, Lapidus R, et al. Dehydroepiandrosterone augmentation in the management of
negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatry 2003;60:133–41.
34. Doruk A, Uzun O, Ozsahin A. A placebo-controlled study of extract of ginkgo biloba added to
clozapine in patients with treatment-resistant schizophrenia. Int Clin Psychopharmacol 2008;23:223–
7.
35. Levkovitz Y, Mendlovich S, Riwkes S, et al. A double-blind, randomized study of minocycline for
the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry
2010;71:138–49.
36. Whitehead C, Moss S, Cardno A, Lewis G. Antidepressants for people with both schizophrenia and
depression. Cochrane Database Syst Rev 2002;(2):CD002305.
37. Siris SG, Bermanzohn PC, Mason SE, Shuwall MA. Maintenance imipramine therapy for secondary
depression in schizophrenia. A controlled trial. Arch Gen Psychiatry 1994; 51:109–15.
38. Kirli S, Caliskan M. A comparative study of sertraline versus imipramine in postpsychotic depressive
disorder of schizophrenia. Schizophr Res 1998;33:103–11.
39. Moller HJ. Antidepressive effects of traditional and second generation antipsychotics: a review of the
clinical data. Eur Arch Psychiatry Clin Neurosci 2005;255:83–93.
40. Zisook S, Kasckow JW, Golshan S, et al. Citalopram augmentation for subsyndromal symptoms of
depression in middle-aged and older outpatients with schizophrenia and schizoaffective disorder: a
randomized controlled trial. J Clin Psychiatry 2009;70:562–71.
41. Trixler M, Gati A, Fekete S, Tenyi T. Use of antipsychotics in the management of schizophrenia
during pregnancy. Drugs 2005;65:1193–206.
42. Gentile S. Antipsychotic therapy during early and late pregnancy. A systematic review. Schizophr
Bull 2010;36:518–44.
43. Collins KO, Comer JB. Maternal haloperidol therapy associated with dyskinesia in a newborn. Am J
Health Syst Pharm 2003;60:2253–5.
44. Diav-Citrin O, Shechtman S, Ornoy S, et al. Safety of haloperidol and penfluridol in pregnancy: a
multicenter, prospective, controlled study. J Clin Psychiatry 2005;66:317–22.
45. Reis M, Kallen B. Maternal use of antipsychotics in early pregnancy and delivery outcome. J Clin
Psychopharmacol 2008;28:279–88.
46. Newham JJ, Thomas SH, MacRitchie K, McElhatton PR, McAllister-Williams RH. Birth weight of
infants after maternal exposure to typical and atypical antipsychotics: prospective comparison study.
Br J Psychiatry 2008;192:333–7.
47. Ernst CL, Goldberg JF. The reproductive safety profile of mood stabilizers, atypical antipsychotics,
and broad-spectrum psychotropics. J Clin Psychiatry 2002;63 suppl 4:42–55.
and broad-spectrum psychotropics. J Clin Psychiatry 2002;63 suppl 4:42–55.
48. McKenna K, Koren G, Tetelbaum M, et al. Pregnancy outcome of women using atypical
antipsychotic drugs: a prospective comparative study. J Clin Psychiatry 2005;66:444–9.
49. Spyropoulou AC, Zervas IM, Soldatos CR. Hip dysplasia following a case of olanzapine exposed
pregnancy: a questionable association. Arch Womens Ment Health 2006;9: 219–22.
50. Arora M, Praharaj SK. Meningocele and ankyloblepharon following in utero exposure to olanzapine.
Eur Psychiatry 2006;21:345–6.
51. National Institute for Health and Clinical Excellence. Antenatal and postnatal mental health. Clinical
management and service guideline. 2007.
http://guidance.nice.org.uk/CG45/NICEGuidance/pdf/Englis h
52. Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry. 11th ed. Padstow,
UK: Wiley-Blackwell, 2012.
53. Kirchner JE, Owen RR, Nordquist C, Fischer EP. Diagnosis and management of substance use
disorders among inpatients with schizophrenia. Psychiatr Serv 1998;49:82–5.
54. Kerfoot KE, Rosenheck RA, Petrakis IL, et al. Substance use and schizophrenia: adverse correlates in
the CATIE study sample. Schizophr Res 2011;132:177–82.
55. Kelly DL, McMahon RP, Wehring HJ, et al. Cigarette smoking and mortality risk in people with
schizophrenia. Schizophr Bull 2011;37:832–8.
57. Petrakis IL, O_Malley S, Rounsaville B, Poling J, McHugh- Strong C, Krystal JH. Naltrexone
augmentation of neuroleptic treatment in alcohol abusing patients with schizophrenia.
Psychopharmacology (Berl) 2004;172:291–7.
58. Tsoi DT, Porwal M, Webster AC. Efficacy and safety of bupropion for smoking cessation and
reduction in schizophrenia: systematic review and meta-analysis. Br J Psychiatry 2010;196:346–53.
59. Weiner E, Buchholz A, Coffay A, et al. Varenicline for smoking cessation in people with
schizophrenia: a double blind randomized pilot study. Schizophr Res 2011;129: 94–5.
60. Chung AK, Chua SE. Effects on prolongation of Bazett_s corrected QT interval of seven second-
generation antipsychotics in the treatment of schizophrenia: a meta-analysis. J Psychopharmacol
2011;25:646–66.
61. Chahine LM, Acar D, Chemali Z. The elderly safety imperative and antipsychotic usage. Harv Rev
Psychiatry 2010; 18:158–72.
62. Pollock BG, Mulsant BH, Rosen J, et al. A double-blind comparison of citalopram and risperidone
for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr
Psychiatry 2007;15:942–52.
63. Crossley NA, Constante M, McGuire P, Power P. Efficacy of atypical v. typical antipsychotics in the
treatment of early psychosis: meta-analysis. Br J Psychiatry 2010;196:434–9.
64. Emsley RA. Risperidone in the treatment of first-episode psychotic patients: a double-blind
multicenter study. Risperidone Working Group. Schizophr Bull 1999;25:721–9.
65. Lieberman JA, Phillips M, Gu H, et al. Atypical and conventional antipsychotic drugs in treatment-
naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine.
Neuropsychopharmacology 2003;28: 995–1003.
66. Schooler N, Rabinowitz J, Davidson M, et al. Risperidone and haloperidol in first-episode psychosis:
a long-term randomized trial. Am J Psychiatry 2005;162:947–53.
a long-term randomized trial. Am J Psychiatry 2005;162:947–53.
67. Green AI, Lieberman JA, Hamer RM, et al. Olanzapine and haloperidol in first episode psychosis:
two-year data. Schizophr Res 2006;86:234–43.
68. Kahn RS, Fleischhacker WW, Boter H, et al. Effectiveness of antipsychotic drugs in first-episode
schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet
2008;371:1085–97.
69. Alvarez-Jimenez M, Parker AG, Hetrick SE, McGorry PD, Gleeson JF. Preventing the second
episode: a systematic review and meta-analysis of psychosocial and pharmacological trials in first-
episode psychosis. Schizophr Bull 2011;37: 619–30.
70. Lieberman JA, Tollefson G, Tohen M, et al. Comparative efficacy and safety of atypical and
conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of
olanzapine versus haloperidol. Am J Psychiatry 2003; 160:1396–404.
71. Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation
antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 2004; 161:414–25.
72. Gharabawi GM, Bossie CA, Zhu Y. New-onset tardive dyskinesia in patients with first-episode
psychosis receiving risperidone or haloperidol. Am J Psychiatry 2006;163: 938–9.
73. Novick D, Haro JM, Bertsch J, Haddad PM. Incidence of extrapyramidal symptoms and tardive
dyskinesia in schizophrenia: thirty-six-month results from the European schizophrenia outpatient
health outcomes study. J Clin Psychopharmacol 2010;30:531–40 .
74. Minzenberg MJ, Poole JH, Benton C, Vinogradov S. Association of anticholinergic load with
impairment of complex attention and memory in schizophrenia. Am J Psychiatry 2004;161:116–24.
75. Tandon R, DeQuardo JR, Goodson J, Mann NA, Greden JF. Effect of anticholinergics on positive
and negative symptoms in schizophrenia. Psychopharmacol Bull 1992;28:297–302.
76. Oosthuizen PP, Emsley RA, Maritz JS, Turner JA, Keyter N. Incidence of tardive dyskinesia in first-
episode psychosis patients treated with low-dose haloperidol. J Clin Psychiatry 2003;64:1075–80.
77. Woods SW, Morgenstern H, Saksa JR, et al. Incidence of tardive dyskinesia with atypical versus
conventional antipsychotic medications: a prospective cohort study. J Clin Psychiatry 2010;71:463–
74.
78. McEvoy JP, Lieberman JA, Perkins DO, et al. Efficacy and tolerability of olanzapine, quetiapine, and
risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am
J Psychiatry 2007;164:1050–60.
79. Robinson DG, Woerner MG, Napolitano B, et al. Randomized comparison of olanzapine versus
risperidone for the treatment of first-episode schizophrenia: 4-month outcomes. Am J Psychiatry
2006;163:2096–102.
80. Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT
psychopharmacological treatment recommendations and summary statements. Schizophr Bull
2010;36:71–93.
81. Zipursky RB, Gu H, Green AI, et al. Course and predictors of weight gain in people with first-
episode psychosis treated with olanzapine or haloperidol. Br J Psychiatry 2005;187: 537–43.
82. Fernandez-Egea E, Miller B, Garcia-Rizo C, Bernardo M, Kirkpatrick B. Metabolic effects of
olanzapine in patients with newly diagnosed psychosis. J Clin Psychopharmacol 2011;31:154–9.
83. Sanger TM, Lieberman JA, Tohen M, Grundy S, Beasley C Jr, Tollefson GD. Olanzapine versus
haloperidol treatment in first-episode psychosis. Am J Psychiatry 1999;156:79–87.
haloperidol treatment in first-episode psychosis. Am J Psychiatry 1999;156:79–87.
84. Patel JK, Buckley PF, Woolson S, et al. Metabolic profiles of second-generation antipsychotics in
early psychosis: findings from the CAFE study. Schizophr Res 2009;111:9–16.
85. Kreyenbuhl J, Slade EP, Medoff DR, et al. Time to discontinuation of first- and second-generation
antipsychotic medications in the treatment of schizophrenia. Schizophr Res 2011;131:127–32.
86. Kasper S, Brecher M, Fitton L, Jones AM. Maintenance of long-term efficacy and safety of
quetiapine in the open-label treatment of schizophrenia. Int Clin Psychopharmacol 2004;19:281–9.
87. Hatta K, Sato K, Hamakawa H, et al. Effectiveness of second-generation antipsychotics with acute-
phase schizophrenia. Schizophr Res 2009;113:49–55.
88. McCue RE, Waheed R, Urcuyo L, et al. Comparative effectiveness of second-generation
antipsychotics and haloperidol in acute schizophrenia. Br J Psychiatry 2006;189:433–40.
89. Suzuki T, Uchida H, Watanabe K, et al. How effective is it to sequentially switch among olanzapine,
quetiapine and risperidone? A randomized, open-label study of algorithm-based antipsychotic
treatment to patients with symptomatic schizophrenia in the real-world clinical setting.
Psychopharmacology (Berl) 2007;195:285–95.
90. Malik P, Kemmler G, Hummer M, Riecher-Roessler A, Kahn RS, Fleischhacker WW. Sexual
dysfunction in first-episode schizophrenia patients: results from European First Episode
Schizophrenia Trial. J Clin Psychopharmacol 2011;31: 274–80.
91. Spollen JJ 3rd, Wooten RG, Cargile C, Bartztokis G. Prolactin levels and erectile function in patients
treated with risperidone. J Clin Psychopharmacol 2004;24:161–6.
92. Holt RI, Peveler RC. Antipsychotics and hyperprolactinaemia: mechanisms, consequences and
management. Clin Endocrinol (Oxf) 2011;74:141–7.
93. Komossa K, Rummel-Kluge C, Schmid F, et al. Aripiprazole versus other atypical antipsychotics for
schizophrenia. Cochrane Database Syst Rev 2009;(4):CD006569.
94. Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK. Cardiometabolic risk of
second-generation antipsychotic medications during first-time use in children and adolescents. JAMA
2009;302:1765–73.
95. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of
sudden cardiac death. N Engl J Med 2009;360:225–35 .
96. Komossa K, Rummel-Kluge C, Hunger H, et al. Ziprasidone versus other atypical antipsychotics for
schizophrenia. Cochrane Database Syst Rev 2009;(4):CD006627.
97. Grootens KP, van Veelen NM, Peuskens J, et al. Ziprasidone vs olanzapine in recent-onset
schizophrenia and schizoaffective disorder: results of an 8-week double-blind randomized controlled
trial. Schizophr Bull 2011;37:352–61.
98. Taylor D. Ziprasidone in the management of schizophrenia : the QT interval issue in context. CNS
Drugs 2003;17: 423–30.
99. Citrome L. Using oral ziprasidone effectively: the food effect and dose-response. Adv Ther
2009;26:739–48.
100. Komossa K, Rummel-Kluge C, Hunger H, et al. Amisulpride versus other atypical antipsychotics
for schizophrenia. Cochrane Database Syst Rev 2010;(1):CD006624.
101. Marino J, Caballero J. Iloperidone for the treatment of schizophrenia. Ann Pharmacother
2010;44:863–70.
102. Janicak PG, Rado JT. Asenapine: a review of the data. Psychopharm Rev 2009;44:89–96.
103. Meyer JM, Loebel AD, Schweizer E. Lurasidone: a new drug in development for schizophrenia.
Expert Opin Investig Drugs 2009;18:1715–26.
104. Potkin SG, Ogasa M, Cucchiaro J, Loebel A. Double-blind comparison of the safety and efficacy
of lurasidone and ziprasidone in clinically stable outpatients with schizophrenia or schizoaffective
disorder. Schizophr Res 2011;132:101–7.
105. Meltzer HY, Cucchiaro J, Silva R, et al. Lurasidone in the treatment of schizophrenia: a
randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry
2011;168:957–67.
106. Harvey PD, Ogasa M, Cucchiaro J, Loebel A, Keefe RS. following in utero exposure to cognitive
change in a randomized, double-blind comparison of lurasidone vs. ziprasidone. Schizophr Res
2011;127:188–94.
107. Kopala LC, Good KP, Honer WG. Extrapyramidal signs and clinical symptoms in first-episode
schizophrenia: response to low-dose risperidone. J Clin Psychopharmacol 1997;17: 308–13.
108. McEvoy JP, Hogarty GE, Steingard S. Optimal dose of neuroleptic in acute schizophrenia. A
controlled study of the neuroleptic threshold and higher haloperidol dose. Arch Gen Psychiatry
1991;48:739–45.
109. Merlo MC, Hofer H, Gekle W, et al. Risperidone, 2 mg/day vs. 4 mg/day, in first-episode, acutely
psychotic patients: treatment efficacy and effects on fine motor functioning. J Clin Psychiatry
2002;63:885–91.
110. Reilly JL, Harris MS, Keshavan MS, Sweeney JA. Adverse effects of risperidone on spatial
working memory in first- episode schizophrenia. Arch Gen Psychiatry 2006;63:1189–97.
111. Lambert M, Conus P, Eide P, et al. Impact of present and past antipsychotic side effects on attitude
toward typical antipsychotic treatment and adherence. Eur Psychiatry 2004;19:415–22.
112. Leucht S, Busch R, Kissling W, Kane JM. Early prediction of antipsychotic nonresponse among
patients with schizophrenia. J Clin Psychiatry 2007;68:352–60.
113. Gallego JA, Robinson DG, Sevy SM, et al. Time to treatment response in first-episode
schizophrenia: should acute treatment trials last several months? J Clin Psychiatry 2011;72:1691–6.
114. Li C, Xia J, Wang J. Risperidone dose for schizophrenia. Cochrane Database Syst Rev 2009;
(4):CD007474.
115. Kinon BJ, Volavka J, Stauffer V, et al. Standard and higher dose of olanzapine in patients with
schizophrenia or schizoaffective disorder: a randomized, double-blind, fixed-dose study. J Clin
Psychopharmacol 2008;28:392–400.
116. Davis JM, Chen N. Dose response and dose equivalence of antipsychotics. J Clin Psychopharmacol
2004;24: 192–208.
117. Citrome L, Yang R, Glue P, Karayal ON. Effect of ziprasidone dose on all-cause discontinuation
rates in acute schizophrenia and schizoaffective disorder: a post-hoc analysis of 4 fixed-dose
randomized clinical trials. Schizophr Res 2009;111:39–45 .
118. Sparshatt A, Taylor D, Patel MX, Kapur S. A systematic review of aripiprazole—dose, plasma
concentration, receptor occupancy, and response: implications for therapeutic drug monitoring. J
Clin Psychiatry 2010;71:1447–56.
119. Citrome L, Stauffer VL, Chen L, et al. Olanzapine plasma concentrations after treatment with 10,
20, and 40 mg/d in patients with schizophrenia: an analysis of correlations with efficacy, weight
20, and 40 mg/d in patients with schizophrenia: an analysis of correlations with efficacy, weight
gain, and prolactin concentration. J Clin Psychopharmacol 2009;29:278–83.
120. Patel MX, Bowskill S, Couchman L, et al. Plasma olanzapine in relation to prescribed dose and
other factors: data from a therapeutic drug monitoring service, 1999–2009. J Clin Psychopharmacol
2011;31:411–7.
121. Sparshatt A, Taylor D, Patel MX, Kapur S. Amisulpride—dose, plasma concentration, occupancy
and response: implications for therapeutic drug monitoring. Acta Psychiatr Scand 2009;120:416–
28.
122. Sparshatt A, Taylor D, Patel MX, Kapur S. Relationship between daily dose, plasma
concentrations, dopamine receptor occupancy, and clinical response to quetiapine: a review. J Clin
Psychiatry 2011;72:1108–23.
123. Olfson M, Marcus SC, Ascher-Svanum H. Treatment of schizophrenia with long-acting
fluphenazine, haloperidol, or risperidone. Schizophr Bull 2007;33:1379–87.
124. Rosenheck RA, Krystal JH, Lew R, et al. Long-acting risperidone and oral antipsychotics in
unstable schizophrenia. N Engl J Med 2011;364:842–51.
125. Tiihonen J, Haukka J, Taylor M, Haddad PM, Patel MX, Korhonen P. A nationwide cohort study
of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry
2011;168:603–9.
126. Leucht C, Heres S, Kane JM, Kissling W, Davis JM, Leucht S. Oral versus depot antipsychotic
drugs for schizophreniaVa critical systematic review and meta-analysis of randomised long-term
trials. Schizophr Res 2011;127: 83–92.
127. Haddad PM, Taylor M, Niaz OS. First-generation antipsychotic long-acting injections v. oral
antipsychotics in schizophrenia: systematic review of randomised controlled trials and
observational studies. Br J Psychiatry Suppl 2009;52:S20–8.
128. Taylor D. Psychopharmacology and adverse effects of antipsychotic long-acting injections: a
review. Br J Psychiatry Suppl 2009;52:S13–9.
129. Adams CE, Fenton MK, Quraishi S, David AS. Systematic meta-review of depot antipsychotic
drugs for people with schizophrenia. Br J Psychiatry 2001;179:290–9.
130. Boaz TL, Constantine RJ, Robst J, Becker MA, Howe AM. Risperidone long-acting therapy
prescribing patterns and their impact on early discontinuation of treatment in a large Medicaid
population. J Clin Psychiatry 2011;72:1079–85.
131. Covell NH, McEvoy JP, Schooler NR, et al. Effectiveness of switching from long-acting injectable
fluphenazine or haloperidol decanoate to long-acting injectable risperidone microspheres: an open-
label, randomized controlled trial. J Clin Psychiatry 2012;73:669–75.
132. Citrome L. Paliperidone palmitate—review of the efficacy, safety and cost of a new second-
generation depot antipsychotic medication. Int J Clin Pract 2010;64:216–39.
133. Bishara D. Once-monthly paliperidone injection for the treatment of schizophrenia. Neuropsychiatr
Dis Treat 2010; 6:561–72.
134. Kane JM, Detke HC, Naber D, et al. Olanzapine long-acting injection: a 24-week, randomized,
double-blind trial of maintenance treatment in patients with schizophrenia. Am J Psychiatry
2010;167:181–9.
135. Detke HC, McDonnell DP, Brunner E, Zhao F, Sorsaburu S, Stefaniak VJ, Corya SA. Post-
injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-
injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-
acting injection, I: analysis of cases. BMC Psychiatry 2010;10:43.
136. Glasgow RE, Vogt TM, Boles SM. Evaluating the public health impact of health promotion
interventions: the REAIM framework. Am J Public Health 1999;89:1322–7.
137. Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus
placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry
2002;63:763–71 .
138. Lindenmayer JP, Citrome L, Khan A, Kaushik S. A randomized, double-blind, parallel-group,
fixed-dose, clinical trial of quetiapine at 600 versus 1200 mg/d for patients with treatment-resistant
schizophrenia or schizoaffective disorder. J Clin Psychopharmacol 2011;31:160– 8.
139. Miller CH, Fleischhacker WW. Managing antipsychotic-induced acute and chronic akathisia. Drug
Saf 2000;22: 73–81.
140. Levinson DF, Simpson GM, Singh H, et al. Fluphenazine dose, clinical response, and
extrapyramidal symptoms during acute treatment. Arch Gen Psychiatry 1990;47:761–8.
141. Sachdev P. The development of the concept of akathisia: a historical overview. Schizophr Res
1995;16:33–45.
142. Crowner ML, Douyon R, Convit A, Gaztanaga P, Volavka J, Bakall R. Akathisia and violence.
Psychopharmacol Bull 1990;26:115–7.
143. Hansen L. A critical review of akathisia, and its possible association with suicidal behaviour. Hum
Psychopharmacol 2001;16:495–505.
144. Kane JM, Fleischhacker WW, Hansen L, Perlis R, Pikalov A 3rd, Assuncao-Talbott S. Akathisia:
an updated review focusing on second-generation antipsychotics. J Clin Psychiatry 2009;70:627–
43.
145. Hirose S. The causes of underdiagnosing akathisia. Schizophr Bull 2003;29:547–58.
146. Farde L. Selective D1- and D2-dopamine receptor blockade both induce akathisia in humans: a
PET study with [11C]SCH 23390 and [11C]raclopride. Psychopharmacology (Berl) 1992;107:23–
9.
147. Adler LA, Peselow E, Rosenthal M, Angrist B. A controlled comparison of the effects of
propranolol, benztropine, and placebo on akathisia: an interim analysis. Psychopharmacol Bull
1993;29:283–6.
148. Fischel T, Hermesh H, Aizenberg D, et al. Cyproheptadine versus propranolol for the treatment of
acute neuroleptic-induced akathisia: a comparative double-blind study. J Clin Psychopharmacol
2001;21:612–5.
149. Poyurovsky M, Pashinian A, Weizman R, Fuchs C, Weizman A. Low-dose mirtazapine: a new
option in the treatment of antipsychotic-induced akathisia. A randomized, doubleblind, placebo-
and propranolol-controlled trial. Biol Psychiatry 2006;59:1071–7.
150. Van Putten T, Marder SR. Behavioral toxicity of antipsychotic drugs. J Clin Psychiatry 1987;48
suppl:13–9.
151. Sachdev P, Loneragan C. Intravenous benztropine and propranolol challenges in acute neuroleptic-
induced akathisia. Clin Neuropharmacol 1993;16:324–31.
152. Rathbone J, Soares-Weiser K. Anticholinergics for neuroleptic-induced acute akathisia. Cochrane
Database Syst Rev 2006;(4):CD003727.
Stryjer R, Rosenzcwaig S, Bar F, Ulman AM, Weizman A, Spivak B. Trazodone for the treatment
153. Stryjer R, Rosenzcwaig S, Bar F, Ulman AM, Weizman A, Spivak B. Trazodone for the treatment
of neuroleptic- induced acute akathisia: a placebo-controlled, double-blind, crossover study. Clin
Neuropharmacol 2010;33:219–22.
154. Avital A, Gross-Isseroff R, Stryjer R, Hermesh H, Weizman A, Shiloh R. Zolmitriptan compared
to propranolol in the treatment of acute neuroleptic-induced akathisia: a comparative double-blind
study. Eur Neuropsychopharmacol 2009;19:476–82.
155. Miodownik C, Lerner V, Statsenko N, et al. Vitamin B6 versus mianserin and placebo in acute
neuroleptic-induced akathisia: a randomized, double-blind, controlled study. Clin Neuropharmacol
2006;29:68–72.
156. Gandelman K, Alderman JA, Glue P, et al. The impact of calories and fat content of meals on oral
ziprasidone absorption: a randomized, open-label, crossover trial. J Clin Psychiatry 2009;70:58–62.
157. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with
chronic schizophrenia. N Engl J Med 2005;353:1209– 23.
158. Mazure CM, Nelson JC, Jatlow PI, Kincare P, Bowers MB Jr. The relationship between blood
perphenazine levels, early resolution of psychotic symptoms, and side effects. J Clin Psychiatry
1990;51:330 –4.
159. Hansen LB, Larsen NE. Therapeutic advantages of monitoring plasma concentrations of
perphenazine in clinical practice. Psychopharmacology (Berl) 1985;87:16–9 .
160. Janicak PG, Marder SR, Pavuluri MN. Principles and practice of psychopharmacotherapy. 5th ed.
New York: Lippincott Williams & Wilkins, 2011.
161. Janicak PG, Javaid JI, Sharma RP, Leach A, Dowd S, Davis JM. A two-phase, double-blind
randomized study of three haloperidol plasma levels for acute psychosis with reassignment of
initial non-responders. Acta Psychiatr Scand 1997; 95:343–50.
162. Stroup TS, Lieberman JA, McEvoy JP, et al. Effectiveness of olanzapine, quetiapine, risperidone,
and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous
atypical antipsychotic. Am J Psychiatry 2006;163:611–22.
163. Essock SM, Covell NH, Davis SM, Stroup TS, Rosenheck RA, Lieberman JA. Effectiveness of
switching antipsychotic medications. Am J Psychiatry 2006;163:2090–5.
164. Kane JM, Cohen M, Zhao J, Alphs L, Panagides J. Efficacy and safety of asenapine in a placebo-
and haloperidol- controlled trial in patients with acute exacerbation of schizophrenia. J Clin
Psychopharmacol 2010;30:106–15.
165. Ashih HW. Saphris and Fanapt: two new antipsychotics. Carlat Psychiatry Rep 2009;7:1–3.
166. Narula PK, Rehan HS, Unni KE, Gupta N. Topiramate for prevention of olanzapine associated
weight gain and metabolic dysfunction in schizophrenia: a double-blind, placebo- controlled trial.
Schizophr Res 2010;118:218–23.
167. Klein DJ, Cottingham EM, Sorter M, Barton BA, Morrison JA. A randomized, double-blind,
placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical
antipsychotic therapy in children and adolescents. Am J Psychiatry 2006;163:2072–9.
168. Wu RR, Zhao JP, Guo XF, et al. Metformin addition attenuates olanzapine-induced weight gain in
drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study. Am J
Psychiatry 2008;165:352–8.
169. Smith RC. Metformin as a treatment for antipsychotic drug side effects: special focus on women
with schizophrenia. Am J Psychiatry 2012;169:774 –6.
171. Meltzer HY. Treatment-resistant schizophrenia—the role of clozapine. Curr Med Res Opin
1997;14:1–20.
172. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A
double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45: 789–96.
173. Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation
antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of
randomized trials. Am J Psychiatry 2001;158:518–26.
174. Essock SM, Hargreaves WA, Covell NH, Goethe J. Clozapine’s effectiveness for patients in state
hospitals: results from a randomized trial. Psychopharmacol Bull 1996;32:683–97.
175. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine,
quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior
atypical antipsychotic treatment. Am J Psychiatry 2006;163:600–10.
176. Lewis SW, Barnes TR, Davies L, et al. Randomized controlled trial of effect of prescription of
clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr
Bull 2006;32:715–23.
177. Conley RR, Kelly DL, Richardson CM, Tamminga CA, Carpenter WT Jr. The efficacy of high-
dose olanzapine versus clozapine in treatment-resistant schizophrenia: a double-blind crossover
study. J Clin Psychopharmacol 2003;23:668–71.
178. Meltzer HY. Dimensions of outcome with clozapine. Br J Psychiatry Suppl 1992;26:46–53.
179. Perry PJ, Miller DD, Arndt SV, Cadoret RJ. Clozapine and norclozapine plasma concentrations and
clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry 1991;148:231–5.
180. Kronig MH, Munne RA, Szymanski S, et al. Plasma clozapine levels and clinical response for
treatment-refractory schizophrenic patients. Am J Psychiatry 1995;152: 179–82 .
181. Hasegawa M, Gutierrez-Esteinou R, Way L, Meltzer HY. Relationship between clinical efficacy
and clozapine concentrations in plasma in schizophrenia: effect of smoking. J Clin
Psychopharmacol 1993;13:383–90.
182. Potkin SG, Bera R, Gulasekaram B, et al. Plasma clozapine concentrations predict clinical response
in treatment-resistant schizophrenia. J Clin Psychiatry 1994;55 suppl B:133–6.
183. Freudenreich O, Weiner RD, McEvoy JP. Clozapine-induced electroencephalogram changes as a
function of clozapine serum levels. Biol Psychiatry 1997;42:132–7.
184. Lu ML, Lane HY, Lin SK, Chen KP, Chang WH. Adjunctive fluvoxamine inhibits clozapine-
related weight gain and metabolic disturbances. J Clin Psychiatry 2004;65:766–71.
185. Faisal I, lindenmayer JP, Taintor Z, Cancro R. Clozapinebenzodiazepine interactions. J Clin
Psychiatry 1997;58: 547–8.
186. Phansalkar S, Osser DN. Optimizing clozapine treatment; part II. Psychopharm Rev 2009;44:9–16.
187. Meltzer HY. Treatment of the neuroleptic-nonresponsive schizophrenic patient. Schizophr Bull
1992;18:515–42.
188. Meltzer HY, Bastani B, Kwon KY, Ramirez LF, Burnett S, Sharpe J. A prospective study of
clozapine in treatment-resistant schizophrenic patients. I. Preliminary report. Psychopharmacology
(Berl) 1989;99 suppl:S68–72.
(Berl) 1989;99 suppl:S68–72.
189. Buckley P, Miller A, Olsen J, Garver D, Miller DD, Csernansky J. When symptoms persist:
clozapine augmentation strategies. Schizophr Bull 2001;27:615–28.
190. Barbui C, Signoretti A, Mule S, Boso M, Cipriani A. Does the addition of a second antipsychotic
drug improve clozapine treatment? Schizophr Bull 2009;35:458–68.
191. Taylor DM, Smith L. Augmentation of clozapine with a second antipsychotic—a meta-analysis of
randomized, placebo-controlled studies. Acta Psychiatr Scand 2009;119:419–25.
192. Sommer IE, Begemann MJ, Temmerman A, Leucht S. Pharmacological augmentation strategies for
schizophrenia patients with insufficient response to clozapine: a quantitative literature review.
Schizophr Bull 2012;38:1003–11.
193. Freudenreich O, Henderson DC, Walsh JP, Culhane MA, Goff DC. Risperidone augmentation for
schizophrenia partially responsive to clozapine: a double-blind, placebo- controlled trial. Schizophr
Res 2007;92:90–4.
194. Honer WG, Thornton AE, Chen EY, et al. Clozapine alone versus clozapine and risperidone with
refractory schizophrenia. N Engl J Med 2006;354:472–82.
195. Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, et al. A double-blind controlled study of
adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine:
efficacy and safety. J Clin Psychiatry 2005;66: 63–72.
196. Josiassen RC, Joseph A, Kohegyi E, et al. Clozapine augmented with risperidone in the treatment
of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry
2005;162:130–6.
197. Weiner E, Conley RR, Ball MP, et al. Adjunctive risperidone for partially responsive people with
schizophrenia treated with clozapine. Neuropsychopharmacology 2010;35: 2274–83.
198. Henderson DC, Kunkel L, Nguyen DD, et al. An exploratory open-label trial of aripiprazole as an
adjuvant to clozapine therapy in chronic schizophrenia. Acta Psychiatr Scand 2006;113:142–7.
199. Barbui C, Accordini S, Nose M, et al. Aripiprazole versus haloperidol in combination with
clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled
trial. J Clin Psychopharmacol 2011;31: 266–73.
200. Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant
schizophrenia: a systematic review and meta-analysis. Schizophr Res 2009;109: 10–4.
201. Goff DC, Keefe R, Citrome L, et al. Lamotrigine as add-on therapy in schizophrenia: results of 2
placebo-controlled trials. J Clin Psychopharmacol 2007;27:582–9.
202. Havaki-Kontaxaki BJ, Ferentinos PP, Kontaxakis VP, Paplos KG, Soldatos CR. Concurrent
administration of clozapine and electroconvulsive therapy in clozapine-resistant schizophrenia.
Clin Neuropharmacol 2006;29:52–6 .
203. Moore TA, Buchanan RW, Buckley PF, et al. The Texas Medication Algorithm Project
antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry 2007;68: 1751–62.
204. De Lucena D, Fernandes BS, Berk M, et al. Improvement of negative and positive symptoms in
treatment-refractory schizophrenia: a double-blind, randomized, placebo-controlled trial with
memantine as add-on therapy to clozapine. J Clin Psychiatry 2009;70:1416–23.
205. Amminger GP, Schafer MR, Papageorgiou K, et al. Long- chain omega-3 fatty acids for indicated
prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry
2010;67:146–54.
2010;67:146–54.
206. Peet M, Horrobin DF. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate
in patients with persistent schizophrenic symptoms. J Psychiatr Res 2002;36: 7–18.
207. Raja M. Improvement or worsening of psychotic symptoms after treatment with low doses of
aripiprazole. Int J Neuro-psychopharmacol 2007;10:107–10.
208. Tadokoro S, Okamura N, Sekine Y, Kanahara N, Hashimoto K, Iyo M. Chronic treatment with
aripiprazole prevents development of dopamine supersensitivity and potentially supersensitivity
psychosis. Schizophr Bull 2012;38: 1012–20.
209. Jong-Yih L. Successful switch from clozapine to aripiprazole: a case report. J Clin
Psychopharmacol 2009;29:93–5.
210. Kane JM, Meltzer HY, Carson WH Jr, McQuade RD, Marcus RN, Sanchez R. Aripiprazole for
treatment-resistant schizophrenia: results of a multicenter, randomized, doubleblind, comparison
study versus perphenazine. J Clin Psychiatry 2007;68:213–23.
211. Meltzer HY, Jayathilake K. Low-dose loxapine in the treatment of schizophrenia: is it more
effective and more Batypical[ than standard-dose loxapine? J Clin Psychiatry 1999;60 suppl 10:47–
51.
212. Joffe G, Terevnikov V, Joffe M, Stenberg JH, Burkin M, Tiihonen J. Add-on mirtazapine enhances
antipsychotic effect of first generation antipsychotics in schizophrenia: a double-blind, randomized,
placebo-controlled trial. Schizophr Res 2009;108:245–51.
213. Terevnikov V, Stenberg JH, Joffe M, et al. More evidence on additive antipsychotic effect of
adjunctive mirtazapine in schizophrenia: an extension phase of a randomized controlled trial. Hum
Psychopharmacol 2010;25:431–8.
214. Berk M, Gama CS, Sundram S, et al. Mirtazapine add-on therapy in the treatment of schizophrenia
with atypical antipsychotics: a double-blind, randomised, placebo-controlled clinical trial. Hum
Psychopharmacol 2009;24:233–8.
215. Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy
reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind,
placebo-controlled trial. J Clin Psychiatry 2010;71:520–7.
216. Riedel M, Strassnig M, Schwarz MJ, Muller N. COX-2 inhibitors as adjunctive therapy in
schizophrenia: rationale for use and evidence to date. CNS Drugs 2005;19:805–19.
217. Chan J, Sweeting M. Review: Combination therapy with non-clozapine atypical antipsychotic
medication: a review of current evidence. J Psychopharmacol 2007;21:657–64.
218. Lerner V, Libov I, Kotler M, Strous RD. Combination of Batypical[ antipsychotic medication in
the management of treatment-resistant schizophrenia and schizoaffective disorder. Prog
Neuropsychopharmacol Biol Psychiatry 2004;28: 89–98.
219. Kane JM, Correll CU, Goff DC, et al. A multicenter, randomized, double-blind, placebo-
controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder
inadequately treated with quetiapine or risperidone monotherapy. J Clin Psychiatry 2009;70:1348–
57.
220. Leucht S, Heres S, Kissling W, Davis JM. Evidence-based pharmacotherapy of schizophrenia. Int J
Neuropsychopharmacol 2011;14:269–84.
221. National Institute for Health and Clinical Excellence. Schizophrenia: core interventions in the
treatment and management of schizophrenia in adults in primary and secondary care (update).
2009. http://www.nice.org.uk/CG82
222. Osser DN. Why physicians do not follow some guidelines and algorithms. Drug Benefit Trends
2009;21:345–54.
he algorithm for the pharmacotherapy of schizophrenia has been
published six times since the first one by this author in 1988. There
have been many changes over those years. However, in the seven years
since its last publication in 2013, the recommendations and flowchart
remain mostly the same. There have been no new studies that seem to
change the overall sequences of the nodes. However, there have been a
variety of studies usually adding support to what was proposed in the 2013
algorithm, but sometimes making adjustments to the risk/benefit analysis
for certain recommendations. There are two new medications for adults
approved in 2015 in the United States for the acute treatment of
schizophrenia: cariprazine and brexpiprazole. They appear to have
comparable efficacy to older antipsychotics and at this time are much more
costly. They produce less weight gain than some and occasionally that may
make them preferable to some lower-cost options, and cariprazine may
have a role for persistent negative symptoms (to be discussed). Lurasidone
is fairly new and was discussed in the previous algorithm, but in 2017 it
received a new indication for schizophrenia in adolescents, and this
changed its placement in the algorithm. Also, there have been several new
products in the category of long-acting injectable antipsychotics (LAIs) that
are discussed in this update.
There is another new antipsychotic that was just approved for the
treatment of schizophrenia as this book was going to press: lumateperone. It
was approved by the U.S. Food and Drug Administration in late December
2019, with expected launch in March 2020. Lumateperone is a
butyrophenone, as is haloperidol, but the molecule has been adjusted and it
seems to cause almost no extrapyramidal side effects, and like haloperidol
it produces very little weight gain. Somnolence, though, was a side effect in
24% versus 10% with placebo. Efficacy seems comparable to
antipsychotics such as quetiapine, aripiprazole, and ziprasidone. Some think
it may “revolutionize” treatment of schizophrenia but future studies will be
needed to make that determination. 1 It is too early to give it a place in the
algorithm .
A change in the diagnostic criteria for schizophrenia occurred with the
2013 publication of the Diagnostic and Statistical Manual of Mental
Disorders Edition 5 (DSM-5). The A criteria for schizophrenia changed. In
the previous version (DSM-IV), five symptoms were listed under the A
criteria and at least two of five had to be present during an acute episode.
The five were delusions, hallucinations, disorganized speech, grossly
disorganized behavior, and negative symptoms (diminished emotional
expression or avolition). In DSM-5, at least one of the first three symptoms
(defined as positive symptoms) must be present. In DSM-IV, you could
meet the A criteria by having both of the other two symptoms and no
positive symptoms. This change actually supports the utility of this
algorithm because positive symptoms were identified as the primary targets
of pharmacotherapy—though management of negative and cognitive
symptoms was also discussed. Thus, with DSM-5, patients diagnosed with
schizophrenia are a little more likely to have the positive symptoms that the
algorithm addresses. However, the quantity of patients who met the A
criteria under DSM-IV by having only non-positive symptoms was very
small—less than 1%. 2
Another more important change in DSM-5 was to the D criterion for
schizophrenia, which differentiates schizophrenia from schizoaffective
disorder. 3 In DSM-IV, the patient had to have no mood episodes
(depression or mania) during the active phase of the illness, or if they
occurred, they were brief compared to the total duration of the illness
(active and residual phases). In the full text of DSM-IV, an example of
“brief” was given, and it was having a five-week period in a mood episode
in a person who had been ill for four years. The five weeks was 2.5% of the
four-year period. Note, though, that the criteria refer to a mood “episode.”
Depressive or manic “symptoms” (short of meeting criteria for the full
syndrome of an episode) could be present even continuously and the
diagnosis would still be schizophrenia if the rest of the criteria were met. In
DSM-5, the D criterion changed to allowing a mood episode for a
“minority” (i.e., up to 50%) of the time compared to the total length of the
illness. Therefore, all the patients who were having mood episodes lasting
anywhere from 2.5% to 49% of the total duration of their illness would now
be reclassified as having schizophrenia and not schizoaffective disorder.
The effect of this change was to significantly decrease the number of
patients who will be diagnosed schizoaffective disorder. 4 The implications
for the use of the schizophrenia algorithm is that these former
schizoaffective patients are now candidates for schizophrenia treatment
recommendations. There has, in fact, been surprisingly little study of
schizoaffective disorder treatment. 5 Indeed, many experts have serious
questions about whether the disorder really exists. 6 In support of this view,
there is evidence the DSM-IV diagnosis of schizoaffective disorder tended
to be unstable and often changed to schizophrenia over time. 7 , 8 Thus,
patients meeting the previous as well as the present more rarefied criteria
for schizoaffective are probably best classified as being either closer to the
schizophrenia spectrum (and should then be treated taking into
consideration this algorithm) or closer to bipolar disorder with psychosis
(and those should be treated with consideration of a mania algorithm such
as the one in this book).
Schizoaffective disorder is being diagnosed frequently. One study
showed that up to 30% of patients admitted for psychosis received this
diagnosis. 9 Many clinicians seem to think they know how to treat it, but
this knowledge is not based on any substantial scientific evidence. Due to
this lack of evidence, the Psychopharmacology Algorithm Project at the
Harvard South Shore Program has not developed an algorithm for
schizoaffective disorder.
Table 1 : Comorbidity and Other Features in Schizophrenia
and How They Affect the Algorithm
In Table 1 , there are ten conditions that are discussed. A few deserve some
additional comments.
Agitation requiring rapid management : To add to the five studies cited
originally, there was a new study that came out in 2013. 10 This was a fairly
large prospective randomized double-blind controlled trial evaluating four
intramuscular (IM) treatments for acute agitation in an emergency room
setting in Brazil. One hundred consecutive patients were randomized to
either haloperidol 2.5 mg plus midazolam 7.5 mg, haloperidol 2.5 mg plus
promethazine 25 mg, olanzapine 10 mg, or ziprasidone 10 mg. The
majority of the patients had schizophrenia with 36% having a diagnosis of
mania. One hour after the treatment, the best results were with the
haloperidol plus benzodiazepine or the olanzapine. However, the odds ratio
for significant side effects was 1.6 higher for olanzapine. The other two
treatments were inferior in effectiveness. The odds ratio for side effects was
highest (3.6) with the haloperidol plus the antiparkinsonian agent
promethazine compared with the haloperidol plus midazolam. This study
further supports the algorithm’s recommendation that haloperidol plus a
benzodiazepine (often it is lorazepam in the United States.) is still the best
and safest IM treatment for acute agitation in the urgent or emergency
setting.
Primary negative or “deficit” symptoms : In addition to the two citations
supporting the benefit of adding an antidepressant for persisting negative
symptoms in schizophrenia, there is a newer meta-analysis of several
studies of mirtazapine finding it useful for this purpose. 11 Also, an
evaluation of a large administrative database of Medicaid patients from
2001 to 2010 found an association with antidepressant use and reduced
rehospitalization and emergency room visits. 12 The reason for the
association was not at all clear and an editorial suggested that more
widespread addition of antidepressants in schizophrenia to improve
maintenance outcome requires more study in randomized trials before it
should become routine. 13
The new (2015) antipsychotic cariprazine had a multicenter trial in
schizophrenia patients who had significant residual negative symptoms for
over six months while being otherwise clinically stable with well-controlled
positive symptoms. 14 About 461 patients were randomized to switch to
either cariprazine (mean final dose 4.2 mg) or risperidone (mean dose 3.8
mg) for six months. In order to be sure that negative symptom improvement
was not due to any difference in secondary negative symptoms from the
prescribed treatment, results were controlled for depression,
extrapyramidal, and positive symptoms. Negative symptoms improved
significantly (>20%) in 69% of the cariprazine patients and 58% of the
risperidone patients (number needed to treat = 9). This is a small difference.
It seems more reasonable to try adding an antidepressant first. But
cariprazine perhaps deserves a try if antidepressants fail.
Another category of medications of possible use for primary negative
symptoms is dopaminergic agents. Modafinil, armodafinil, L -dopa, and
pramipexole were reviewed in a recent meta-analysis. 15 Ten randomized
controlled trials (six with modafinil) were assessed and the net result was
that there was no significant improvement. They did not increase positive
symptom scores, however.
Memantine was mentioned in 2013 as an option for negative/cognitive
symptoms in Table 1 . Since then, there have been more studies using it for
this indication. Five controlled trials have been published, and the latest
study was positive at a dose of 20 mg daily, so there are now three positive
and two negative studies in the literature. 16
Remember that primary negative symptoms are diagnosed by first
excluding secondary negative symptoms. Negative symptoms can be a
consequence of positive symptoms, can result from excessive sedative
effects of the medication regimen, and can be produced by parkinsonian
and other extrapyramidal side effects. These should all be managed first
with appropriate interventions.
Major depression : The Table 1 text presented a guarded perspective on
the value of adding an antidepressant for major depression or depressive
symptoms occurring during the active phase of schizophrenia-related
psychosis. “Postpsychotic depression,” as discussed in Table 1 , was (and
remains) a clear target for antidepressants. A newer meta-analysis of 82
randomized controlled trials of antidepressants in schizophrenia found that
antidepressants seem a little more effective for active-phase depressive
symptoms than we previously thought. 17 Reduction in depressive
symptoms overall had an effect size of 0.25 standardized mean difference,
which translated to about one in nine patients improving. The improvement
in negative symptoms in the meta-analysis was 0.30. Depressive symptoms
overlap with negative symptoms and they can be difficult to distinguish
clinically and in the research setting. Antidepressants were generally well
tolerated, so this small rate of improvement was at a relatively small cost in
terms of side effects. Therefore, the perspective on adding antidepressants
for depressive symptoms has moved a bit in the direction of being more
acceptable.
Women of childbearing potential : Major studies have appeared
evaluating the risk of antipsychotics in pregnancy, all generally supporting
the original recommendations in the table. First-generation antipsychotics
(FGAs) still seem a little safer than second-generation antipsychotics
(SGAs) with respect to fetal congenital malformation risk, according to a
review of 1.3 million pregnancies covered by Medicaid. 18 The rate was
3.3% in those with no exposure to an antipsychotic, versus 3.8% with FGAs
and 4.4% with SGAs. After adjustment for confounding variables, the rate
was 0.90% for FGAs and 1.05% for SGAs. Among the SGAs, risperidone
was somewhat higher (risk ratio 1.26). In another study, quetiapine had a
very low rate, no different from controls. 19 However, weight gain can be
very significant with SGAs, especially quetiapine and olanzapine, which
were found in a study to be associated with gestational diabetes in 7% and
12%, respectively, compared with 5% with aripiprazole and 4% with
ziprasidone. 20 Women on SGAs very frequently gained considerable
weight prior to their pregnancy, 21 and quetiapine may raise triglycerides
more than others. 22 These considerations should all be actively discussed
with women of childbearing potential and collaborative decisions made
taking them into account.
While on the subject of women of childbearing potential, it is worth
mentioning that valproate is perhaps the most dangerous medication to use
in such women. It has little proven value in schizophrenia, is associated
with an increased mortality risk when used in these patients (hazard ratio
1.31),12 and is associated with severe teratogenicity. It should be nearly a
last choice compared to any other psychotropic medication. 23
Effects of antipsychotics on QTc prolongation : Previous reviews
suggested that aripiprazole was the least likely antipsychotic to prolong
QTc. A new meta-analysis finds that lurasidone has the least. 24
Paliperidone and cariprazine were low, as well.
Node 1: Recommendations for the First Antipsychotic Trial in
a New-Onset Patient
In addition to the medications recommended in the 2013 algorithm:
amisulpride, aripiprazole, risperidone, and ziprasidone—add lurasidone. In
the initial draft of the algorithm submitted for review, lurasidone was
included in the first-line choices because of its reasonable effectiveness and
modest side effect profile. However, reviewers pointed out that there were
no studies showing effectiveness in first-onset patients. Response patterns
can be different in this group, compared to patients who have had multiple
past exposures to antipsychotics but who are not considered treatment
resistant. In 2017, the FDA approved lurasidone for adolescents (aged 13–
17) with schizophrenia based on a randomized trial of 40 or 80 mg versus
placebo. 25 The subjects were not all youth who had no previous treatment
for their schizophrenia, but this positive study seems to supply the missing
evidence base for considering lurasidone among the first-line choices in the
algorithm.
Another new study suggesting need for a slight adjustment to the first-
line recommendations was by Robinson et al. 26 Both risperidone and
aripiprazole were among the recommendation in 2013, but here was a head-
to-head comparison of these two in 198 acutely psychotic first-onset
patients who had no more than two weeks of exposure to any antipsychotic.
The rate of significant response on positive symptoms was 63% with
aripiprazole and 57% with risperidone. This equivalence (with slight
numerical advantage to aripiprazole) could be considered somewhat
unexpected because the weight of the evidence in multi episode
schizophrenia patients (summarized in the algorithm paper) is that
aripiprazole is somewhat inferior to risperidone. One might speculate that
this difference in response to aripiprazole in antipsychotic-naïve patients
has something to do with the fact that dopamine receptors can be
upregulated secondary to the dopamine blockade produced by previous
exposure to dopamine-blocking antipsychotics. Medications with partial
dopamine agonist effect, like aripiprazole, might produce more undesirable
stimulation of those upregulated receptors than they would in the
antipsychotic-naïve individuals. Consistent with that, akathisia was more
common with aripiprazole than with risperidone. However, metabolic side
effects were greater with risperidone, and there was significantly more
improvement in negative symptoms with aripiprazole (p < .03). The authors
concluded that aripiprazole was a better initial medication with first-onset
schizophrenia compared with risperidone, and this seems a reasonable
conclusion. Aripiprazole also performed better than quetiapine in an open-
label randomized comparison in first-episode patients, while being equally
effective with ziprasidone in this three-armed trial. 27
Among the antipsychotics not recommended for first-line use in patients
having their first episode and/or getting their first treatment with an
antipsychotic, olanzapine continues to stand out as undesirable for all the
reasons cited in 2013, including the near-universal agreement on its
undesirability with other national and international guidelines and
algorithms. An additional consideration would be a newer report that even
one dose of olanzapine, 10 mg, given to healthy volunteers, produces
significant insulin resistance and inflammatory abnormalities within hours
after oral administration. 28 The study did not evaluate how long it took for
those abnormalities to return to normal, but this “requires elucidation.”
Quetiapine probably has similar effects on insulin resistance, 29 and
clozapine almost surely does as well.
It was also mentioned in the 2013 algorithm that quetiapine is also
undesirable as a first-onset choice because it seems to be one of the
antipsychotics with the least effectiveness in preventing the next episode of
schizophrenia or rehospitalization. Newer studies confirm this. 30 , 31
Poorly Adherent Patients: The Role of Long-Acting
Injectable Antipsychotics
In the 2013 algorithm draft that was submitted for consideration for
publication, the discussion of LAIs was praised by all (blinded) reviewers
as particularly useful and was considered to be a reasonable statement of
their appropriate place in the treatment of schizophrenia. Since then, we
have many more LAIs that have been marketed but the reasoning regarding
their basic roles and use seems to still be valid.
An important comment about LAI usage in the algorithm paper is that
LAIs may be necessary to complete an adequate first (or second) trial of an
antipsychotic on the way to seeing if clozapine is going to be indicated as
the third trial. Adherence with oral trials has long been recognized as
problematic. Poor adherence is often not recognized by the prescribing
clinician, and it was recommended to routinely check plasma levels of oral
antipsychotics as a way of evaluating possible adherence problems. Plasma
levels can also suggest rapid metabolism (or slow metabolism with elevated
blood levels which could explain unexpectedly severe side effects). This
recommendation was, and still is, not often implemented. Hiemke et al. 32
have recently revised their comprehensive listing of psychotropic
medication plasma levels and clinicians should retain their paper for
reference. There was an editorial accompanying this paper, which made the
following statement: “While ‘individualization’ or ‘personalization’ of
treatment is a top priority on the research agenda of most psychiatric
scientific societies, therapeutic drug monitoring (TDM) is indeed the only
clinically proven approach for personalized treatment in psychiatry. This is
in sharp contrast to the fact that—although cheap and widely available—
TDM is not systematically established in routine patient care.” 33
In a recent study evaluating the value of TDM with antipsychotics, 99
patients were identified who appeared treatment-resistant and were being
considered for clozapine. Plasma antipsychotic levels were measured. 34
About 35% had subtherapeutic levels, and of these 34% were
unmeasurable. These patients typically were on lower-than-usual doses, and
they had a higher rate of readmissions (p = .02).
TDM may also be helpful in minimizing side effects. A recent report
showed that higher plasma levels of antipsychotics with strong dopamine-
receptor blocking properties (such as FGAs and some SGAs like olanzapine
—and probably risperidone) correlate negatively with patient subjective
sense of both physical and mental well-being. 35 This is distinct from
extrapyramidal side effects, and may be equivalent to what in the past has
been termed “neuroleptic induced dysphoria.” It is likely to be associated
with higher rates of nonadherence. Higher levels of partial dopamine
agonists (aripiprazole was the one studied) were correlated with impaired
physical well-being, probably from akathisia. Monitoring plasma levels and
keeping them at the low to medium optimal range may reduce these
phenomena.
One of the best uses of an LAI, therefore, should be to correct inadequate
adherence as demonstrated by a low or zero plasma level (that is not due to
a genetic or drug-interaction pharmacokinetic issue) and minimize the side
effect burden. This enables completion of an adequate trial so that it can be
determined if the medication being used has the potential to produce a
satisfactory therapeutic response and be well-tolerated over the long term.
If, despite correction of a low blood level with an LAI, the response
remains unsatisfactory, the patient is eligible to move on to the next node of
the algorithm for another medication trial.
Patients who should continue on an LAI are those who get a satisfactory
response and still need the LAI to optimize adherence. This can produce
improvement in rehospitalization rates as well as reduce mortality (33%
reduction compared with oral).30 , 36 For this purpose, we do have more
choices. For example, if the patient is started in aripiprazole and then needs
an LAI, we now have several formulations of aripiprazole LAI. Injections
can last four, six, or eight weeks. There is also a new formulation in which
patients receive an oral dose of 30 mg at the same time that they receive a
four-week injection; this results in therapeutic plasma levels developing in
four days. Paliperidone now has an injection lasting 12 weeks, which can
be started after the patient has been on the 4-week formulation for 4
months. Risperidone now has the first formulation of an LAI that is injected
subcutaneously; it lasts four weeks.
Node 2: The Second Antipsychotic Trial
There has been no change in the recommendations here, which are to try
one of the more effective antipsychotics as demonstrated in trials with
patients who have had previous exposures to antipsychotics: risperidone,
olanzapine, or one of the FGAs like perphenazine. 37 , 38 If the patient was
on one of these for the first trial, then any antipsychotic may be selected for
the second trial.
Node 3: The Third Antipsychotic Trial—Clozapine
In the last seven years, there have been many studies, reviews, and
guidelines debating the role of clozapine, but the bottom line is that the
strong recommendation for clozapine is still supported despite the
considerable side effects of this medicine. 39 , 40 These patients have
treatment-resistant schizophrenia (TRS) and nothing else has come along
that is clearly effective for TRS. Despite this it remains underutilized. 41
Yet, it appears likely that real-world outcomes would be better if more
clinicians utilized clozapine when indicated. 42 , 43 This algorithm update
has provided further refinement of the parameters for adequate trials of the
first two antipsychotics prior to clozapine (e.g., use of plasma levels and
LAIs), and confidence in the appropriateness of turning to clozapine for the
third trial should be enhanced.
Node 4: Augmentations and Alternatives to Clozapine
The 2013 algorithm offered five ideas to consider, none of which had
strong support. As of this writing, some have stronger support, others
weaker.
Augmentations with other antipsychotics : Previously risperidone,
lamotrigine, and FGAs were considerations. There seems to have been little
interest in further study of these particular options. The evidence remains as
it was in the 2013 paper: The support is weak at best. Aripiprazole as an
augmentation, however, has had significant new study and discussion in the
literature. In a meta-analysis of four short-term (8–24 weeks) randomized
placebo-controlled trials of adding aripiprazole to clozapine involving 347
patients, the improvement in positive symptoms was at a trend level (p =
.12) only. 44 All-cause discontinuation rates were higher with placebo (risk
ratio 1.4) but this too was nonsignificant. The patients lost a mean of three
pounds but they were eight times more likely to get agitation or akathisia.
These data did not seem to particularly support adding aripiprazole to the
option list. However, a new meta-analysis of psychiatric rehospitalization (a
measure of maintenance effectiveness) with different antipsychotics and
combinations of antipsychotics involving 62,250 patients in Sweden found
that aripiprazole plus clozapine was associated with the lowest rate of
rehospitalization.31 Other combinations involving clozapine, clozapine
alone, and combinations involving an LAI comprised the ten best
treatments associated with reduced rehospitalization. The best results on
mortality and medical hospitalizations were also found with the same
leading options. Editorial comment, however, urged caution and that these
observational studies should be considered preliminary and more high-
quality randomized controlled trials are needed to confirm the efficacy of
these combinations (apart from the well-established efficacy of clozapine
and the benefits of LAIs for addressing adherence issues).13 Major newer
meta-analyses of up to 62 studies of acute treatment (as opposed to relapse
prevention) have found no greater efficacy for any antipsychotic
combinations. 45 , 46
Augmentations with anticonvulsants : Previously, lamotrigine was
discussed because it has had five placebo-controlled trials as an
augmentation for clozapine. New data suggest topiramate is also an option.
47 This is an addition to the previous algorithm recommendations. Zheng et
al. found a significant improvement in positive symptoms (standardized
mean difference: −0.37) and negative symptoms (SMD: –0.58). Patients
also lost a mean of 6 pounds, and improved in other metabolic indices as
well, including insulin resistance. However, there were high discontinuation
rates due to paresthesias and cognitive difficulties. 48 Valproate was also
studied in five trials in China and seemed comparably effective to
topiramate as an augmentation of clozapine48 but the studies were faulted
for not controlling for clozapine levels, high heterogeneity of the studies,
and peculiarities of ethnicity-based genetic metabolic issues with clozapine
in the population treated. 49
Augmentation with electroconvulsive therapy (ECT) : The previous
algorithm included ECT as an option for augmenting clozapine, based on
case report data only. Since then, there was a controlled trial of ECT with
clozapine continuation as the control, showing efficacy. 50 However, a small
sham-controlled trial published two years later in 2017 was disappointing in
showing no difference in outcome versus sham. 51 Sham produced a 28%
improvement in Positive and Negative Symptom Scale scores, compared
with a 19% reduction in the group getting ECT, which was a nonsignificant
difference. The study diminishes enthusiasm for this strategy though it is
still retained as a consideration. Sham and real ECT procedures both
produced some benefit.
Switching to aripiprazole to replace clozapine after the clozapine trial
must end : Though there are very little data supporting the theoretical
notion that after a trial of an antipsychotic like clozapine that has weak
affinity for the dopamine receptor (and which, as a consequence does not
upregulate those receptors), a trial with a medicine that is both a dopamine
blocker and a partial agonist at the dopamine receptor, like aripiprazole,
could be timely and effective. One more case report has appeared that
supports this possibility. 52
Something really new and unexpected : A 24-year-old man with chronic
TRS had a bone marrow transplantation for cancer treatment. 53 His
schizophrenia remitted in a remarkable way and continued in remission at
four-year follow-up. Did this have something to do with addressing
immune system dysregulation? Further studies are required.
REFERENCES
1. Vyas P, Hwang BJ, Brasic JR. An evaluation of lumateperone tosylate for the treatment of
2. Tandon R, Gaebel W, Barch DM, et al. Definition and description of schizophrenia in the DSM-
5. Schizophr Res 2013;150:3–10.
3. Malaspina D, Owen MJ, Heckers S, et al. Schizoaffective disorder in the DSM-5. Schizophr Res
2013;150:21–5.
4. Kotov R, Leong SH, Mojtabai R, et al. Boundaries of schizoaffective disorder: revisiting
Kraepelin. JAMA Psychiatry 2013;70:1276–86.
5. Murru A, Pacchiarotti I, Nivoli AM, Grande I, Colom F, Vieta E. What we know and what we
don’t know about the treatment of schizoaffective disorder. Eur Neuropsychopharmacol
2011;21:680–90.
6. Cheniaux E, Landeira-Fernandez J, Lessa Telles L, et al. Does schizoaffective disorder really
exist? A systematic review of the studies that compared schizoaffective disorder with
schizophrenia or mood disorders. J Affect Disord 2008;106:209–17.
7. Bromet EJ, Kotov R, Fochtmann LJ, et al. Diagnostic shifts during the decade following first
admission for psychosis. Am J Psychiatry 2011;168:1186–94.
8. Jager M, Haack S, Becker T, Frasch K. Schizoaffective disorder—an ongoing challenge for
psychiatric nosology. Eur Psychiatry 2011;26:159–65.
9. Azorin JM, Kaladjian A, Fakra E. Current issues on schizoaffective disorder. Encephale
2005;31:359–65.
10. Mantovani C, Labate CM, Sponholz A Jr, et al. Are low doses of antipsychotics effective in
the management of psychomotor agitation? A randomized, rated-blind trial of 4 intramuscular
interventions. J Clin Psychopharmacol 2013;33:306–12.
11. Vidal C, Reese C, Fischer BA, Chiapelli J, Himelhoch S. Meta-analysis of efficacy of
mirtazapine as an adjunctive treatment of negative symptoms in schizophrenia. Clin Schizophr
Relat Psychoses 2015;9:88–95.
12. Stroup TS, Gerhard T, Crystal S, et al. Comparative effectiveness of adjunctive psychotropic
medications in patients with schizophrenia. JAMA Psychiatry 2019;76:508–15.
medications in patients with schizophrenia. JAMA Psychiatry 2019;76:508–15.
13. Goff DC. Can adjunctive pharmacotherapy reduce hospitalization in schizophrenia?: insights
from administrative databases. JAMA Psychiatry 2019;76:468–70.
14. Nemeth G, Laszlovszky I, Czobor P, et al. Cariprazine versus risperidone monotherapy for
treatment of predominant negative symptoms in patients with schizophrenia: a randomised,
double-blind, controlled trial. Lancet 2017;389:1103–13 .
15. Sabe M, Kirschner M, Kaiser S. Prodopaminergic drugs for treating the negative symptoms of
schizophrenia: systematic review and meta-analysis of randomized controlled trials. J Clin
Psychopharmacol 2019;39:658–64.
16. Hassanpour F, Zarghami M, Mouodi S, et al. Adjunctive memantine treatment of
schizophrenia: a double-blind, randomized placebo-controlled study. J Clin Psychopharmacol
2019;39:634–8.
17. Helfer B, Samara MT, Huhn M, et al. Efficacy and safety of antidepressants added to
antipsychotics for schizophrenia: a systematic review and meta-analysis. Am J Psychiatry
2016;173:876–86.
18. Huybrechts KF, Hernandez-Diaz S, Patorno E, et al. Antipsychotic use in pregnancy and the
risk for congenital malformations. JAMA Psychiatry 2016;73:938–46.
19. Cohen LS, Goez-Mogollon L, Sosinsky AZ, et al. Risk of major malformations in infants
following first-trimester exposure to quetiapine. Am J Psychiatry 2018;175:1225–31.
20. Park Y, Hernandez-Diaz S, Bateman BT, et al. Continuation of atypical antipsychotic
medication during early pregnancy and the risk of gestational diabetes. Am J Psychiatry
2018;175:564–74.
21. Freeman MP, Sosinsky AZ, Goez-Mogollon L, et al. Gestational weight gain and pre-
pregnancy body mass index associated with second-generation antipsychotic drug use during
pregnancy. Psychosomatics 2018;59:125–34.
22. Correll CU, Robinson DG, Schooler NR, et al. Cardiometabolic risk in patients with first-
episode schizophrenia spectrum disorders: baseline results from the RAISE-ETP study. JAMA
Psychiatry 2014;71:1350–63.
23. Balon R, Riba M. Should women of childbearing potential be prescribed valproate? A call to
action. J Clin Psychiatry 2016;77:525–6.
24. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability
of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a
systematic review and network meta-analysis. Lancet 2019;394:939–51.
25. Goldman R, Loebel A, Cucchiaro J, Deng L, Findling RL. Efficacy and safety of lurasidone in
adolescents with schizophrenia: a 6-week, randomized placebo-controlled study. J Child
Adolesc Psychopharmacol 2017;27:516–25.
26. Robinson DG, Gallego JA, John M, et al. A randomized comparison of aripiprazole and
risperidone for the acute treatment of first-episode schizophrenia and related disorders: 3-
month outcomes. Schizophr Bull 2015;41:1227–36.
27. Crespo-Facorro B, Perez-Iglesias R, Mata I, et al. Aripiprazole, ziprasidone, and quetiapine in
the treatment of first-episode nonaffective psychosis: results of a 6-week, randomized,
flexible-dose, open-label comparison. J Clin Psychopharmacol 2013;33:215–20.
28. Hahn MK, Wolever TM, Arenovich T, et al. Acute effects of single-dose olanzapine on
metabolic, endocrine, and inflammatory markers in healthy controls. J Clin Psychopharmacol
metabolic, endocrine, and inflammatory markers in healthy controls. J Clin Psychopharmacol
2013;33:740–6.
29. Ngai YF, Sabatini P, Nguyen D, et al. Quetiapine treatment in youth is associated with
decreased insulin secretion. J Clin Psychopharmacol 2014;34:359–64.
30. Tiihonen J, Mittendorfer-Rutz E, Majak M, et al. Real-world effectiveness of antipsychotic
treatments in a nationwide cohort of 29823 patients with schizophrenia. JAMA Psychiatry
2017;74:686–93.
31. Tiihonen J, Taipale H, Mehtala J, Vattulainen P, Correll CU, Tanskanen A. Association of
antipsychotic polypharmacy vs monotherapy with psychiatric rehospitalization among adults
with schizophrenia. JAMA Psychiatry 2019;76:499–507.
32. Hiemke C, Bergemann N, Clement HW, et al. Consensus guidelines for therapeutic drug
monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry 2018;51:9–62.
33. Grunder G. Editorial to consensus guidelines for therapeutic drug monitoring in
neuropsychopharmacology. Pharmacopsychiatry 2018;51:5–6.
34. McCutcheon R, Beck K, D’Ambrosio E, et al. Antipsychotic plasma levels in the assessment
of poor treatment response in schizophrenia. Acta Psychiatr Scand 2018;137:39–46.
35. Veselinovic T, Scharpenberg M, Heinze M, et al. Dopamine D2 receptor occupancy estimated
from plasma concentrations of four different antipsychotics and the subjective experience of
physical and mental well-being in schizophrenia: results from the randomized NeSSy trial. J
Clin Psychopharmacol 2019;39:550–60 .
36. Taipale H, Mittendorfer-Rutz E, Alexanderson K, et al. Antipsychotics and mortality in a
nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res 2018;197:274–80.
37. Hatta K, Sato K, Hamakawa H, et al. Effectiveness of second-generation antipsychotics with
acute-phase schizophrenia. Schizophr Res 2009;113:49–55.
38. McCue RE, Waheed R, Urcuyo L, et al. Comparative effectiveness of second-generation
antipsychotics and haloperidol in acute schizophrenia. Br J Psychiatry 2006;189:433–40.
39. Kane JM, Agid O, Baldwin ML, et al. Clinical guidance on the identification and management
of treatment-resistant schizophrenia. J Clin Psychiatry 2019;80(2).
40. Masuda T, Misawa F, Takase M, Kane JM, Correll CU. Association with hospitalization and
all-cause discontinuation among patients with schizophrenia on clozapine vs other oral
second-generation antipsychotics: a systematic review and meta-analysis of cohort studies.
JAMA Psychiatry 2019;76:1052–62.
41. Stroup TS. Clozapine and evidence-based psychopharmacology for schizophrenia. JAMA
Psychiatry 2019;76:1007–8.
42. Krivoy A, Joyce D, Tracy D, et al. Real-world outcomes in the management of refractory
psychosis. J Clin Psychiatry 2019;80.
43. Wimberley T, MacCabe JH, Laursen TM, et al. Mortality and self-harm in association with
clozapine in treatment-resistant schizophrenia. Am J Psychiatry 2017;174:990–8.
44. Srisurapanont M, Suttajit S, Maneeton N, Maneeton B. Efficacy and safety of aripiprazole
augmentation of clozapine in schizophrenia: a systematic review and meta-analysis of
randomized-controlled trials. J Psychiatr Res 2015;62:38–47.
45. Galling B, Roldan A, Rietschel L, et al. Safety and tolerability of antipsychotic co-treatment in
patients with schizophrenia: results from a systematic review and meta-analysis of randomized
patients with schizophrenia: results from a systematic review and meta-analysis of randomized
controlled trials. Expert Opin Drug Saf 2016;15:591–612.
46. Ortiz-Orendain J, Castiello-de Obeso S, Colunga-Lozano L, Hu Y, Maayan N, Adams C.
Antipsychotic combinations for schizophrenia. Schizophr Bull 2018;44:15–7.
47. Zheng W, Xiang YT, Xiang YQ, et al. Efficacy and safety of adjunctive topiramate for
schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatr Scand
2016;134:385–98.
48. Zheng W, Xiang YT, Yang XH, Xiang YQ, de Leon J. Clozapine augmentation with
antiepileptic drugs for treatment-resistant schizophrenia: a meta-analysis of randomized
controlled trials. J Clin Psychiatry 2017;78:e498–505.
49. Faden J. Treatment-resistant schizophrenia: a brief overview of treatment options. J Clin
Psychiatry 2019;80.
50. Petrides G, Malur C, Braga RJ, et al. Electroconvulsive therapy augmentation in clozapine-
resistant schizophrenia: a prospective, randomized study. Am J Psychiatry 2015;172:52–8.
51. Melzer-Ribeiro DL, Rogonatti SP, Kayo M, et al. Efficacy of electroconvulsive therapy
augmentation for partial response to clozapine: a pilot randomized ECT-sham controlled trial.
Arch Clin Psychiatry 2017;44:45–50.
52. Feeley RJ, Arnaout B, Yoon G. Effective switch from clozapine to aripiprazole in treatment-
resistant schizophrenia and comorbid alcohol use disorder. J Clin Psychopharmacol
2017;37:729–30.
53. Miyaoka T, Wake R, Hashioka S, et al. Remission of psychosis in treatment-resistant
schizophrenia following bone marrow transplantation: a case report. Front Psychiatry
2017;8:174.
* I thank Robert D. Patterson, MD for his contributions to the text of this update and also for
preparing the revised flowchart for the schizophrenia algorithm.
G
The Psychopharmacology Algorithm Project at the
Harvard South Shore Program: An Algorithm for
Generalized Anxiety Disorder
Harmony Raylen Abejuela, MD and David N. Osser, MD
Learning Objective: After participating in this activity, learners should be better able to:
Evaluate pharmacotherapy options for patients with generalized
anxiety disorder
Abstract: This revision of previous algorithms for the pharmacotherapy of generalized anxiety
disorder was developed by the Psychopharmacology Algorithm Project at the Harvard South Shore
Program. Algorithms from 1999 and 2010 and associated references were reevaluated. Newer
studies and reviews published from 2008–14 were obtained from PubMed and analyzed with a focus
on their potential to justify changes in the recommendations. Exceptions to the main algorithm for
special patient populations, such as women of childbearing potential, pregnant women, the elderly,
and those with common medical and psychiatric comorbidities, were considered. Selective serotonin
reuptake inhibitors (SSRIs) are still the basic first-line medication. Early alternatives include
duloxetine, buspirone, hydroxyzine, pregabalin, or bupropion, in that order. If response is
inadequate, then the second recommendation is to try a different SSRI. Additional alternatives now
include benzodiazepines, venlafaxine, kava, and agomelatine. If the response to the second SSRI is
unsatisfactory, then the recommendation is to try a serotonin-norepinephrine reuptake inhibitor
(SNRI). Other alternatives to SSRIs and SNRIs for treatment-resistant or treatment-intolerant
patients include tricyclic antidepressants, second-generation antipsychotics, and valproate. This
revision of the GAD algorithm responds to issues raised by new treatments under development (such
as pregabalin) and organizes the evidence systematically for practical clinical application.
eneralized anxiety disorder (GAD) is a chronic, debilitating condition
characterized by excessive and persistent worrying that interferes with many
aspects of daily life. 1 – 7 Symptoms include both somatic (physical)
symptoms, such as tremor and palpitations, and psychic (psychological)
symptoms, particularly apprehensive expectations about major and minor
concerns. It is the most common anxiety disorder seen in the primary care
setting. 8 Nearly seven million Americans suffer from GAD. 2
In this article, we present an algorithm for selecting medication treatments for
GAD. This algorithm is an update of a 1999 version from the
Psychopharmacology Algorithm Project at the Harvard South Shore Program
(PAPHSS). 9 It was also influenced by a 2010 GAD algorithm from an
international psychopharmacology group, to which one of the authors (DNO)
contributed. 10 Although psychosocial interventions are of unquestioned
importance in the armamentarium for treating GAD, this algorithm is limited to
psychopharmacology interventions and may be applied if and when the
prescribing clinician and patient determine that medication is appropriate. In
some patients, combinations of medication and psychotherapy are utilized,
though the effectiveness of combination treatment compared to either treatment
alone is unclear. 11
GAD is frequently comorbid with other disorders. Major depressive disorder
is found in nearly 50% of patients, and over 60% have other anxiety disorders. 12
It is important to address the impact of these and other comorbidities when
approaching patients with GAD.
In the United States, the selective serotonin reuptake inhibitors (SSRIs)
escitalopram and paroxetine, the serotonin-norepinephrine reuptake inhibitors
(SNRIs) venlafaxine XR and duloxetine, the benzodiazepine alprazolam, and
buspirone are approved by the Food and Drug Administration (FDA) for GAD.
Other medications such as pregabalin are approved for GAD in some other
countries but available in the United States only because of approval for other
indications. Other off-label options have been evaluated in GAD—including
other benzodiazepines (e.g., diazepam), hydroxyzine, bupropion, tricyclic
antidepressants (e.g., imipramine), kava (Piper methysticum ), and rhodax
(Rhodiola rosea ).1 , 13 – 17 Antipsychotics (quetiapine) have also been found to
have efficacy in randomized, controlled trials. 18 In this algorithm, the evidence
for the effectiveness and safety of these and other possible options are evaluated
and sequenced in accordance with their potential value in particular contexts.
These contexts include the presence of various medical and psychiatric
comorbidities, as well as other situations such as women who have the potential
to become pregnant. Cost-effectiveness is occasionally a consideration when
options seem equivalent in overall benefit and risk.
METHODS
Prior publications have described the PAPHSS method of algorithm
development. 19 – 24 The algorithms are structured like a hallside
psychopharmacology consultation. They present a series of question about
diagnoses and the history of previous treatment that the consultant might ask.
The questions are designed to efficiently characterize the clinical situation. Then,
recommendations are offered that are derived from an analysis of evidence
pertinent to that situation. The authors reviewed their previous GAD algorithms,9
, 10 consulted other recent algorithms and guidelines, and focused on the key
randomized, controlled trials (RCTs), especially recent ones not considered in
the previous reviews.
In constructing the decision tree, the authors considered efficacy, tolerability,
and safety as the main bases for prioritizing treatments. All hierarchical and
other clinical recommendations were the result of agreement by the two authors.
Their conclusions were opinion-based distillations of the body of evidence
reviewed that could be subject to conflicting interpretation by other experts.
However, the peer-review process that follows submission of the article adds
some validation to the reasoning in this algorithm and other PAPHSS
algorithms. If the reasoning, based on the authors’ interpretation of the pertinent
evidence, is plausible to reviewers, then it is retained. When differences of
opinion occur, the authors make adjustments to achieve consensus with the
reviewers or have probed the relevant evidence further in order to present a
stronger argument in support of their position.
At each decision point, different options are available for consideration,
enabling prescribers to select what seems best and most acceptable to the patient
in each particular clinical situation.
FLOW CHART FOR THE ALGORITHM
A summary and overview of the algorithm is presented in Figure 1 . Each
numbered “node” represents a key question or decision point that delineates
patients ranging from those who are treatment naive to those who are
increasingly treatment refractory. The questions and evidence-based rationales
that support the recommendations at each node are presented below .
NODE 1: DOES THE PATIENT MEET DSM-5
CRITERIA FOR GENERALIZED ANXIETY
DISORDER?
First, confirm a diagnosis of GAD based on the criteria present in the most
recent, fifth edition of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-5), 25 and note any comorbid medical or psychiatric diagnoses
that may affect decision making, as will be discussed in Node 2.
Regarding the DSM-5 diagnostic criteria, it may be that no diagnostic
category changed as much as GAD between DSM-III/III-R and DSM-IV, though
the changes from DSM-IV to DSM-5 were minor. The current criteria describe
patients with a core problem of chronic excessive worrying, focused in a number
of areas, that is difficult to control and causes impairment. If the worry is
confined to the typical worries associated with other mental disorders (e.g.,
negative evaluation in social anxiety disorder), then GAD would not be
diagnosed. In DSM-III/III-R, the condition was predominantly a disorder of
autonomic, motor, or other somatic manifestations of anxiety. These symptoms
turned out not to be particularly specific to GAD, and many DSM-III/III-R GAD
patients would now be classified with other anxiety disorders or somatic
symptom disorders. 26 , 27
NODE 2: CONSIDER SPECIAL PATIENT
POPULATIONS AND COMORBIDITIES
Table 1 summarizes common comorbid considerations in patients with GAD and
how they might influence the algorithm—including insomnia, major depression,
bipolar disorder, substance use disorders, and posttraumatic stress disorder.
Other relevant considerations are whether patients are elderly and whether a
woman has child-bearing potential. These factors should be reviewed both
before beginning to consult the algorithm and subsequent to considering the next
node if treatment response is unsatisfactory. A more thorough analysis of this
important material is beyond the scope of this article, though the reader is
encouraged to consult the cited studies and reviews.
NODE 3: HAS THE PATIENT HAD AN
ADEQUATE TRIAL OF AN SSRI?
Having confirmed the diagnosis of GAD and considered the comorbidity and
related issues in Node 2, the authors found that the evidence still supports SSRIs
as the first-line medication for uncomplicated cases of GAD, based on their
safety and tolerability, but with some reservations, as will be discussed. Two
SSRIs are FDA approved for use in GAD: escitalopram and paroxetine.
However, sertraline has also been used with comparable efficacy in three RCTs
in comparison to placebo. 58 If a patient has not been tried on an SSRI, the
recommendation is to try one, with both prescriber and patient taking into
account the particular side-effect profiles of the three main options. Consider
avoiding citalopram, particularly in the elderly with a history of cardiovascular
disease, given concerns about its ability to prolong the QTc interval in doses >40
mg daily, as outlined in FDA guidelines announced in March 2012. 59 , 60 The
new maximum dose in the elderly is 20 mg daily. But some controversy remains.
Recently published observational data show no cardiovascular safety issues in a
sample of patients who received doses over 40 mg daily, 61 and the authors of
that study suggest that this finding is consistent with extensive literature. In the
unpublished RCTs that the FDA relied upon to develop the new warning,
however, escitalopram had much less effect on QTc than citalopram.60
Table 1 | Comorbidity and Other Features in GAD and How They Affect
the Algorithm
Comorbid
conditions and
other
circumstances
Evidence considerations Recommendations
Sleep disturbance There may be multiple contributing
causes from comorbid medical and
psychiatric conditions
Some treatments may result in
worsening or treatment-emergent
insomnia (e.g., SSRIs and SNRIs) 28
More sedating agents like hydroxyzine
and pregabalin may be better than
SSRIs and SNRIs 29
Evaluate and manage contributing
causes to the insomnia
Adjunctive trazodone added to an SSRI
was helpful for improving sleep in two
placebo-controlled trials 30 , 31
GABA agonists can work 32 but may
cause rebound effects the night after
discontinuation 33
Consider hydroxyzine or pregabalin29
over SSRIs as alternative primary
treatments
Hydroxyzine could be an alternative
hypnotic
Elderly patients All GAD treatments have additional or
increased risks or require closer
monitoring in the elderly
Consider sertraline and escitalopram,
34 , 35 although risks could include gait
impairment, GI bleeding, bone loss,
and hyponatremia
One small study comparing sertraline
and buspirone found a trend favoring
buspirone, but this result requires
replication 36
The SNRI venlafaxine was also
effective 37 but can be associated with
a high rate of blood pressure problems
when used at a mean dose of 196 mg 38
Pregabalin was effective, but caution is
Pregabalin was effective, but caution is
advised for somnolence and dizziness;
falls with fracture occurred 39
Benzodiazepines can produce falls,
decreased respiratory drive, substance
use disorders, and additive sedation, 40
and are not recommended
Quetiapine has metabolic risks, and a
new warning in 2011 on QTc
prolongation 41
Neuropathic pain Patients with neuropathic pain can
respond to pregabalin 42
Consider pregabalin rather than an
SSRI
Women of
childbearing
potential and
women who
become pregnant
during treatment
Benzodiazepines have a “D” rating for
pregnancy due to some risk for cleft
palate 43
SSRIs and SNRIs are all “C” (except
paroxetine, which is “D”) but are
associated with some pre- and
postnatal complications 44 , 45
Avoid benzodiazepines and paroxetine
Active substance
use disorders
15% have this comorbidity 46
Though controversial, experts
concluded that benzodiazepines should
be avoided in such patients 47
Avoid benzodiazepines and related
agents
Avoid pregabalin, which is also a
Schedule IV controlled substance
Major depression GAD and depression can coexist and
be distinguishable27
Major depression with comorbid
anxiety responds less well to
antidepressants than depression
without anxiety 48
Try treating with SSRIs (second
choice, SNRIs), which treat both
depression and anxiety
Consider adjunctive treatment focused
on GAD, if necessary
Bipolar
depression
Rates of GAD are higher in bipolar
compared to unipolar depression27
Antidepressants, including SSRIs, are
usually not recommended, especially if
the patient is a rapid cycler or presents
with mixed features48 , 49 ; efficacy is
doubtful, and the risk of mood switch
For the depression, consider lithium,
lamotrigine, and lurasidone 21 , 51
For the GAD, consider pregabalin,
hydroxyzine, and benzodiazepines
Quetiapine was not effective in one
study of patients with GAD and bipolar
depression 52
doubtful, and the risk of mood switch
is significant49 , 50
depression 52
Bipolar mania Manic patients have high rates of
GAD, and response to lithium and
anticonvulsants may be reduced 53
Valproate was effective compared to
placebo in a small study on men with
comorbid GAD 54
Avoid antidepressants
Quetiapine is effective for GAD 55 and
may be preferred here
Consider preferring valproate over
lithium in men with mania and GAD,
but not in women of childbearing
potential due to teratogenicity 56
Posttraumatic
stress disorder
Prazosin is highly effective as an add-
on treatment for insomnia, nightmares,
disturbed awakenings, and daytime
symptoms of PTSD in 4 small placebo-
Of the three recommended SSRIs, paroxetine produces the most side effects.
Its H1 antihistaminic effects are probably the reason that it causes more weight
gain, constipation, and daytime sedation than others (though unexpectedly, it can
be activating and is just as likely to impair sleep as the others). 62 , 63 Weight gain
may be as high with escitalopram, however, as with paroxetine; an observational
study found both were associated with >14% of patients gaining more than 7%
of body weight during extended treatment of obsessive-compulsive disorder,
versus <5% with sertraline. 64 Paroxetine is associated with the most sexual side
effects, 65 has more cytochrome P450 drug interactions than escitalopram or
sertraline, and can produce discontinuation symptoms if a dose is missed, due to
its short half-life. Additionally, paroxetine is the only SSRI with a pregnancy
category D classification, because of reports of increased cardiac septal defects.
Recent studies have replicated this finding. 66
The overall effect size of SSRIs in GAD in a 2007 metaanalysis was 0.36
(standardized mean difference from placebo), which is a modest effect, 67 though
in some studies remission rates were as high as 50%. 68 In the elderly, in whom
GAD is particularly common, 69 the evidence base with SSRIs is limited.
Sertraline seemed inferior to buspirone in a small RCT without placebo
control,36 but escitalopram was effective compared to placebo in a larger study.35
Paroxetine was found to be effective at daily dosages of 20 mg or 40 mg,
while the optimal daily dosage of escitalopram compared to placebo was 10 mg
and not 20 mg. 3 , 4 Sertraline doses have ranged from 50–200 mg daily. A dose-
response relationship has not been demonstrated for any SSRI, and no research
has compared higher-dose SSRIs to longer time on the initial dose. 70
The time required for an adequate trial of an SSRI for GAD varies with the
individual. Studies with escitalopram have found that if response commences
within two weeks (defined as a 20% improvement in Hamilton Anxiety Rating
Scale [HAM-A] scores), the prognosis for remission is good. 71 By the same
token, if there is no response in two weeks, the initial dose should be increased.
If there is no response in four weeks, meta-analysis suggests that the patient is
unlikely to respond.70 Assuming that the patient has been adherent to treatment
and that there is no reason to suspect the patient to be an ultra-rapid metabolizer
of the medication, it is reasonable to consider such a trial to be adequate.
When prescribing SSRIs, clinicians are urged to be mindful of their typical
adverse effects. Sexual side effects, in particular, are common, disturbing for
many patients, and difficult to discuss, and they usually do not remit with time. 72
In addition to the other side effects noted above, upper gastrointestinal tract
bleeding was nine times more common over three months in patients on an SSRI
and a nonsteroidal anti-inflammatory medication than in a control group not on
those medications. 73 This risk is mitigated, however, if the patient is also on an
acid-controlling agent such as a proton-pump inhibitor. Even short-term use of
an SSRI (7–28 days) increases the odds of a upper gastrointestinal tract bleed by
67%-84%. 74 Osteoporosis and fracture risk increase twofold with long-term
SSRI use. 75 Suicidal ideation and behavior may increase in patients younger
than 25 years, 76 as noted in the package-insert warning of all antidepressants.
Because of these side effects and the high placebo-response rate in GAD
studies,70 it is recommended that prescribers attempt to confirm that any apparent
response of GAD to SSRI treatment was medication related and not due to
nonspecific aspects of care (e.g., a placebo response). Usually, the best way to
make this determination is a trial off the medication at a time when the patient is
doing reasonably well and can receive suitable support and observation. Some
may relapse, but many more will not and are spared the side effects. If
medication-related benefit seems likely, maintenance treatment for one year or
more is reasonably well established and endorsed by most evidence-based
guidelines, since GAD is often a chronic condition.3 For example, escitalopram
recipients (compared to placebo) took a significantly longer time to relapse and
had a markedly decreased risk of relapse than those on placebo. 77
Node 3A: Other Options to Consider
If the risks of adverse effects from an SSRI are considered unacceptable to the
prescribing clinician or patient, several reasonable options are worth
considering. We will briefly discuss the rationale for each of these, their
advantages and disadvantages, and when they might be considered preferable to
SSRIs.
The serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine and
duloxetine are also FDA approved for GAD and have comparable efficacy to
SSRIs.3 Of the two, the side effects of venlafaxine seem to relegate it to, at best,
a second choice. While causing the same liability to sexual side effects as SSRIs,
venlafaxine produces dose-related hypertension requiring clinical monitoring,
and causes more problems with sweating. 78 By contrast, duloxetine was found to
have significantly lower rates of sexual side effects than paroxetine, although
they were higher than placebo. 79 Blood pressure effects seemed comparable to
SSRIs.79 These considerations could elevate duloxetine to a first-line option.
However, risks of liver abnormalities, though small, suggest that it would be
prudent to assess baseline liver function function (an inconvenience); duloxetine
is contraindicated in patients with hepatic impairment.78 Perspiration and
infrequent urinary retention (0.4%) are other concerns with duloxetine.78
Efficacy and dosing requirements with duloxetine were demonstrated in four
RCTs. The medication was effective at 60–120 mg, with no advantage to the
higher dose.4 , 80 The GAD symptoms earliest to respond included anxious mood
and muscle tension, and the symptoms last to respond included insomnia and
common gastrointestinal and autonomic symptoms (all part of the adverse-effect
profile of SNRIs). 81 The most common adverse effects reported were nausea,
dizziness, dry mouth, fatigue, somnolence, and constipation, but otherwise
duloxetine was reported to be generally well tolerated.80 , 82 – 84 It should be noted
that despite intensive marketing to the contrary, the analgesic effects of
duloxetine in depressed patients were found (in a metaanalysis of five trials) to
be clinically insignificant. 85 The effect size of the analgesia was only 0.115 by
Cohen’s d.85 This analysis excluded studies of patients with comorbid
fibromyalgia or musculoskeletal disorders.
Buspirone is an azapirone that received FDA approval as a monotherapy agent
for DSM-III GAD in 1986, with double-blind, placebo-controlled studies mostly
demonstrating effectiveness comparable to benzodiazepines. A meta-analysis in
1992 of eight placebo-controlled RCTs involving buspirone in doses ranging
from 15 to 60 mg daily found the typical effective dose to be 30 mg. 86 It was
found very useful in a placebo-controlled trial in recently abstinent anxious
alcoholics (almost half of whom met DSM-III criteria for GAD) at an average
dose of 50 mg daily. 87 Advantages over benzodiazepines included no abuse
potential and a good side-effect profile. 83 , 88 Buspirone has little overdose
toxicity, no impairment of cognitive or psychomotor performance, and no sexual
side effects. Only one placebo-controlled trial, however, has been undertaken to
confirm buspirone’s efficacy as monotherapy for DSM-IV GAD. In a
comparison to venlafaxine (sponsored by the manufacturer of venlafaxine),
buspirone 30 mg daily was no better than placebo on some measures, and on
others it was inferior to venlafaxine. 89 Therefore, it is somewhat in doubt
whether buspirone, despite its advantages in side effects, is a first-line agent in
DSM-IV or DSM-5 GAD. Clinicians may nevertheless want to consider it
because of its benign side effects.
Hydroxyzine is an antihistamine with mild 5-HT2 receptor blocking effects
that has shown both efficacy over placebo and safety at doses around 50 mg
daily in three placebo-controlled RCTs in GAD patients, one using DSM-III
criteria 90 and two using DSM-IV criteria. 91 , 92 Given its low abuse potential,
sedating properties, lack of sexual side effects, and mean effect size of 0.45 in
these studies, it appears to be a viable alternative to SSRIs. Clinicians seem
skeptical about this product, however, and it is not known to have any benefit for
disorders like depression and other anxiety states that are common comorbidities
with GAD. Nevertheless, it is commonly used as a PRN (as needed) medication
on inpatient units because of its rapid onset of sedation (15–30 minutes), half-
life of three hours, and duration of effect, lasting 4–6 hours with no known
potential for dependence. 93 It is also prescribed this way for outpatients, with
doses ranging from 37.5 mg to 75 mg.88 In a Cochrane Review comparing
hydroxyzine to other anxiolytic agents, such as benzodiazepines and buspirone,
hydroxyzine was found to be equivalent in tolerability, efficacy, and
acceptability among patients. 94 The third RCT92 was particularly interesting in
that, over the 12 weeks of the comparison to placebo and the benzodiazepine
bromazepam, the difference between hydroxyzine and placebo gradually
enlarged, suggesting an accumulating effect rather than an immediate and
plateauing effect, which one might expect from a purely sedative agent. A
replication trial comparing hydroxyzine to an SSRI would be of great interest.
Pregabalin is approved throughout Europe for treating GAD and is widely
used there and recommended in international guidelines. 95 It has at least seven
positive RCTs versus placebo and several comparators, and was at least
comparably effective to other medications for both somatic and psychic
symptoms of GAD.70 Compared to SSRIs, it seemed to have a relatively rapid
onset and was more beneficial for sleep.70 Unlike antidepressants, there seemed
to be a dose response relationship in GAD, where doses over 300 mg daily were
more effective. 96 , 97 Surprisingly, the medication was not approved in the
United States for GAD despite two submissions of data to the FDA. The “non-
approvable letter” explaining the FDA reasoning has not been made public by
the manufacturer. They are not required to disclose the letter, and the company
refused to share it with the authors of this article. It has been speculated that the
treatment effect size, though statistically significant, was considered too small to
be clinically significant in the reviewed trials (e.g., three points or less on the
HAM-A). 98
Pregabalin was found to be effective in elderly patients in one study, though
caution is required since pregabalin’s most common side effects include
somnolence and dizziness, and one patient fell and sustained a fracture.39 , 98
Cost considerations may result in some pharmacy-benefit managers in the
United States refusing to allow use of pregabalin for GAD. It is possible that
gabapentin could be used instead of pregabalin here and throughout the
algorithm when pregabalin is recommended. This substitution is speculative
because there are no controlled studies of gabapentin in GAD. However,
gabapentin has some of the same FDA indications as pregabalin (neuropathic
pain and convulsions), and it is frequently used off-label as an anxiolytic. In an
RCT, Clarke and collaborators 99 found that gabapentin was effective for a
variety of chronic anxiety disorders, particularly preoperative anxiety. In another
RCT, gabapentin 300 mg and 900 mg were compared to placebo for anxiety
symptoms in 420 breast cancer survivors. 100 Both doses were associated with
significant improvements in anxiety symptoms compared to placebo, with a
greater improvement reported in patients with higher baseline levels of anxiety.
Notably, pregabalin is a Schedule IV controlled substance. Gabapentin is not,
though some concerns have been raised about its potential for misuse by patients
with tendencies in that direction. 101
Bupropion is an antidepressant that clinicians do not tend to consider for
patients with anxiety disorders. 102 However, there is an intriguing, though small,
double-blind, controlled trial in 24 outpatients aged 18–64 with DSM-IV GAD.
103 They were randomized to receive either bupropion XL (extended release)
150–300 daily or escitalopram (FDA approved for GAD) 10–20 daily. The main
efficacy measures used were the Clinical Global Impression of Improvement
(CGI-I) and the HAM-A. Anxiety symptoms improved in both groups, but the
difference in mean HAM-A scores was significant (p = .01) in favor of
bupropion, which produced an endpoint score of 5.3, whereas escitalopram
resulted in a mean score of 11.4. Response and remission rates as measured by
the CGI-I also favored bupropion, but differences in depression ratings were
nonsignificant. The study was sponsored by the manufacturer of bupropion.103
How seriously should one take these data? Trivedi and colleagues 104
compared the effects of bupropion and sertraline on anxiety symptoms in
patients with major depression using pooled data from two eight-week, double-
blind, placebo-controlled trials involving almost 700 patients. The two
medications had comparable anxiolytic and antidepressant effects, and onset of
improvement from both was equally rapid. There were no differences in
activation side effects or insomnia. Because of these findings and other data,
including bupropion’s relatively low incidence of sexual side effects,
Zimmerman and colleagues102 suggested that the evidence base might actually
support bupropion as the first-line antidepressant over SSRIs for most patients
with major depression. Without question, sexual side effects are one of the chief
concerns of patients about to try an antidepressant for depression or GAD,
presuming that they are fully informed about them. Bupropion’s advantage in
this respect may be balanced with the modest risk of seizures associated with the
longer-acting versions of bupropion, 105 though bupropion is contraindicated if
the patient has a past history of seizures or a history of an eating disorder. These
considerations suggest that bupropion may be a possible option to bring up with
patients considering their first treatment for GAD.
Other agents with some effectiveness for GAD include benzodiazepines,
mirtazapine, quetiapine, agomelatine (not available in the United States), and
kava. These will be discussed as options at Node 4.
Node 3B: Did You Try an SSRI and Get a Partial Response?
Consider Augmentations
Partial improvement occurs frequently in GAD—perhaps more commonly than
remissions.3 Augmentation may be considered if the partial improvement is
thought to be due to the medication and not the concomitant psychotherapy or
nonspecific aspects of treatment. As noted above, this determination may be
difficult but is of crucial importance. As a general principle, one should avoid
adding another medication when partial response to the first medication is likely
a placebo response. Unnecessary polypharmacy increases the risks of adverse
effects and drug interactions, reduces adherence due to complexity of the
regimen, and increases costs. Clinicians should evaluate for other possible
causes of incomplete response such as comorbidity, nonadherence, and
pharmacokinetic/pharmacogenetic variables.
If a true partial response is nevertheless suspected, there is only weak or
equivocal evidence available for guidance regarding what to choose for
augmentation. Quetiapine has received the most study, with three placebo-
controlled augmentation RCTs. 106 – 108 Though one RCT (not double-blind; n =
20) found efficacy,106 two double-blind RCTs 107 , 108 did not. The larger of those
two studies (n = 409) found a trend favoring quetiapine (p = .079), but the
difference from placebo on the HAM-A was only one point, which seems
clinically insignificant.107 Risperidone has two augmentation studies that were
positive—one of which was large. 109 , 110 A small, underpowered study
demonstrated that olanzapine can be added to SSRIs with augmenting effects in
GAD. 111 However, given the high risks of metabolic side effects, negative
effects on insulin resistance in the cases of olanzapine and quetiapine, 112 , 113 and
weight gain, among other considerations, these second-generation antipsychotics
are not recommended as augmenters at this early point in the algorithm.
Buspirone was not impressive as an augmenter of citalopram in outpatients
with major depression and high levels of anxiety in the STAR*D study. It
produced a remission rate of only 9% over 14 weeks.48 No studies have used
buspirone as an augmenter in GAD without depression, but the STAR*D results
and the general concerns raised earlier about the effectiveness of buspirone in
DSM-5 GAD suggest buspirone would not be a prime option for augmentation.
It seems reasonable to consider adding one of three alternatives: hydroxyzine
and pregabalin, which are well-tolerated options discussed in Node 3A above, or
a benzodiazepine. Though no augmentation trials with hydroxyzine have been
published, an eight-week, randomized, double-blind, placebo-controlled trial of
pregabalin augmentation in GAD (150–600 mg daily) found it to be somewhat
effective. 114 The changes in HAM-A scores compared to placebo were
significant but not clinically impressive: -7.6 versus -6.4 (p < .05).
Benzodiazepines have also received no formal study of augmentation in GAD,
but their use seems to be common in clinical practice. Benzodiazepines as
monotherapy for GAD will be discussed in Node 4A, where it will be suggested
that the usual objection to these products concerns their risks of abuse, tolerance,
and dependence. However, in a recent RCT of clonazepam as an augmentation
of sertraline for generalized social anxiety disorder, the clonazepam addition
seemed effective and safe. 115 This study provides indirect support for the
possible use of clonazepam here, but testing in GAD patients is necessary.
NODE 4: HAS THE PATIENT TRIED A SECOND
SSRI OR DULOXETINE?
If the patient has had no response (or a partial response presumed to be due to
placebo effect or the nonspecific effects of other aspects of care) after an
adequately dosed initial trial of an SSRI, no evidence is available to help guide
the second step of psychopharmacology treatment for GAD. Assuming that
adherence issues and pharmacokinetic/pharmacogenetic influences on dose
bioavailability have been considered, and that the diagnosis is verified, it seems
reasonable to try another evidence-supported medication. Often that will be
another SSRI or duloxetine because of their advantages as outlined in Node 3.
Since the SSRIs are not identical in their spectra of receptor activity, it may be
that a different one will have a better constellation of effects to address the
patient’s needs.
Node 4A: Other Options to Consider
The four alternatives suggested and discussed in Node 3A may also be
considered: buspirone, hydroxyzine, pregabalin, and bupropion. To this list,
some others may be added that have a sufficient evidence base for usage but that
present issues or problems suggesting that they should not be alternative first-
line (Node 3) agents: benzodiazepines, venlafaxine, agomelatine (not available
in the United States), and kava. Some other medications, including atypical
antipsychotics and tricyclic antidepressants, have evidence of efficacy but, due
to their side-effect burden, are postponed for consideration later, at the next
node. We will review the rationales for the four new options.
Benzodiazepines are effective for GAD and are perhaps the most widely
prescribed anxiolytic agents. Alprazolam was FDA approved for GAD at the
time of DSM-III. Placebo-controlled comparator trials in DSM-IV GAD with
agents such as pregabalin 116 confirm their efficacy using the more recent GAD
criteria. An advantage appreciated by patients is the rapid effect, appearing soon
after treatment is begun. However, benzodiazepines have many disadvantages.
After treatment for several months, about 40% of patients develop tolerance and
dependence,47 and they should particularly be avoided in patients with a history
of substance use disorders, though with some exceptions.9 They are also
commonly associated with increased sedation, memory impairment,
psychomotor incoordination resulting in increased motor vehicle accidents, and
rebound anxiety. 5 Long-acting benzodiazepines such as clonazepam, however,
may help decrease breakthrough anxiety during treatment with an SSRI. Both
somatic and psychic symptoms may improve, although somatic symptoms may
be the better targets for benzodiazepine therapy.83 , 97 If benzodiazepines are to
be given at this node, they are suggested primarily for patients who have no
history of any substance use disorders, as noted above. They may be combined
with an SSRI in the early phase of treatment (e.g., 4–8 weeks) while waiting for
the SSRI to work,88 and then tapered and discontinued if possible.
Venlafaxine XR is a reasonable alternative treatment to consider here instead
of a second SSRI, though as noted earlier it seems that duloxetine would be a
better choice in the SNRI class if it was not tried as initial treatment in Node 3.
Overall acute efficacy of venlafaxine XR is at least as good as with the SSRIs,67
and most studies show only minimal additional improvement at the higher doses
at which side effects like hypertension are more common. 117 Notably, in a
randomized, placebo-controlled trial comparing escitalopram with venlafaxine
XR in patients with GAD, escitalopram was found to be better tolerated.
Discontinuations due to adverse effects did not differ between escitalopram and
placebo (7% vs. 5%; p = .61) but were significantly higher for venlafaxine XR
(13%) compared to placebo (p = .03). 118 The study was sponsored by the makers
of escitalopram.
Because relapse rates in GAD treatment after one year of follow-up are
generally high, a 2010 study examined the benefits of 6 and 12 months of
continued treatment with venlafaxine XR (75–225 mg/daily) or placebo in 268
patients who had achieved improvement after an initial 6 months of open-label
treatment.82 Relapse rates were over 50% for patients on placebo versus just
under 10% for those who stayed on venlafaxine XR (p < .001). Remissions were
most likely at the maximum dose of 225 mg daily. The most common adverse
events in this longer trial were dry mouth, drowsiness, lightheadedness,
headaches, and increased sweating.
Agomelatine is an antidepressant that works by a novel mechanism blocking
serotonin 2C receptors and stimulating melatonin receptors. It has undergone 20
RCTs in depression. In the three U.S. studies, however, it did not do well, and
perhaps that is why it was not granted FDA approval. In a metaanalysis, the
overall effect size in depression treatment was found to be small (0.24) and
inferior to SSRIs. 119 However, it was more helpful for insomnia than SSRIs or
SNRIs. In GAD patients, two 12-week, placebo-controlled RCTs17 , 120 and one
26-week maintenance RCT 121 have demonstrated efficacy at doses of 25–50 mg
daily. It was especially useful for sleep, and side effects were minimal. In
countries where it is available, agomelatine may be a reasonable alternative to an
SSRI or SNRI for patients with insomnia and who want to avoid sexual side
effects.
Plant-based medications, such as kava (also known as Piper methysticum ),
have shown efficacy in RCTs in GAD. Kava (120/240 mg of kavalactones per
day) was compared to placebo in a recent six-week trial in 75 GAD patients
without comorbid mood disorders. 14 Kava had efficacy on the HAM-A (p =
.046; effect size [Cohen’s d] = 0.62); 26% of participants in the kava group were
classified as remitted (HAM-A < 7) versus 6% of participants in the placebo
group (p = .04). Side effects that were greater in the kava group were limited to
headaches. Earlier trials of kava had more mixed results, however, and a report
of severe hepatotoxicity was concerning. 122
Rhodax (also known as Rhodiola rosea ) is another herbal medication that has
been studied in GAD. In a small study from the UCLA Anxiety Disorders
Program of 10 GAD subjects aged 34 to 44, Rhodax extract (340 mg) was given
daily for 10 weeks. Rhodax-treated patients improved significantly on the HAM-
A (p = .01), but there were some anticholinergic side effects. 15 Riluzole, a
glutamate modulator, was promising as a treatment for GAD in an open-label
trial in 18 patients. 123 Eighty percent responded positively, and 53% remitted,
though this result needs replication. Lavender oil was reported to be effective
compared to placebo and at least as good as 20 mg of paroxetine in a recent
German study involving 539 patients. 124
Node 4B: Did You Try an SSRI and Get a Partial Response?
Consider Augmentations
If the second SSRI or SNRI trial resulted in a partial response that is thought to
be credited to the medication, the same augmentations may be considered as in
Node 3B. See Figure 1 .
NODE 5: HAS THE PATIENT TRIED AN SNRI?
If the patient has had two trials (from among the recommended first- and
second-line treatments in Nodes 3 and 4) and has not had a trial of an SNRI, the
next trial might be with an SNRI. Their advantages and disadvantages were
reviewed in earlier nodes. The growing list of alternatives that can be considered
at this point includes benzodiazepines, bupropion, buspirone, hydroxyzine,
pregabalin, agomelatine (not available in the United States), and herbs such as
kava. Some other options will be reviewed below.
Node 5A: Other Options to Consider
The first new option at this point is a second-generation antipsychotic (SGA).
Quetiapine has been the most studied, with five double-blind, placebo-controlled
RCTs as monotherapy for GAD, four of which demonstrated efficacy.58 , 125 , 126
As noted earlier, the weight gain, insulin resistance, and other metabolic side
effects, as well as the 2011 package insert warning on QTc prolongation, all
suggest quetiapine should not be an early choice in treating GAD. Because of the
toxicity, both the FDA and the European regulatory agency did not approve
quetiapine for any use in GAD. Quetiapine has good efficacy data, however, and
it may be a reasonable option for a treatment-resistant patient at this node of the
algorithm.
Risperidone was found effective in two augmentation trials when added to an
SSRI in GAD.109 , 110 It has not been studied as a monotherapy but might be a
reasonable second-choice SGA here. Ziprasidone was used in a small, placebo-
controlled trial as monotherapy for GAD; the trend toward efficacy 127 supported
the findings of an earlier open-label trial. 128 Ziprasidone had no efficacy,
however, in a cohort of patients in which it was used to augment an
antidepressant; a larger study was recommended.127 Risperidone has moderate
metabolic side effects and significant issues with prolactin elevation, but
ziprasidone has more tendency to elevate QTc, and many patients do not tolerate
its side effects. 129
Some tricyclic antidepressants have been found effective in GAD. Of all the
TCAs, imipramine is the only one with significant data for decreasing overall
anxiety, particularly for the psychic symptoms (anxious mood, muscle tension,
difficulty concentrating, and insomnia). Prior studies have compared imipramine
to benzodiazepines for GAD and found that while both medications significantly
decreased the somatic symptoms of GAD and the HAM-A scores, imipramine
was more effective at decreasing anxiety symptoms starting at two weeks. Other
studies have found that imipramine at a dose of 90–135 mg has efficacy for
GAD similar to that of benzodiazepines.5 However, given the many side effects
of TCAs—including anticholinergic effects (e.g., urinary retention), alpha-
adrenergic blockade (e.g., postural hypotension), seizures, cardiac conduction
delay, other cardiac-related problems, and fatality risk with overdose—TCAs are
still not particularly favored even at this node. If other alternative options are
viable and have not been tried, then the recommendation is to try those first.5 , 88 ,
100
Among the first-generation antipsychotics, trifluoperazine was found effective
for “anxiety neurosis” decades ago. The lack of studies with more modern
definitions of GAD, coupled with the risk of tardive dyskinesia, precludes
considering first-generation antipsychotics even at this point in the algorithm. 130
Node 5B: Did You Try an SNRI and Get a Partial Response?
Consider Augmentations
As in Nodes 3B and 4B, it is reasonable to consider augmenting what appears to
be a partial but real response to the chosen Node 5 treatment. To the list of
previous augmentation options, one could add SGAs at this point: the patient is
quite treatment resistant now, having had three trials. Quetiapine, though side-
effect prone, may be acceptable. A small study in 2011 investigated 24 GAD
outpatient adults who had failed at least one eight-week treatment trial of an
SSRI (citalopram) or an SNRI (venlafaxine) for their GAD. 131 These patients
received quetiapine XR to augment their antidepressant for 12 weeks. Primary
outcome measures were CGI-S and HAM-A scores. At 4 weeks, there was a
significant and rapid decrease of their anxiety symptoms as measured by CGI-S
and HAM-A scores, with improvements maintained at week 12. In this study
there were no significant weight changes after 12 weeks.
A small (n = 18) augmentation trial with ziprasidone or placebo over eight
weeks in treatment-resistant GAD patients on SSRIs or other medications,
including benzodiazepines, found no efficacy and many more side effects than
when ziprasidone was used as a monotherapy (60% vs. 28%).127
Risperidone was studied in an RCT with placebo control in 40 treatment-
resistant patients with primarily GAD.109 While staying on their previous
medications, they were given risperidone 0.5–1.5 mg daily or placebo for five
weeks. Patients in the risperidone group showed greater improvements on the
HAM-A and other anxiety scales at endpoint. Risperidone was also generally
well tolerated, with the most common complaint being somnolence, followed by
dizziness and blurred vision. In an open-label trial, a few patients seemed to
respond to risperidone at a dose of 0.25 to 3 mg daily. 132
Aripiprazole has been used with promising results in two small, open-label 6–
8 week trials as an augmenting agent at doses near 10 mg daily.
5 , 133 , 134
Pollack and colleagues5 , 111 examined olanzapine as an augmentation for
fluoxetine in treatment-refractory GAD in a placebo-controlled RCT involving
46 patients. After six weeks (mean dose = 8.7 ± 7.1 mg daily), there were no
statistically significant differences from placebo on the HAM-A, but remission
rates (HAM-A of 7 or less) were higher on olanzapine. The mean weight gain
for those on olanzapine augmentation was greater (11.0 ± 5.1 lb vs. -0.7±2.4 lb
on placebo; p < .001).
Should SGA augmentation be considered, it would be important to monitor
for weight gain, body mass index, fasting glucose, hemoglobin A1C, and
triglycerides.18
A final option for a treatment-resistant male patient with GAD would be
valproate, which has one small RCT demonstrating efficacy.54 Side effects might
include weight gain and elevated liver enzymes.
COMPARISON TO THE RECOMMENDATIONS
IN OTHER ALGORITHMS AND GUIDELINES
The present algorithm for selecting psychopharmacology treatment for GAD
summarizes and organizes the available evidence for effectiveness and safety of
the available medications in a sequence of steps from first treatment to very
treatment-resistant cases. It differs in some respects from other published
algorithms and guidelines. Its proposal of SSRIs as first-line treatment is in
agreement with a 2010 international consensus algorithm10 but differs from
another by Linden and colleagues in 2013 135 that recommends pregabalin first-
line, followed by hydroxyzine and then venlafaxine. The present algorithm
suggests pregabalin as an alternate agent for first-line use. The authors of this
algorithm found reasons to think about bupropion as an option for first-line use,
whereas others did not. This algorithm positions venlafaxine lower than on other
algorithms due to side effects, but agrees with having duloxetine as a first-line
option. The British National Institute for Health and Clinical Excellence
guideline for GAD (2011) is more similar to this algorithm in that it
recommends an SSRI first, then another SSRI or SNRI, and then pregabalin (not
FDA approved for GAD); benzodiazepines are not recommended except for
short-term use, and SGAs should not be offered, at least in 136 primary care.
The latest (2014) revision of guidelines for treatment of GAD from the British
Association for Psychopharmacology (BAP)95 suggests considering SSRIs for
first-line and SNRIs and pregabalin, especially in higher doses, as alternatives.
The present algorithm adds buspirone, hydroxyzine, and bupropion as other
possible, though less favored, options because their side-effect profiles may be
more acceptable for some patients even if their efficacy is much less well
established. The present algorithm places venlafaxine lower in the options than
the BAP guideline because of its greater risk of hypertension, gastrointestinal
side effects, and discontinuation symptoms after abrupt withdrawal. Also, some
treatments recommended by the BAP because of their evidence base—such as
tricyclics and atypical antipsychotics—are placed low in priority in the present
algorithm because of their side effects. In this algorithm, gabapentin—despite
the lack of evidence for its efficacy—is mentioned as a possible option to be
considered when pregabalin, due to formulary restrictions, is not allowed.95
FINAL COMMENT
Results in the few studies of evidence-based, algorithm-guided
psychopharmacology care have modestly favored the algorithms compared to
treatment-as-usual. 137 Clinicians in the control groups often selected treatments
that were fairly similar to those selected by algorithm consulters. Better results
with algorithms have occurred when considerable time is spent educating users
in the accurate use of the algorithms and educating patients about the reasoning
involved, since they may have their own opinions about what is best for them.137
In other branches of medicine, promoting the use of evidence-supported
treatment algorithms has produced impressive economic results. 138
This heuristic may serve clinicians as an anchor to the evidence base for the
psychopharmacology treatment of GAD. It should be kept in mind, however,
that medication has an important, but fairly modest, role in altering the course of
the lives of people with this disorder. At any point, psychosocial interventions
may take precedence over, or at least add to, the options discussed here.
Practitioners should be alert to new evidence and new research that may improve
outcomes and alter the recommendations provided here. Clinical experience
remains an important consideration in managing patients with GAD: such
experience can contradict, support, or add to what is derived from the scientific
evidence. Consideration of the evidence base is viewed as necessary, but by no
means sufficient, for clinical decision making.
Declaration of interest: The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of the article.
REFERENCES
1. Lakhan SE, Vieira KF. Nutritional and herbal supplements for anxiety and anxiety-related disorders:
systematic review. Nutr J 2010;9:42.
2. Reinhold JA, Mandos LA, Rickels K, Lohoff FW. Pharmacological treatment of generalized anxiety
disorder. Expert Opin Pharmacother 2011;12:2457–67.
3. Baldwin DS, Waldman S, Allgulander C. Evidence-based pharmacological treatment of generalized
anxiety disorder. Int J Neuropsychopharmacol 2011;14:697–710.
4. Stein DJ, Lerer B, Stahl SM. Essential evidence-based psychopharmacology. 2nd ed. Cambridge, New
York: Cambridge University Press, 2012.
5. Huh J, Goebert D, Takeshita J, Lu BY, Kang M. Treatment of generalized anxiety disorder: a
comprehensive review of the literature for psychopharmacologic alternatives to newer antidepressants
and benzodiazepines. Prim Care Companion CNS Disord 2011;13(2).
6. Bereza BG, Machado M, Einarson TR. Systematic review and quality assessment of economic
evaluations and quality-of-life studies related to generalized anxiety disorder. Clin Ther 2009;31:1279–
308.
8. Wittchen HU, Hoyer J. Generalized anxiety disorder: nature and course. J Clin Psychiatry 2001;62
suppl 11:15–9 discussion 20–1.
9. Osser DN, Renner JA Jr, Bayog R. Algorithms for the pharmacotherapy of anxiety disorders in patients
with chemical abuse and dependence. Psychiatr Ann 1999;29:285–300.
10. Davidson JR, Zhang W, Connor KM, et al. A psychopharmacological treatment algorithm for
generalised anxiety disorder (GAD). J Psychopharmacol 2010;24:3–26.
11. Bandelow B, Seidler-Brandler U, Becker A, Wedekind D, Ruther E. Meta-analysis of randomized
controlled comparisons of psychopharmacological and psychological treatments for anxiety
disorders. World J Biol Psychiatry 2007;8:175–87.
12. Kessler RC, Keller MB, Wittchen HU. The epidemiology of generalized anxiety disorder. Psychiatr
Clin North Am 2001;24:19–39.
13. Sarris J, Kavanagh DJ. Kava and St. John’s Wort: current evidence for use in mood and anxiety
disorders. J Altern Complement Med 2009;15:827–36.
14. Sarris J, Stough C, Bousman CA, et al. Kava in the treatment of generalized anxiety disorder: a
double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol 2013;33:643–8.
15. Bystritsky A, Kerwin L, Feusner JD. A pilot study of Rhodiola rosea (Rhodax) for generalized
anxiety disorder (GAD). J Altern Complement Med 2008;14:175–80.
16. Amsterdam JD, Li Y, Soeller I, Rockwell K, Mao JJ, Shults J. A randomized, double-blind, placebo-
controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalized anxiety
disorder. J Clin Psychopharmacol 2009;29: 378–82.
disorder. J Clin Psychopharmacol 2009;29: 378–82.
17. Stein DJ, Ahokas AA, de Bodinat C. Efficacy of agomelatine in generalized anxiety disorder: a
randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol 2008;28:561–6.
18. Khan A, Joyce M, Atkinson S, Eggens I, Baldytcheva I, Eriksson H. A randomized, double-blind
study of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients
with generalized anxiety disorder. J Clin Psychopharmacol 2011;31:418–28.
19. Bajor LA, Ticlea AN, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South
Shore Program: an update on posttraumatic stress disorder. Harv Rev Psychiatry 2011;19:240–58.
20. Hamoda HM, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: an update on psychotic depression. Harv Rev Psychiatry 2008;16:235–47.
21. Ansari A, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: an update on bipolar depression. Harv Rev Psychiatry 2010;18:36–55.
22. Osser DN, Roudsari MJ, Manschreck T. The Psychopharmacology Algorithm Project at the Harvard
South Shore Program: an update on schizophrenia. Harv Rev Psychiatry 2013;21:18–40.
23. Mohammad OM, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: an algorithm for acute mania. Harv Rev Psychiatry 2014;22:274–94 .
24. Osser DN, Dunlop LR. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program. Psychopharm Rev 2010;45:91–8.
25. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed.
Arlington, VA: APA, 2013.
26. Brown TA, Barlow DH, Liebowitz MR. The empirical basis of generalized anxiety disorder. Am J
Psychiatry 1994;151:1272–80.
27. Goldberg D, Kindler KS, Sirovatka PJ, Regier DA, eds. Diagnostic issues in depression and
generalized anxiety disorder. Arlington, VA: American Psychiatric Publishing, 2010.
28. Allgulander C, Dahl AA, Austin C, et al. Efficacy of sertraline in a 12-week trial for generalized
anxiety disorder. Am J Psychiatry 2004;161:1642–9.
29. Holsboer-Trachsler E, Prieto R. Effects of pregabalin on sleep in generalized anxiety disorder. Int J
Neuropsychopharmacol 2013;16:925–36.
30. Kaynak H, Kaynak D, Gozukirmizi E, Guilleminault C. The effects of trazodone on sleep in patients
treated with stimulant antidepressants. Sleep Med 2004;5:15–20.
31. Nierenberg AA, Adler LA, Peselow E, Zornberg G, Rosenthal M. Trazodone for antidepressant-
associated insomnia. Am J Psychiatry 1994;151:1069–72.
32. Pollack M, Kinrys G, Krystal A, et al. Eszopiclone coadministered with escitalopram in patients with
insomnia and comorbid generalized anxiety disorder. Arch Gen Psychiatry 2008;65:551–62.
33. Walsh JK, Krystal AD, Amato DA, et al. Nightly treatment of primary insomnia with eszopiclone for
six months: effect on sleep, quality of life, and work limitations. Sleep 2007;30:959–68.
34. Schuurmans J, Comijs H, Emmelkamp PM, et al. A randomized, controlled trial of the effectiveness
of cognitive-behavioral therapy and sertraline versus a waitlist control group for anxiety disorders in
older adults. Am J Geriatr Psychiatry 2006;14: 255–63.
35. Lenze EJ, Rollman BL, Shear MK, et al. Escitalopram for older adults with generalized anxiety
disorder: a randomized controlled trial. JAMA 2009;301:295–303.
Mokhber N, Azarpazhooh MR, Khajehdaluee M, Velayati A, Hopwood M. Randomized, single-
36. Mokhber N, Azarpazhooh MR, Khajehdaluee M, Velayati A, Hopwood M. Randomized, single-
blind, trial of sertraline and buspirone for treatment of elderly patients with generalized anxiety
disorder. Psychiatry Clin Neurosci 2010;64: 128–33.
37. Katz IR, Reynolds CF 3rd, Alexopoulos GS, Hackett D. Venlafaxine ER as a treatment for
generalized anxiety disorder in older adults: pooled analysis of five randomized placebo-controlled
clinical trials. J Am Geriatr Soc 2002;50:18–25.
38. Johnson EM, Whyte E, Mulsant BH, et al. Cardiovascular changes associated with venlafaxine in the
treatment of late-life depression. Am J Geriatr Psychiatry 2006;14:796–802.
39. Montgomery S, Chatamra K, Pauer L, Whalen E, Baldinetti F. Efficacy and safety of pregabalin in
elderly people with generalised anxiety disorder. Br J Psychiatry 2008;193:389–94.
40. Benitez CI, Smith K, Vasile RG, Rende R, Edelen MO, Keller MB. Use of benzodiazepines and
selective serotonin reuptake inhibitors in middle-aged and older adults with anxiety disorders: a
longitudinal and prospective study. Am J Geriatr Psychiatry 2008;16:5–13.
41. Hasnain M, Vieweg WV, Howland RH, et al. Quetiapine, QTc interval prolongation, and torsade de
pointes: a review of case reports. Ther Adv Psychopharmacol 2014;4:130–8.
42. Wettermark B, Brandt L, Kieler H, Boden R. Pregabalin is increasingly prescribed for neuropathic
pain, generalised anxiety disorder and epilepsy but many patients discontinue treatment. Int J Clin
Pract 2014;68:104–10.
43. Wikner BN, Kallen B. Are hypnotic benzodiazepine receptor agonists teratogenic in humans? J Clin
Psychopharmacol 2011;31:356–9.
44. Suri R, Altshuler L, Hellemann G, Burt VK, Aquino A, Mintz J. Effects of antenatal depression and
antidepressant treatment on gestational age at birth and risk of preterm birth. Am J Psychiatry
2007;164:1206–13.
45. Palmsten K, Hernandez-Diaz S, Huybrechts KF, et al. Use of antidepressants near delivery and risk
of postpartum hemorrhage: cohort study of low income women in the United States. BMJ
2013;347:f4877 .
46. Kessler RC, Nelson CB, McGonagle KA, Edlund MJ, Frank RG, Leaf PJ. The epidemiology of co-
occurring addictive and mental disorders: implications for prevention and service utilization. Am J
Orthopsychiatry 1996;66:17–31.
47. Salzman C. Benzodiazepine dependence, toxicity, and abuse: a task force report of the American
Psychiatric Association. Washington, DC: American Psychiatric Association, 1990.
48. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious
versus nonanxious depression: a STAR*D report. Am J Psychiatry 2008;165:342–51.
49. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania
in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and
bupropion as adjuncts to mood stabilizers. Am J Psychiatry 2006;163:232–9.
50. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders
(ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry 2013;170:1249–
62.
51. Ketter TA, Wang PW, Miller S. Bipolar therapeutics update 2014: a tale of 3 treatments. J Clin
Psychiatry 2015;76: 69–70.
52. Gao K, Wu R, Kemp DE, et al. Efficacy and safety of quetiapine-XR as monotherapy or adjunctive
therapy to a mood stabilizer in acute bipolar depression with generalized anxiety disorder and other
therapy to a mood stabilizer in acute bipolar depression with generalized anxiety disorder and other
comorbidities: a randomized, placebo-controlled trial. J Clin Psychiatry 2014;75:1062–8.
53. Keck PE Jr, Strawn JR, McElroy SL. Pharmacologic treatment considerations in co-occurring bipolar
and anxiety disorders. J Clin Psychiatry 2006;67 suppl 1:8–15.
54. Aliyev NA, Aliyev ZN. Valproate (depakine-chrono) in the acute treatment of outpatients with
generalized anxiety disorder without psychiatric comorbidity: randomized, doubleblind placebo-
controlled study. Eur Psychiatry 2008;23: 109–14.
55. Bandelow B, Chouinard G, Bobes J, et al. Extended-release quetiapine fumarate (quetiapine XR): a
once-daily monotherapy effective in generalized anxiety disorder. Data from a randomized, double-
blind, placebo- and active-controlled study. Int J Neuropsychopharmacol 2010;13:305–20.
56. Jentink J, Loane MA, Dolk H, et al. Valproic acid monotherapy in pregnancy and major congenital
malformations. N Engl J Med 2010;362:2185 – 93.
57. Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with
nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry
2013;170:1003–10.
58. Van Ameringen M, Mancini C, Patterson B, Simpson W, Truong C. Pharmacotherapy for
generalized anxiety disorder. In: Stein DJ, Hollander E, Rothbaum BO, eds. Textbook of anxiety
disorders. Washington, DC: American Psychiatric Publishing, 2010;193–218.
59. U.S. Food and Drug Administration. FDA drug safety communication: revised recommendations for
Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high
doses. 2012. http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm
60. Bird ST, Crentsil V, Temple R, Pinheiro S, Demczar D, Stone M. Cardiac safety concerns remain for
citalopram at dosages above 40 mg/day. Am J Psychiatry 2014;171:17–9.
61. Zivin K, Pfeiffer PN, Bohnert AS, et al. Safety of high-dosage citalopram. Am J Psychiatry
2014;171:20–2.
62. Fava M, Judge R, Hoog SL, Nilsson ME, Koke SC. Fluoxetine versus sertraline and paroxetine in
major depressive disorder: changes in weight with long-term treatment. J Clin Psychiatry
2000;61:863–7.
63. Preskorn SH. Outpatient management of depression: a guide for the practitioner. 2nd ed. Professional
Communications: Caddo, OK, 1999.
64. Maina G, Albert U, Salvi V, Bogetto F. Weight gain during long-term treatment of obsessive-
compulsive disorder: a prospective comparison between serotonin reuptake inhibitors. J Clin
Psychiatry 2004;65:1365–71.
65. Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants: a meta-
analysis. J Clin Psychopharmacol 2009;29:259–66.
66. Reefhuis J, Devine O, Friedman JM, Louik C, Honein M. Specific SSRIs and birth defects: Bayesian
analysis to interpret new data in the context of previous reports. BMJ 2015;351:h3190 .
67. Hidalgo RB, Tupler LA, Davidson JR. An effect-size analysis of pharmacologic treatments for
generalized anxiety disorder. J Psychopharmacol 2007;21:864–72.
68. Baldwin DS, Huusom AK, Maehlum E. Escitalopram and paroxetine in the treatment of generalised
anxiety disorder: randomised, placebo-controlled, double-blind study. Br J Psychiatry 2006;189:264–
72.
69. Beekman AT, Bremmer MA, Deeg DJ, et al. Anxiety disorders in later life: a report from the
Longitudinal Aging Study Amsterdam. Int J Geriatr Psychiatry 1998;13:717–26.
http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm
Longitudinal Aging Study Amsterdam. Int J Geriatr Psychiatry 1998;13:717–26.
70. Baldwin D, Woods R, Lawson R, Taylor D. Efficacy of drug treatments for generalised anxiety
disorder: systematic review and meta-analysis. BMJ 2011;342:d1199.
71. Baldwin DS, Stein DJ, Dolberg OT, Bandelow B. How long should a trial of escitalopram treatment
be in patients with major depressive disorder, generalised anxiety disorder or social anxiety disorder?
An exploration of the randomised controlled trial database. Hum Psychopharmacol 2009; 24:269–75.
72. Cascade E, Kalali AH, Kennedy SH. Real-world data on SSRI antidepressant side effects. Psychiatry
(Edgmont) 2009;6: 16–8.
73. de Abajo FJ, Garcia-Rodriguez LA. Risk of upper gastrointestinal tract bleeding associated with
selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-
inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry 2008;65:795–803.
74. Wang YP, Chen YT, Tsai CF, et al. Short-term use of serotonin reuptake inhibitors and risk of upper
gastrointestinal bleeding. Am J Psychiatry 2014;171:54–61.
75. Richards JB, Papaioannou A, Adachi JD, et al. Effect of selective serotonin reuptake inhibitors on the
risk of fracture. Arch Intern Med 2007;167:188–94.
76. Stone M, Laughren T, Jones ML, et al. Risk of suicidality in clinical trials of antidepressants in
adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ
2009;339:b2880.
77. Pelissolo A. [Efficacy and tolerability of escitalopram in anxiety disorders: a review]. Encephale
2008;34:400–8.
78. Whiskey E, Taylor D. A review of the adverse effects and safety of noradrenergic antidepressants. J
Psychopharmacol 2013; 27:732–9.
79. Delgado PL, Brannan SK, Mallinckrodt CH, et al. Sexual functioning assessed in 4 double-blind
placebo- and paroxetine-controlled trials of duloxetine for major depressive disorder. J Clin
Psychiatry 2005;66:686–92.
80. De Berardis D, Serroni N, Carano A, et al. The role of duloxetine in the treatment of anxiety
disorders. Neuropsychiatr Dis Treat 2008;4:929–35.
81. Stahl SM, Ahmed S, Haudiquet V. Analysis of the rate of improvement of specific psychic and
somatic symptoms of general anxiety disorder during long-term treatment with venlafaxine ER. CNS
Spectr 2007;12:703–11.
82. Rickels K, Etemad B, Khalid-Khan S, Lohoff FW, Rynn MA, Gallop RJ. Time to relapse after 6 and
12 months’ treatment of generalized anxiety disorder with venlafaxine extended release. Arch Gen
Psychiatry 2010;67:1274–81.
83. Hoffman EJ, Mathew SJ. Anxiety disorders: a comprehensive review of pharmacotherapies. Mt Sinai
J Med 2008;75: 248–62.
84. Carter NJ, McCormack PL. Duloxetine: a review of its use in the treatment of generalized anxiety
disorder. CNS Drugs 2009;23:523–41.
85. Spielmans GI. Duloxetine does not relieve painful physical symptoms in depression: a meta-analysis.
Psychother Psychosom 2008;77:12–6.
86. Gammans RE, Stringfellow JC, Hvizdos AJ, et al. Use of buspirone in patients with generalized
anxiety disorder and coexisting depressive symptoms. A meta-analysis of eight randomized,
controlled studies. Neuropsychobiology 1992;25: 193–201.
87. Kranzler HR, Burleson JA, Del Boca FK, et al. Buspirone treatment of anxious alcoholics. A
placebo-controlled trial. Arch Gen Psychiatry 1994;51:720–31.
88. Bandelow B, Boerner JR, Kasper S, Linden M, Wittchen HU, Moller HJ. The diagnosis and
treatment of generalized anxiety disorder. Dtsch Arztebl Int 2013;110:300–9 .
89. Davidson JR, DuPont RL, Hedges D, Haskins JT. Efficacy, safety, and tolerability of venlafaxine
extended release and buspirone in outpatients with generalized anxiety disorder. J Clin Psychiatry
1999;60:528–35.
90. Darcis T, Ferreri M, Natens J. A multicenter, double-blind placebo-controlled study investigating the
anxiolytic efficacy of hydroxyzine in patients with generalized anxiety. Hum Psychopharmacol
1995;10:181–7.
91. Lader M, Scotto JC. A multicentre double-blind comparison of hydroxyzine, buspirone and placebo
in patients with generalized anxiety disorder. Psychopharmacology (Berl) 1998;139: 402–6.
92. Llorca PM, Spadone C, Sol O, et al. Efficacy and safety of hydroxyzine in the treatment of
generalized anxiety disorder: a 3-month double-blind study. J Clin Psychiatry 2002; 63:1020–7.
93. Dowben JS, Grant JS, Froelich KD, Keltner NL. Biological perspectives: hydroxyzine for anxiety:
another look at an old drug. Perspect Psychiatr Care 2013;49:75–7.
94. Guaiana G, Barbui C, Cipriani A. Hydroxyzine for generalised anxiety disorder. Cochrane Database
Syst Rev 2010;12: CD006815.
95. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based pharmacological treatment of anxiety
disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005
guidelines from the British Association for Psychopharmacology. J Psychopharmacol 2014;28:403–
39.
96. Bech P. Dose-response relationship of pregabalin in patients with generalized anxiety disorder. A
pooled analysis of four placebo-controlled trials. Pharmacopsychiatry 2007; 40:163–8.
97. Lydiard RB, Rickels K, Herman B, Feltner DE. Comparative efficacy of pregabalin and
benzodiazepines in treating the psychic and somatic symptoms of generalized anxiety disorder. Int J
Neuropsychopharmacol 2010;13:229–41.
98. Wensel TM, Powe KW, Cates ME. Pregabalin for the treatment of generalized anxiety disorder. Ann
Pharmacother 2012;46: 424–9.
99. Clarke H, Kirkham KR, Orser BA, et al. Gabapentin reduces preoperative anxiety and pain
catastrophizing in highly anxious patients prior to major surgery: a blinded randomized placebo-
controlled trial. Can J Anaesth 2013;60:432–43.
100. Ravindran LN, Stein MB. The pharmacologic treatment of anxiety disorders: a review of progress.
J Clin Psychiatry 2010;71:839–54.
101. Schifano F, D’Offizi S, Piccione M, et al. Is there a recreational misuse potential for pregabalin?
Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data.
Psychother Psychosom 2011;80:118–22.
102. Zimmerman M, Posternak MA, Attiullah N, et al. Why isn’t bupropion the most frequently
prescribed antidepressant? J Clin Psychiatry 2005;66:603–10.
103. Bystritsky A, Kerwin L, Feusner JD, Vapnik T. A pilot controlled trial of bupropion XL versus
escitalopram in generalized anxiety disorder. Psychopharmacol Bull 2008;41:46–51.
104. Trivedi MH, Rush AJ, Carmody TJ, et al. Do bupropion SR and sertraline differ in their effects on
anxiety in depressed patients? J Clin Psychiatry 2001;62:776–81.
anxiety in depressed patients? J Clin Psychiatry 2001;62:776–81.
105. Dunner DL, Zisook S, Billow AA, Batey SR, Johnston JA, Ascher JA. A prospective safety
surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry
1998;59:366–73.
106. Altamura AC, Serati M, Buoli M, Dell’Osso B. Augmentative quetiapine in partial/nonresponders
with generalized anxiety disorder: a randomized, placebo-controlled study. Int Clin
Psychopharmacol 2011;26:201–5.
107. Khan A, Atkinson S, Mezhebovsky I, She F, Leathers T, Pathak S. Extended-release quetiapine
fumarate (quetiapine XR) as adjunctive therapy in patients with generalized anxiety disorder and a
history of inadequate treatment response: a randomized, double-blind study. Ann Clin Psychiatry
2013;25: E7–22.
108. Simon NM, Connor KM, LeBeau RT, et al. Quetiapine augmentation of paroxetine CR for the
treatment of refractory generalized anxiety disorder: preliminary findings. Psychopharmacology
(Berl) 2008;197:675–81 .
109. Brawman-Mintzer O, Knapp RG, Nietert PJ. Adjunctive risperidone in generalized anxiety
disorder: a double-blind, placebo-controlled study. J Clin Psychiatry 2005;66:1321–5.
110. Pandina GJ, Canuso CM, Turkoz I, Kujawa M, Mahmoud RA. Adjunctive risperidone in the
treatment of generalized anxiety disorder: a double-blind, prospective, placebo-controlled,
randomized trial. Psychopharmacol Bull 2007;40:41–57.
111. Pollack MH, Simon NM, Zalta AK, et al. Olanzapine augmentation of fluoxetine for refractory
generalized anxiety disorder: a placebo controlled study. Biol Psychiatry 2006;59:211–5.
112. Hahn MK, Wolever TM, Arenovich T, et al. Acute effects of single-dose olanzapine on metabolic,
endocrine, and inflammatory markers in healthy controls. J Clin Psychopharmacol 2013;33:740–6.
113. Ngai YF, Sabatini P, Nguyen D, et al. Quetiapine treatment in youth is associated with decreased
insulin secretion. J Clin Psychopharmacol 2014;34:359–64.
114. Rickels K, Shiovitz TM, Ramey TS, Weaver JJ, Knapp LE, Miceli JJ. Adjunctive therapy with
pregabalin in generalized anxiety disorder patients with partial response to SSRI or SNRI
treatment. Int Clin Psychopharmacol 2012;27:142–50.
115. Pollack MH, Van Ameringen M, Simon NM, et al. A doubleblind randomized controlled trial of
augmentation and switch strategies for refractory social anxiety disorder. Am J Psychiatry
2014;171:44–53.
116. Rickels K, Pollack MH, Feltner DE, et al. Pregabalin for treatment of generalized anxiety disorder:
a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Arch
Gen Psychiatry 2005;62:1022–30.
117. Rickels K, Pollack MH, Sheehan DV, Haskins JT. Efficacy of extended-release venlafaxine in
nondepressed outpatients with generalized anxiety disorder. Am J Psychiatry 2000;157:968–74.
118. Bose A, Korotzer A, Gommoll C, Li D. Randomized placebo-controlled trial of escitalopram and
venlafaxine XR in the treatment of generalized anxiety disorder. Depress Anxiety 2008;25:854–61.
119. Taylor D, Sparshatt A, Varma S, Olofinjana O. Antidepressant efficacy of agomelatine: meta-
analysis of published and unpublished studies. BMJ 2014;348:g1888.
120. Stein DJ, Ahokas A, Marquez MS, et al. Agomelatine in generalized anxiety disorder: an active
comparator and placebo-controlled study. J Clin Psychiatry 2014;75:362–8.
Stein DJ, Ahokas A, Albarran C, Olivier V, Allgulander C. Agomelatine prevents relapse in
121. Stein DJ, Ahokas A, Albarran C, Olivier V, Allgulander C. Agomelatine prevents relapse in
generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled
discontinuation study. J Clin Psychiatry 2012;73:1002–8.
122. Russmann S, Lauterburg BH, Helbling A. Kava hepatotoxicity. Ann Intern Med 2001;135:68–9.
123. Mathew SJ, Amiel JM, Coplan JD, Fitterling HA, Sackeim HA, Gorman JM. Open-label trial of
riluzole in generalized anxiety disorder. Am J Psychiatry 2005;162:2379–81.
124. Kasper S, Gastpar M, Muller WE, et al. Lavender oil preparation Silexan is effective in generalized
anxiety disorder—a randomized, double-blind comparison to placebo and paroxetine. Int J
Neuropsychopharmacol 2014;17:859–69.
125. Katzman MA, Brawman-Mintzer O, Reyes EB, Olausson B, Liu S, Eriksson H. Extended release
quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized
anxiety disorder: a long-term, randomized, placebo-controlled trial. Int Clin Psychopharmacol
2011;26:11–24.
126. Merideth C, Cutler AJ, She F, Eriksson H. Efficacy and tolerability of extended release quetiapine
fumarate monotherapy in the acute treatment of generalized anxiety disorder: a randomized,
placebo controlled and active-controlled study. Int Clin Psychopharmacol 2012;27:40–54.
127. Lohoff FW, Etemad B, Mandos LA, Gallop R, Rickels K. Ziprasidone treatment of refractory
generalized anxiety disorder: a placebo-controlled, double-blind study. J Clin Psychopharmacol
2010;30:185–9.
128. Snyderman SH, Rynn MA, Rickels K. Open-label pilot study of ziprasidone for refractory
generalized anxiety disorder. J Clin Psychopharmacol 2005;25:497–9.
129. Suppes T, McElroy SL, Sheehan DV, et al. A randomized, double-blind, placebo-controlled study
of ziprasidone monotherapy in bipolar disorder with co-occurring lifetime panic or generalized
anxiety disorder. J Clin Psychiatry 2014;75:77–84 .
130. Gao K, Muzina D, Gajwani P, Calabrese JR. Efficacy of typical and atypical antipsychotics for
primary and comorbid anxiety symptoms or disorders: a review. J Clin Psychiatry 2006;67:1327–
40.
131. Gabriel A. The extended-release formulation of quetiapine fumarate (quetiapine XR) adjunctive
treatment in partially responsive generalized anxiety disorder (GAD): an open label naturalistic
study. Clin Ter 2011;162:113–8.
132. Simon NM, Hoge EA, Fischmann D, et al. An open-label trial of risperidone augmentation for
refractory anxiety disorders. J Clin Psychiatry 2006;67:381–5.
133. Menza MA, Dobkin RD, Marin H. An open-label trial of aripiprazole augmentation for treatment-
resistant generalized anxiety disorder. J Clin Psychopharmacol 2007;27:207–10.
134. Hoge EA, Worthington JJ 3rd, Kaufman RE, Delong HR, Pollack MH, Simon NM. Aripiprazole as
augmentation treatment of refractory generalized anxiety disorder and panic disorder. CNS Spectr
2008;13:522–7.
135. Linden M, Bandelow B, Boerner RJ, et al. The best next drug in the course of generalized anxiety
disorders: the “PN-GAD-algorithm.” Int J Psychiatry Clin Pract 2013;17:78–89.
136. National Institute for Health and Clinical Excellence. Generalized anxiety disorder and panic
disorder (with or without agoraphobia) in adults: management in primary, secondary and
community care. NICE clinical guideline 113. London: Gaskell and British Psychological Society,
2011.
137. Osser DN, Patterson RD. On the value of evidence-based psychopharmacology algorithms. Bull
Clin Psychopharmacol 2013;23:1–5.
138. Mullaney TJ. Doctors wielding data. Bus Week 2005;94:98.
n the last four years since the publication of this algorithm, the
recommendations and flowchart for the psychopharmacology of
generalized anxiety disorder (GAD) remain almost the same. There have
been no new studies that change the overall sequences of the nodes.
However, there have been important studies adding support to what was
proposed in the 2016 algorithm. One new treatment that has received study
is repetitive transcranial magnetic stimulation (rTMS).
Node 2: Comorbidity and Special Patient Populations That
Might Alter the Core Algorithm
In the discussion of medications to avoid in women of childbearing
potential in Table 1 , paroxetine is noted to have a D rating because of atrial
septal defects. A newer large observational study confirmed that paroxetine
does indeed have a high incidence of this fetal abnormality. 1 Contrary to
previous data, though, the incidence with fluoxetine was almost as high as
with paroxetine. Also, in this table, comorbidity with bipolar is considered
and antidepressants are to be avoided in favor of some of the
nonantidepressant options in the algorithm. A new meta-analysis of six
studies in which an antidepressant was added to a mood stabilizer in bipolar
patients confirmed that there is increased risk of mood stabilization to
(hypo)mania if the antidepressant is continued over the long term (e.g., one
year). 2 Finally, in the same table, there is discussion of management of
comorbid posttraumatic stress disorder (PTSD) with GAD. Prazosin was
recommended on the basis of four small placebo-controlled studies with
large effect sizes in favor of prazosin. Since then, a large important
multicenter trial published in 2018 found no efficacy for prazosin. 3 The
evidence on prazosin is discussed in detail in the chapter on the PTSD
algorithm. It is concluded that this (and perhaps similar products like
doxazosin) is still first-line for PTSD patients with significant sleep
problems including nightmares and disturbed awakenings, even though it is
clear that it does not work for everyone. More research is needed to help
define which patients are the best candidates for prazosin. 4
Node 3a: Alternatives to an SSRI as the First-Line Choice for
GAD
The first alternative discussed was duloxetine, which is FDA-approved for
GAD and has comparable efficacy though somewhat different side effects.
The advantages and disadvantages were discussed. It was mentioned that
duloxetine is FDA-approved for a number of painful conditions which
could be seen as an advantage, though a meta-analysis by Spielmans in
2008 of the effect on pain concluded that the effect size was too small to be
clinically significant. 5 The author concluded that the effect on pain was not
evidence-supported and that duloxetine was not likely to be useful for pain
in the context of treating depression (and presumably, for treating GAD
with comorbid pain as well). There is a new, much more comprehensive
meta-analysis of the effect of various antidepressants on pain as an outcome
measure, confirming the previous review. 6 All antidepressants had only
small independent effects on pain and the effect size of duloxetine was right
in the middle of the group of antidepressants studied.
Another alternative discussed was hydroxyzine, which has several
controlled studies finding efficacy in GAD. In the discussion of advantages
and disadvantages, there is a new concern about QT prolongation with this
product. The Pharmacovigilance Risk Assessment Committee of the
European Medicines Agency (comparable to the US Food and Drug
Administration) of the European Union performed a detailed review and
concluded that there are small but significant risks of QT prolongation and
torsade de pointes with hydroxyzine. 7 They recommended that the total
dose be limited to 100 mg daily (50 mg in the elderly when use cannot be
avoided in this population). Risk factors for torsades include bradycardia,
low potassium, and taking other medications that prolong QTc.
Node 4a: Alternatives to the First-Choice Option for the
Second Medication Trial for GAD
After failure on the first medication trial, the recommendation is to try a
different SSRI or duloxetine. But as with the first trial, there are several
alternatives that may be considered, and some new ones are added for this
second trial, including benzodiazepines. They were not considered
appropriate for first-line use (despite their efficacy and FDA approval in the
case of alprazolam) because of their many side effects including memory
impairment, excessive sedation, auto accidents, falls (especially in the
elderly), dependence and use disorders, discontinuation syndromes on
withdrawal, respiratory depression (e.g., in patients with sleep apnea), and
because they should be avoided in patients with use disorders with other
substances. Also, in 2017, the FDA issued a new black box warning for
benzodiazepines (e.g., clonazepam and diazepam) indicating that serious
risks could occur in combination with opiates including profound sedation,
respiratory depression, coma, and death. To this list of problems may be
added renewed concerns about long-term memory problems that may not
remit on discontinuation of the medication. Studies have been contradictory
on this matter, but the latest meta-analysis of 50 different studies concluded
that the odds risk over suitable controls of the development of dementia
was about 1.4. 8 This was considered not likely to be an artifact of other
confounding variables, and it seemed to be a reasonable concern. Reduction
of inappropriate benzodiazepine use should be a goal.
Another option for the second trial could be agomelatine, though this is
still not available in the United States. It was initially proposed for U.S.
approval as an antidepressant, but as was noted, it did not do well in the
registration studies and was not approved. However, in addition to the three
studies cited for treatment of GAD, there are now two more. One found
efficacy at doses as low as 10 mg (previous studies were with 25 or 50 mg),
9 and the other compared 25–50 mg of agomelatine with escitalopram 10–
20 mg in a randomized (but not placebo-controlled) trial. 10 The latter found
“noninferior” response (61% with agomelatine and 65% with escitalopram).
Side effects were fewer with agomelatine. For prescribers in countries
where agomelatine is available, it appears to compete favorably with SSRIs
for GAD, and if it was not for cost considerations compared with generic
SSRIs, it could be among the first-line choices.
The last option mentioned previously at this node was lavender oil,
which is marketed in Germany as a treatment for GAD. There are now two
placebo-controlled 10-week trials showing efficacy, and an analysis of
pooled data on 925 subjects examined, for the first time, the dose–response
relationship. 11 The therapeutic range seemed to be 80–160 mg daily. The
extract was well tolerated.
Finally, there is a new option to add at this node—rTMS. There have
been two small sham-controlled trials in patients who have failed one or
more pharmacotherapies. In the first, 25 sessions of high-frequency (20 Hz)
rTMS was applied to the right dorsolateral prefrontal cortex in 15 subjects
and the results compared with 25 sham-treated individuals. 12 Active
treatment was superior, and the results were sustained at two- and four-
week follow-up. In the second trial, 10 sessions of low-frequency (1 Hz)
rTMS was applied to the right parietal lobe in 18 patients and compared
with 18 sham-treated controls. 13 It was effective both for the GAD and for
comorbid insomnia. The optimal parameters for this investigational use of
rTMS have obviously not been established as yet, these studies are small
and the results difficult to generalize to other GAD patients, the procedure
is very costly, and the maintenance requirements are unknown.
We did not include vilazodone as an option. There was an initial positive
study in GAD patients followed by two others which barely found any
difference from placebo. 14 As a result, the manufacturer did not pursue
further efforts to get FDA approval for the product.
REFERENCES
1. Reefhuis J, Devine O, Friedman JM, Louik C, Honein MA. Specific SSRIs and birth defects:
Bayesian analysis to interpret new data in the context of previous reports. BMJ (Clinical
research ed) 2015;351:h3190.
2. McGirr A, Vohringer PA, Ghaemi SN, Lam RW, Yatham LN. Safety and efficacy of adjunctive
second-generation antidepressant therapy with a mood stabiliser or an atypical antipsychotic in
acute bipolar depression: a systematic review and meta-analysis of randomised placebo-
controlled trials. Lancet Psychiatry 2016;3:1138–46.
3. Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in
military veterans. N Engl J Med 2018;378:507–17 .
4. Raskind MA, Peskind ER. Prazosin for post-traumatic stress disorder. N Engl J Med
2018;378:1649–50.
5. Spielmans GI. Duloxetine does not relieve painful physical symptoms in depression: a meta-
analysis. Psychother Psychosom 2008;77:12–6.
6. Gebhardt S, Heinzel-Gutenbrunner M, Konig U. Pain relief in depressive disorders: a meta-
analysis of the effects of antidepressants. J Clin Psychopharmacol 2016;36:658–68.
7. Vigne J, Alexandre J, Fobe F, et al. QT prolongation induced by hydroxyzine: a
pharmacovigilance case report. Eur J Clin Pharmacol 2015;71:379–81.
8. Penninkilampi R, Eslick GD. A systematic review and meta-analysis of the risk of dementia
associated with benzodiazepine use, after controlling for protopathic bias. CNS Drugs
2018;32:485–97.
9. Stein DJ, Khoo JP, Ahokas A, et al. 12-week double-blind randomized multicenter study of
efficacy and safety of agomelatine (25-50mg/day) versus escitalopram (10-20mg/day) in out-
patients with severe generalized anxiety disorder. Eur Neuropsychopharmacol 2018;28:970–9.
Stein DJ, Ahokas A, Jarema M, et al. Efficacy and safety of agomelatine (10 or 25 mg/day) in
10. Stein DJ, Ahokas A, Jarema M, et al. Efficacy and safety of agomelatine (10 or 25 mg/day) in
non-depressed out-patients with generalized anxiety disorder: a 12-week, double-blind,
placebo-controlled study. Eur Neuropsychopharmacol 2017;27:526–37.
11. Kasper S, Moller HJ, Volz HP, Schlafke S, Dienel A. Silexan in generalized anxiety disorder:
investigation of the therapeutic dosage range in a pooled data set. Int Clin Psychopharmacol
2017;32:195–204.
12. Dilkov D, Hawken ER, Kaludiev E, Milev R. Repetitive transcranial magnetic stimulation of
the right dorsal lateral prefrontal cortex in the treatment of generalized anxiety disorder: a
randomized, double-blind sham controlled clinical trial. Prog Neuropsychopharmacol Biol
Psychiatry 2017;78:61–5.
13. Huang Z, Li Y, Bianchi MT, et al. Repetitive transcranial magnetic stimulation of the right
parietal cortex for comorbid generalized anxiety disorder and insomnia: a randomized, double-
blind, sham-controlled pilot study. Brain Stimul 2018;11:1103–9.
14. Zareifopoulos N, Dylja I. Efficacy and tolerability of vilazodone for the acute treatment of
generalized anxiety disorder: a meta-analysis. Asian J Psychiatr 2017;26:115–22.
T
The Psychopharmacology Algorithm Project at the
Harvard South Shore Program: An Update on
Generalized Social Anxiety Disorder
David N. Osser, MD and Lance R. Dunlop, MD
LEARNING OBJECTIVES
After participating in this activity, the psychiatrist should be better able to:
Evaluate the evidence base for the advantages and disadvantages of
the various pharmacotherapies for generalized social anxiety disorder.
Select first-line, second-line, and third-line medication options.
Assess additional choices with less supporting evidence.
here is considerable interest in psychopharmacologic treatment of
generalized social anxiety disorder (SAD). Some claim that the concept of
SAD as a mental disorder is championed, if not invented, by the
pharmaceutical industry and the proposed medication treatments are over-sold. 1
However, these assertions are adequately rebutted. 2 New evidence of
impairment in neuropharmacologic and neuroanatomical systems suggests that
biologic treatments may play an important role in SAD. 3 , 4
In this article, we present an algorithm for the selection of medication
treatments of SAD. This is an update of a previous algorithm from the
Psychopharmacology Algorithm Project at the Harvard South Shore Program
(PAPHSS). 5 It is also influenced by an algorithm for treating SAD in primary
care to which one of the authors (D.N.O.) contributed. 6 Although psychosocial
interventions are of unquestioned importance in the treatment of SAD, this
algorithm is limited to pharmaceutical interventions and may be applied if and
when the prescribing clinician and patient determine that medication is
appropriate. In many patients, the role of medication is to facilitate psychosocial
approaches such as cognitive-behavioral or psychodynamic therapies. 7 , 8
The algorithms developed by the PAPHSS should not be understood as
discounting the importance of clinical experience. Individual experience can
contradict, support, or add to what is derived from the scientific evidence.
Consideration of the evidence base for practice is viewed as necessary but by no
means sufficient for clinical decision making.
The roles of selective serotonin reuptake inhibitors (SSRIs) and serotonin
norepinephrine reuptake inhibitors (SNRIs) in the treatment of SAD
deserve special attention . Recent reviews of the treatment of major depression
and posttraumatic stress disorder with these agents propose that their efficacy
compared with placebo seems less robust than previously assumed. 9 , 10 Further,
the adverse effects of SSRIs and SNRIs affect the risk-benefit analysis of their
usefulness. 11 In the treatment of SAD, SSRIs are prominent in the
recommendations of previous practice guidelines and algorithms. Given the
concerns about these antidepressants for other disorders, is there any basis for
hesitation regarding their role in SAD treatment? This will be a focus of our
review.
METHODS
The method of algorithm development employed by the PAPHSS is described in
previous publications. 12 , 13 These algorithms model the cognitive process of a
psychopharmacology consultation. Each algorithm is structured with a series of
questions that a consultant would ask, in the order they would be asked, to
provide an evidence-supported recommendation. The evidence is provided and
then appraised. In situations where the available data are contradictory,
equivocal, or inadequate, this ambiguity is acknowledged.
We reviewed previous algorithms and conducted a literature search in
PubMed to find all relevant studies published since the last version of the
PAPHSS SAD algorithm. All proposed psychopharmacologic agents for SAD
were entered in Boolean (AND) searches with the key words “social anxiety
disorder.” All resultant studies in English were selected. Other relevant studies
or reviews referenced in those articles were also examined. A total of 1932
studies were located, entered into an Endnote library, and reviewed. The
algorithm was then updated on the basis of this material.
For comparing the effectiveness of various medication treatments of SAD,
this review focuses on results with the Clinical Global Impression of
Improvement Scale (CGI-I), one of the primary outcome measures in almost all
major psychopharmacology studies of SAD. “Improvement” on the CGI-I is
generally defined as a score of 1 or 2 (very much or much improved). Meta-
analysis demonstrates that CGI-I outcomes (eg, effect sizes compared with
placebo) are highly comparable with the outcomes of other frequently used
scales, such as the Liebowitz Social Anxiety Scale (LSAS). 14
We reference the CGI-I improvement percentages from most of the
randomized controlled trials (RCTs) reviewed here and calculated the number
needed to treat (NNT) for improvement in each study. This is the number of
patients who must be treated before one of them improves (ie, CGI of 1 or 2)
because of the active medication rather than from a placebo effect. The NNT is
easily calculated by subtracting the percentage improvement on placebo from the
percentage improvement on active medication, and then taking the reciprocal of
this difference. Because placebo effects are rather large in most SAD studies, 15
comparing NNTs assists with appreciating the relative ability of the various
medications to produce more improvement than placebo.
It should be noted that even when patients with SAD are rated as very much
improved in these studies, the patients are usually not remitted. Thus, strategies
for approaching partial response will also be considered in the algorithm.
COMORBIDITY
Psychopharmacologic studies of SAD treatment typically exclude patients with
common comorbidities such as unipolar and bipolar depression, alcohol and
substance dependence, and other anxiety disorders. If any of these conditions are
present, confidence in the basic algorithm sequence may be reduced.
Regarding comorbid unipolar depression , it is usually assumed that because
SAD and unipolar depression are 2 disorders that respond to antidepressants, one
could expect a good response when they occur together. Recent evidence from
the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study
and other data, however, suggest that major depression comorbid with anxiety
responds poorly to antidepressants. 16 Hence, the expectations for antidepressant
effectiveness with SAD comorbid with depression may be lowered. With
comorbid bipolar I depression , most experts conclude that antidepressants are
ineffective and, in some circumstances, may destabilize the patient.13 Although
comorbid bipolar II depression may respond to antidepressants in the short term,
long-term outcome studies are required to see whether this improvement is
stable. 17 Thus, when SAD is comorbid with bipolar depression, clinicians may
wish to consider the evidence for the non-antidepressant options in the algorithm
or emphasize psychotherapeutic treatments.
Comorbid alcohol and substance misuse is common in patients with SAD.
In these patients, use of benzodiazepines (BZs) is discouraged, although in
general, this class of medication was not determined to be a first-line option for
treatment of SAD because of adverse effects. If the patient is currently abusing
or dependent on alcohol or drugs, these substances should be withdrawn, if
possible, before the algorithm is applied. It seems reasonable to help the patient
achieve abstinence for at least 1 week before initiating psychopharmacologic
treatment of SAD. This may be the minimal time required to demonstrate drug-
placebo differences in the treatment of anxiety and depressive disorders that
persist after withdrawal.5
Finally, some evidence suggests that comorbid anxiety disorders (eg, panic
disorder, generalized anxiety disorder) will not diminish the responsiveness of
SAD to SSRIs. 18
FLOWCHART FOR THE ALGORITHM
A flowchart of our updated psychopharmacologic treatment algorithm for SAD
is presented in Figure 1 . Each numbered “node” represents a key question or
decision point that delineates populations of patients ranging from treatment-
naive to treatment-resistant. In the following sections, the rationales for the
questions and recommendations at each node are presented .
Figure 1. Flowchart showing treatment algorithm for generalized social anxiety disorder.
Node 1: Diagnosis of SAD and Comorbidities
The algorithm begins after the confirmation of a DSM-IV-TR criteria-based SAD
diagnosis, including relevant comorbidities that affect decision making.
Node 2: SSRI Trial?
Our review concludes that the first-line medication for SAD is usually an
SSRI. Three SSRIs are FDA approved for use in patients with SAD:
paroxetine, sertraline, and fluvoxamine controlled release (CR) . Other
SSRIs (eg, citalopram, escitalopram, fluoxetine) have varying strengths of
evidence but are likely effective. To assist with selection of a particular SSRI (or
other antidepressant) for an individual patient, we will review the details of the
antidepressant data on the treatment of SAD.
Paroxetine was the first SSRI to achieve FDA approval and has among the
best effect sizes of the antidepressants, with an excellent NNT of 3 (ie, to
achieve a score of 1 or 2 on the CGI-I at 8 weeks). Another 28% of patients
responded by 12 weeks, compared with only 8% on placebo. 19 Doses were
usually 50 to 60 mg daily after titration at clinicians’ discretion during the study.
Another large RCT (N = 384), using 3 fixed doses (ie, 20, 40, and 60 mg daily)
versus placebo, is one of the few dose-finding studies in the SAD literature. 20
All 3 doses had similar effect sizes compared with placebo on the CGI-I (ie, an
NNT of just over 3). The 40-mg dose was slightly more effective than 20 mg but
produced more early dropouts, probably from adverse effects due to the
protocol’s rapid escalation of dose. The investigators recommend that if an
initial dose of 20 mg is unsatisfactory after an adequate trial (eg, 8 weeks), an
increase to 40 mg or more might be beneficial and better tolerated than in the
study.
The disadvantage of paroxetine is more adverse effects compared with
other SSRIs. It is associated with the most weight gain, constipation, and
sedation due to its H1 antihistamine effects, and among the most sexual side
effects 21 (although ejaculation delay can be an advantage for male patients with
SAD who frequently have premature ejaculation). 22 Paroxetine’s short half-life
can result in discontinuation symptoms if the patient misses a dose, and it is the
only SSRI in pregnancy category D due to reports of cardiac septal
malformations in fetuses. Although more recent studies did not replicate this
finding, 23 the D rating remains in place. Because a substantial number of
patients with SAD are women of childbearing potential, it is important to be
aware of possible pregnancy-related risks.
Sertraline demonstrated good efficacy at a mean dose of about 150 mg daily.
The NNT was 4 in the best short-term study (20 weeks, 204 randomized
patients). 24 In a 24-week extension of this study, responders were randomized to
stay on sertraline or switch to placebo. Thirty-six percent relapsed on placebo
and only 4% on sertraline. 25 It is important to note, however, that almost two-
thirds of patients did well despite switching to placebo. Perhaps other aspects of
their care or coincidental stress reduction resulted in a situation where they no
longer needed active drug. Thus, this study suggests that many patients with
SAD who respond to SSRIs can eventually discontinue them, avoiding
exposure to long-term adverse effects.
Fluvoxamine CR is usually employed at a mean dose of 200 mg daily by the
endpoint of titration. The NNT was 5 in the best study. 26 In 2 recent RCTs, one
demonstrated a difference from placebo on the CGI-I and one did not. 27 , 28
Regarding non-FDA-approved SSRIs, escitalopram was tested in 2 major
acute SAD studies. One RCT (N = 358) produced a less impressive NNT of 7 for
improvement on the CGI-I with a mean dose of 18 mg daily. 29 There was only a
6.6-point difference in the outcome with the LSAS versus placebo. Given that
the starting scores on the LSAS were 95 to 96, this does not seem like a
clinically significant difference. The second RCT was a large, dose-finding study
comparing escitalopram (5, 10, or 20 mg), paroxetine (20 mg), and placebo (N =
839). 30 The 20-mg dose of escitalopram produced a better short-term result than
the lower doses, suggesting that the dose-response curve for escitalopram
between 5 and 20 mg was not flat. This was a surprise because, as noted earlier,
the dose-response curve for paroxetine in SAD was almost flat between 20 and
60 mg.20 Further, in the treatment of major depression with escitalopram, 10 mg
is equivalent to 20 mg according to the package insert’s interpretation of the
available data, suggesting a flat dose-response curve in the treatment of
depression.
Lader et al’s study also demonstrated that the 20-mg dose of escitalopram was
more effective than the 20-mg dose of paroxetine.30 For a more objective
comparison of escitalopram and paroxetine, however, they should have included
2 or more doses of each medication to evaluate the dose-response relationships
in the same patient population.
Citalopram is not the subject of any placebo-controlled RCTs. In 2 open-label
trials, however, the improvement rate was comparable to outcomes in RCTs with
the other SSRIs.
Fluoxetine effects are less clear than for the FDA-approved SSRIs. In the
largest (N = 295) study, the NNT of 5 was comparable with the others. 31
Although some patients were randomized to cognitive behavioral therapy in this
study, it provided no additional benefit. In 2 smaller RCTs (both with N = 60),
however, fluoxetine did not differ from placebo.
The Cochrane collaboration found a number of unpublished studies of SSRIs
in SAD. Because these studies probably failed to demonstrate efficacy,
“significant publication bias” in the data set for SAD is likely. 32 Thus, some
caution should be added to the generally favorable impression conveyed by the
published studies discussed above.
Conclusion : In Node 2, an SSRI is recommended. In this context, clinicians
should be mindful of the general adverse effect profile of SSRIs. Sexual effects
(eg, impotence, delayed ejaculation, loss of libido) are common, disturbing for
many patients, and usually do not remit with time.11 Cytochrome P450 drug
interactions are common with paroxetine and fluoxetine, but less so with
citalopram and escitalopram. Insomnia and nightmares are troublesome for many
patients on SSRIs and a concomitant sedative-hypnotic is often necessary.
Upper gastrointestinal track bleeding is 9 times more common in patients
on an SSRI and a nonsteroidal anti-inflammatory medication compared
with a control group not on these medications. 33 The risk is mitigated,
however, by adding an acid-controlling agent such as a proton-pump inhibitor.
Osteoporosis and fracture risk increase 2-fold with long-term SSRI use. 34 SSRIs
may increase progression of cataracts in the elderly. 35 Suicidal ideation may
increase in patients younger than 25 years, according to the new package-insert
warning. For all these reasons, it is recommended that careful assessment of
improvement on SSRIs is made to confirm whether response was medication-
related and not due to nonspecific aspects of care. Usually, the best way to make
this determination is a trial off the medication at a time when the patient is doing
reasonably well and can receive suitable support and observation from the
clinician and significant others.
Other options to consider at Node 2 (and later): If the risks of adverse effects
from an SSRI are considered unacceptable to the prescribing clinician or patient,
there are several reasonable options for first-line use, but they are not necessarily
preferred in this algorithm.
Venlafaxine (an SNRI), has comparable effect sizes to SSRIs in large studies
(ie, NNT of 4-7), using doses ranging from 75 to 225 mg daily. 36 , 37 There was
no dose-response relationship, which suggests that the norepinephrine effect
seen at higher doses with this medication did not affect efficacy. Short-term
adverse effects are generally a little greater with venlafaxine compared with
SSRIs, including nausea, other gastrointestinal symptoms, and elevated blood
pressure. Therefore, it seems reasonable to use this agent second line.
Phenelzine, a monoamine oxidase inhibitor (MAOI), has excellent efficacy
with the largest effect size of any antidepressant (ie, NNT of 2.3 in one study
at a dose of 65 mg daily). 38 Three other placebo-controlled trials found
comparable efficacy. The dietary requirements and risk of hypertensive crisis,
however, limit this option to patients who respond poorly to the safer
medications.
Mirtazapine (a tetracyclic), at a dose of 30 mg was effective compared with
placebo on the LSAS in a study of 66 women with SAD, but the CGI-I was not
recorded. 39 Weight gain was a significant problem with this agent.
Clonazepam (a BZ), was effective in one RCT involving 75 patients,
producing the best effect size in any study on record (ie, an NNT of 1.7 on the
CGI-I). 40 Seventy-eight percent responded to a dose averaging 2.4 mg daily,
versus 20% on placebo. This outstanding result, however, has not been
replicated. A study with alprazolam (dose: 4.2 mg daily) reported only a 38%
response using an atypical rating instrument. 41 The problem with BZs is that
they produce significant cognitive impairment and performance/coordination
deficits not seen with antidepressants. 42 Further, BZs should be avoided in most
patients with a history of substance or alcohol abuse or dependence. Finally, they
probably do not benefit comorbid depression associated with SAD.
Node 2a: Partial response to the antidepressant trial
As noted earlier, partial improvement with antidepressant therapy occurs
frequently in SAD. Augmentation may be considered if the partial improvement
is thought to be due to medication and not psychotherapy and/or nonspecific
aspects of treatment. This can be difficult to determine but of crucial importance.
As a general principle, one should avoid adding another medication when partial
response to the first medication is likely a placebo response. This is because
augmentation increases the risks of adverse effects and drug interactions,
reduces adherence due to complexity of the regimen, and increases cost. We
recommend careful evaluation for other possible contributing factors to the
unsatisfactory response such as comorbidity, nonadherence, and
pharmacokinetic/ pharmacogenetic variables. Because of the earlier-mentioned
issues, the algorithm indicates a preference for switching rather than
augmentation, especially in the first node of psychopharmacology treatment (see
Figure 1 ).
One possible medication augmentation strategy that is reasonably safe
and inexpensive involves buspirone added to an SSRI. This agent, however,
has not demonstrated efficacy as a monotherapy and the evidence base for it as
an augmentation is quite limited. There is only one small study involving 10
patients given adjunctive buspirone (up to 60 mg daily; mean dose 45 mg) for 8
weeks with 70% responding in this uncontrolled, prospective trial. 43 Buspirone
also surprised investigators by doing quite well in the STAR*D study as an
augmentation to citalopram for major depression. 44 Since then, there are more
frequent recommendations for this unlabeled indication.
Psychotherapy augmentation is always a viable option, but the timing of this
important intervention is not addressed in this algorithm.
Node 3: Tried a Second SSRI or Venlafaxine? Considered
Clonazepam or an MAOI?
If a patient fails to respond adequately to the first antidepressant, anecdotal
reports support trying a different antidepressant or other medication. 45 There is,
however, no systematic study of this logical approach. The lack of data is most
unfortunate, and the algorithm from Node 3 onward must rely on application of
general principles of conservative, safety-conscious, and cost-effective practice
rather than on specific evidence pertaining to each node. It is suggested that the
clinician review the efficacy and safety considerations presented in node 2 for
the various options and choose the one that seems most reasonable for a specific
patient. If a second SSRI is chosen, escitalopram (20 mg) may deserve
consideration given the slight, and, in our view, somewhat unconvincing
evidence of better results (compared with paroxetine) reported in the Lader et al
study.30 Unfortunately, 20 mg of escitalopram is very costly, because it is the
only remaining branded SSRI in the US market.
See the discussion of partial response at node 2a.
Node 4: Tried a Third Medication: Another SSRI, Venlafaxine,
Nefazodone, Clonazepam, or MAOI?
A third monotherapy trial is recommended. Nefazodone is included as one of the
options here for the first time. Because of the risks of liver toxicity, this agent
should not be used unless at least 2 other antidepressants were tried. Further,
evidence for benefit in SAD is limited to a number of encouraging open-label
trials and one placebo-controlled RCT with a negative outcome, in which 105
patients received a mean dose just under 500 mg daily 46 with no significant
improvement compared with placebo. The NNT was 14 on the CGI-I.
Node 5: Have You Considered Some of the Experimental Options
in Addition to Trying Another of the Options Already Discussed
but Not Yet Tried?
Under the heading of experimental options, some promising choices include the
following (not listed in order of preference).
Gabapentin was the subject of one placebo-controlled RCT. 47 Sixty-nine
patients participated but 49% on placebo and 38% on gabapentin dropped out.
The mean dose of gabapentin ranged from 600 to 3600 mg daily. On the basis of
the LSAS, 32% improved on active drug and 14% on placebo (ie, NNT of 5.5).
Quetiapine monotherapy in doses up to 400 mg daily was used in a small (N =
15), placebo-controlled, 8-week RCT. 48 Although there was no difference in
improvement on the primary outcome measure (the Brief Social Phobia Scale),
40% of quetiapine patients improved (score of 1 or 2) on the CGI-I versus none
of the placebo patients (ie, NNT of 2.5). Because the CGI-I is the measure we
used to compare the various studies, this result suggests that quetiapine may be
effective, though probably rarely producing remission, as is the case with most
of the other psychopharmacologic treatments. Quetiapine has significant
metabolic side effects and, like other antipsychotics, may double the risk of
sudden cardiac death at these doses. 49
Risperidone at a mean dose of 1 mg was used to augment an SSRI in an 8-
week, open-label trial in 7 patients. 50 LSAS scores improved from a mean of 81
to 38, which seems encouraging.
Pregabalin at a dose of 600 mg daily had slight benefits for SAD in a RCT. 51
Tiagabine in an open-label trial was somewhat promising. 52
CONCLUSIONS
This algorithm summarizes and organizes the available evidence pertaining
to the choice of pharmacotherapy for patients with SAD, a disabling
condition that significantly affects quality of life . A structure for
consideration of sequential medication options is proposed. Although SSRIs are
still first-line treatments, it is evident that they have significant limitations. In
general, medication seems to have an important but fairly modest role in altering
the course of the lives of people with this disorder. Some patients decide that the
adverse effects are not worth the benefits over the long term, whereas others are
grateful for the help they receive from this approach. The prescribing clinician
should be prepared to discuss the quality of the evidence base in detail and
collaborate with the patient to find the treatments most acceptable and helpful to
him or her.
REFERENCES
1. Lane C. Shyness: How Normal Behavior Became a Sickness. New Haven, CT: Yale University Press;
2007.
2. Campbell-Sills L, Stein MB. Justifying the diagnostic status of social phobia: a reply to Wakefield,
Horwitz, and Schmitz. Can J Psychiatry. 2005;50(6):320–323; discussion 324–326.
3. Akimova E, Lanzenberger R, Kasper S. The serotonin-1A receptor in anxiety disorders. Biol
Psychiatry. 2009;66(7):627–635.
4. Irle E, Ruhleder M, Lange C, et al. Reduced amygdalar and hippocampal size in adults with
generalized social phobia. J Psychiatry Neurosci. 2010;35(2):126–131.
5. Osser DN, Renner JA, Bayog R. Algorithms for the pharmacotherapy of anxiety disorders in patients
with chemical abuse and dependence. Psychiatric Ann. 1999;29:285–301.
6. Stein DJ, Kasper S, Matsunaga H, et al. Pharmacotherapy of social anxiety disorder: an algorithm for
primary care. Prim Care Psychiatry. 2001;7(3):107–110.
Knijnik DZ, Blanco C, Salum GA, et al. A pilot study of clonazepam versus psychodynamic group
7. Knijnik DZ, Blanco C, Salum GA, et al. A pilot study of clonazepam versus psychodynamic group
therapy plus clonazepam in the treatment of generalized social anxiety disorder. Eur Psychiatry.
2008;23(8):567–574.
8. Blanco C, Heimberg RG, Schneier FR, et al. A placebo-controlled trial of phenelzine, cognitive
behavioral group therapy, and their combination for social anxiety disorder. Arch Gen Psychiatry.
2010;67(3):286–295.
9. Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a
patient-level meta-analysis. JAMA. 2010;303(1):47–53.
10. Baker DG, Nievergelt CM, Risbrough VB. Post-traumatic stress disorder: emerging concepts of
pharmacotherapy. Expert Opin Emerg Drugs. 2009;14(2):251–272.
11. Cascade E, Kalali AH, Kennedy SH. Real-world data on SSRI antidepressant side effects. Psychiatry
(Edgmont). 2009;6(2):16–18.
12. Hamoda HM, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: an update on psychotic depression. Harv Rev Psychiatry. 2008;16(4):235–247.
13. Ansari A, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore
Program: an update on bipolar depression. Harv Rev Psychiatry. 2010;18(1):36–55 .
14. Hedges DW, Brown BL, Shwalb DA. A direct comparison of effect sizes from the Clinical Global
Impression-Improvement Scale to effect sizes from other rating scales in controlled trials of adult
social anxiety disorder. Hum Psychopharmacol. 2009;24(1):35–40.
15. Oosterbaan DB, van Balkom AJ, Spinhoven P, et al. The placebo response in social phobia. J
Psychopharmacol. 2001;15(3):199–203.
16. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious
versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165(3):342–351.
17. Suppes T. Is there a role for antidepressants in the treatment of bipolar II depression? Am J
Psychiatry. 2010;167(7):738–740.
18. Brady KT, Clary CM. Affective and anxiety comorbidity in post-traumatic stress disorder treatment
trials of sertraline. Compr Psychiatry. 2003;44(5):360–369.
19. Stein DJ, Versiani M, Hair T, et al. Efficacy of paroxetine for relapse prevention in social anxiety
disorder: a 24-week study. Arch Gen Psychiatry. 2002;59(12):1111–1118.
20. Liebowitz MR, Stein MB, Tancer M, et al. A randomized, double-blind, fixed-dose comparison of
paroxetine and placebo in the treatment of generalized social anxiety disorder. J Clin Psychiatry.
2002;63(1):66–74.
21. Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants: a meta-
analysis. J Clin Psychopharmacol. 2009;29(3):259–266.
22. Munoz V, Stravynski A. Social phobia and sexual problems: a comparison of social phobic, sexually
dysfunctional and normal individuals. Br J Clin Psychol. 2010;49(Pt 1):53–66.
23. Einarson A, Pistelli A, DeSantis M, et al. Evaluation of the risk of congenital cardiovascular defects
associated with use of paroxetine during pregnancy. Am J Psychiatry. 2008;165(6): 749–752.
24. Van Ameringen MA, Lane RM, Walker JR, et al. Sertraline treatment of generalized social phobia: a
20-week, double-blind, placebo-controlled study. Am J Psychiatry. 2001;158(2):275–281.
25. Walker JR, Van Ameringen MA, Swinson R, et al. Prevention of relapse in generalized social
phobia: results of a 24-week study in responders to 20 weeks of sertraline treatment. J Clin
Psychopharmacol. 2000;20(6):636–644.
Psychopharmacol. 2000;20(6):636–644.
26. Stein MB, Fyer AJ, Davidson JR, et al. Fluvoxamine treatment of social phobia (social anxiety
disorder): a double-blind, placebo-controlled study. Am J Psychiatry. 1999;156(5):756–760.
27. Davidson J, Yaryura-Tobias J, DuPont R, et al. Fluvoxamine-controlled release formulation for the
treatment of generalized social anxiety disorder. J Clin Psychopharmacol. 2004;24:118–125.
28. Westenberg HG, Stein DJ, Yang H, et al. A double-blind placebo-controlled study of controlled
release fluvoxamine for the treatment of generalized social anxiety disorder. J Clin Psychopharmacol.
2004;24:49–55.
29. Kasper S, Stein DJ, Loft H, et al. Escitalopram in the treatment of social anxiety disorder:
randomised, placebo-controlled, flexible-dosage study. Br J Psychiatry. 2005;186(3):222–226.
30. Lader M, Stender K, Burger V, et al. Efficacy and tolerability of escitalopram in 12- and 24-week
treatment of social anxiety disorder: randomised, double-blind, placebo-controlled, fixed-dose study.
Depress Anxiety. 2004;19(4):241–248.
31. Davidson JR, Foa EB, Huppert JD, et al. Fluoxetine, comprehensive cognitive behavioral therapy,
and placebo in generalized social phobia. Arch Gen Psychiatry. 2004;61(10):1005–1013.
32. Stein DJ, Ipser JC, Balkom AJ. Pharmacotherapy for social phobia. Cochrane Database Syst Rev.
2004;(4):CD001206.
33. de Abajo FJ, Garcia-Rodriguez LA. Risk of upper gastrointestinal tract bleeding associated with
selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-
inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry. 2008;65(7):795–
803.
34. Richards JB, Papaioannou A, Adachi JD, et al. Effect of selective serotonin reuptake inhibitors on the
risk of fracture. Arch Intern Med. 2007;167(2):188–194 .
35. Etminan M, Mikelberg FS, Brophy JM. Selective serotonin reuptake inhibitors and the risk of
cataracts: a nested case-control study. Ophthalmology. 2010;117(6):1251–1255.
36. Liebowitz MR, Gelenberg AJ, Munjack D. Venlafaxine extended release vs placebo and paroxetine
in social anxiety disorder. Arch Gen Psychiatry. 2005;62(2):190–198.
37. Stein MB, Pollack MH, Bystritsky A, et al. Efficacy of low and higher dose extended-release
venlafaxine in generalized social anxiety disorder: a 6-month randomized controlled trial.
Psychopharmacology (Berl). 2005;177(3):280–288.
38. Liebowitz MR, Schneier F, Campeas R, et al. Phenelzine vs atenolol in social phobia. A placebo-
controlled comparison. Arch Gen Psychiatry. 1992;49(4):290–300.
39. Muehlbacher M, Nickel MK, Nickel C, et al. Mirtazapine treatment of social phobia in women: a
randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2005;25(6):580–583.
40. Davidson JR, Potts N, Richichi E, et al. Treatment of social phobia with clonazepam and placebo. J
Clin Psychopharmacol. 1993;13(6):423–428.
41. Gelernter CS, Uhde TW, Cimbolic P, et al. Cognitive-behavioral and pharmacological treatments of
social phobia. A controlled study. Arch Gen Psychiatry. 1991;48(10):938–945.
42. Hindmarch I. Cognitive toxicity of pharmacotherapeutic agents used in social anxiety disorder. Int J
Clin Pract. 2009;63(7):1085–1094.
43. Van Ameringen M, Mancini C, Wilson C. Buspirone augmentation of selective serotonin reuptake
inhibitors (SSRIs) in social phobia. J Affect Disord. 1996;39(2):115–121.
inhibitors (SSRIs) in social phobia. J Affect Disord. 1996;39(2):115–121.
44. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for
depression. N Engl J Med. 2006;354(12):1243–1252.
45. Altamura AC, Pioli R, Vitto M, et al. Venlafaxine in social phobia: a study in selective serotonin
reuptake inhibitor non-responders. Int Clin Psychopharmacol. 1999;14(4):239–245.
46. Van Ameringen M, Mancini C, Oakman J, et al. Nefazodone in the treatment of generalized social
phobia: a randomized, placebo-controlled trial. J Clin Psychiatry. 2007;68(2):288–295.
47. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-
controlled study. J Clin Psychopharmacol. 1999;19(4):341–348.
48. Vaishnavi S, Alamy S, Zhang W, et al. Quetiapine as monotherapy for social anxiety disorder: a
placebo-controlled study. Prog Neuro-Psychopharmacol Biol Psychiatry. 2007;31(7):1464–1469.
49. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac
death. N Engl J Med. 2009;360(3):225–235.
50. Simon NM, Hoge EA, Fischmann D, et al. An open-label trial of risperidone augmentation for
refractory anxiety disorders. J Clin Psychiatry. 2006;67(3):381–385.
51. Pande AC, Feltner DE, Jefferson JW, et al. Efficacy of the novel anxiolytic pregabalin in social
anxiety disorder: a placebo-controlled, multicenter study. J Clin Psychopharmacol. 2004; 24(2):141–
149.
52. Dunlop BW, Papp L, Garlow SJ, et al. Tiagabine for social anxiety disorder. Hum Psychopharmacol.
2007;22(4):241–244.
Dr. Osser is Associate Professor of Psychiatry, Harvard Medical School, 150 Winding River Road,
Needham, MA 02492, E-mail: dno@theworld.com ; and Dr. Dunlop is Acting Medical Director, Cambria
County Mental Health/Mental Retardation Clinic, Johnstown, PA 15901.
All faculty and staff in a position to control the content of this CME activity and their spouses/life partners
(if any) have disclosed that they have no financial relationships with, or financial interests in, any
commercial organizations pertaining to this educational activity.
The authors have disclosed that the use of citalopram, escitalopram, fluoxetine, phenelzine, clonazepam,
alprazolam, buspirone, nefazodone, gabapentin, quetiapine, risperidone, pregabalin, and tiagabine for
treatment of social anxiety disorder has not been approved by the U.S. Food and Drug Administration.
mailto:dno@theworld.com
T
UPDATE
SOCIAL ANXIETY DISORDER ALGORITHM
here have been few new psychopharmacology studies of generalized
social anxiety disorder (SAD) in the decade since the last publication of
this algorithm. Of the relevant studies, nothing changes the basic
recommendations until Node 2b, which is when you have had a partial
response to the first selective serotonin reuptake inhibitor (SSRI) trial, a
response that appears to be due to the effect of the SSRI rather than a
placebo effect (which is often the cause of partial responses in this and
many other disorders). In the previous algorithm version, buspirone was
suggested as a possible augmentation on the basis of an uncontrolled case
series. However, a new study came out in 2014 that resulted in an
additional option at this point: clonazepam. 1
Node 2b: Augmentation of a Partial Response to the Initial
SSRI
In this large trial sponsored by the National Institute of Mental Health, 397
patients with SAD were treated with open-label sertraline at a mean dose of
180 mg for 10 weeks. Subjects were excluded if they had more than two
previous medication trials—but only 25% to 30% had received any
previous trials; 32% responded (50% drop in the Liebowitz Social Anxiety
Scale [LSAS]) and 13% remitted. These results are notably lower than the
rates of response in the initial citalopram trial for depression in the
STAR*D study (47% and 28%, respectively), suggesting that SAD is a
more difficult disorder to treat. 2 A total of 181 patients failed to achieve
better than a partial response and agreed to be randomized to one of three
treatment options for 12 weeks2 : a switch to venlafaxine (mean dose
eventually was 186 mg daily), addition of clonazepam (mean dose initially
1.5 mg and at endpoint 2.3 mg), or addition of placebo.
Clonazepam jumped ahead of the other two arms of the study in the first
2 weeks and stayed there for the remainder of the trial. At endpoint, there
were >56% responses on clonazepam versus >36% responses on placebo (p
= .027). The number needed to treat was 5. Additional patients achieving
remission were 27% on clonazepam and 17% on placebo, although this was
statistically nonsignificant. Number needed to treat for remission was 10.
Switching to venlafaxine was not different from adding placebo (19% vs.
17% remissions). Improvement was gradual over the 12 weeks in all three
arms of the study, which highlighted the importance of giving the
treatments adequate time. Indeed, except for placebo, the active treatments
seemed to still be on a trend toward further improvement: results had not
plateaued at 12 weeks.
Side-effect differences were nonsignificant but somnolence was
numerically higher with clonazepam (32%) compared with venlafaxine
(23%) and placebo (15%). Discontinuations were lowest with clonazepam
(10%) compared with venlafaxine (15%) and placebo (20%). Consistent
with many other studies in other disorders, subjects like to stay on
benzodiazepines.
There were quite a few additional exclusion criteria for this study that
render the results less generalizable to “real-world” SAD patients than
would be ideal. The following were excluded: women of childbearing
potential not on good birth control; patients with psychosis, bipolar
disorder, comorbid obsessive-compulsive disorder, suicidality, substance
abuse within the last 3 months, and substance dependence within the last 6
months (8%-16% had lifetime history); and people in psychotherapy.
As a result of this study, the algorithm is changed at Node 2b and the
first recommendation for an augmentation is clonazepam if the patient
would have met these rather stringent criteria for inclusion in the study. If
not, then there must be questions about benefits versus the risks of adding
clonazepam and the prescriber should consider those before prescribing
clonazepam here and consider the alternative of the next augmentation
option, which is buspirone. Though uncontrolled, the response rate to
adding buspirone (mean dose 45 mg) in the one study cited earlier was
70%. 3
This study also indirectly enhances the status of clonazepam
monotherapy in other places where it was mentioned as an option in the
algorithm, especially Node 3.
Node 5: The Fourth Medication Trial—Some New Studies
But No New Recommendations
For treatment-resistant cases of SAD, several options including gabapentin
and pregabalin were suggested. There was a new, large placebo-controlled
trial of pregabalin published in 2011. 4 Three doses were compared but only
the top dose of 600 mg daily was significantly effective (p =.01) on the
LSAS. There was also a maintenance trial with pregabalin. 5 After
collecting 153 responders to open-label treatment with 450 mg daily,
patients were randomized to continue on it or be switched to placebo.
Various outcome measures favored pregabalin, and significant side effects
were limited to dizziness (number needed to harm [NNH] = 14) and
infections (NNH = 20). Currently, pregabalin is a brand product and much
more expensive than gabapentin, yet their pharmacodynamic properties and
approved indications are very similar. 6
REFERENCES
1. Pollack MH, Van Ameringen M, Simon NM, et al. A double-blind randomized controlled trial
of augmentation and switch strategies for refractory social anxiety disorder. Am J Psychiatry.
2014;171:44–53.
2. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for
depression using measurement-based care in STAR*D: implications for clinical practice. Am J
Psychiatry. 2006;163:28–40 .
3. Van Ameringen M, Mancini C, Wilson C. Buspirone augmentation of selective serotonin
reuptake inhibitors (SSRIs) in social phobia. J Affect Disord. 1996;39:115–121.
4. Feltner DE, Liu-Dumaw M, Schweizer E, et al. Efficacy of pregabalin in generalized social
anxiety disorder: results of a double-blind, placebo-controlled, fixed-dose study. Int Clin
Psychopharmacol. 2011;26:213–220.
5. Greist JH, Liu-Dumaw M, Schweizer E, et al. Efficacy of pregabalin in preventing relapse in
patients with generalized social anxiety disorder: results of a double-blind, placebo-controlled
26-week study. Int Clin Psychopharmacol. 2011;26:243–251.
6. Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and
pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49:661–669.
The Psychopharmacology Algorithm Project at the
Harvard South Shore Program: An Update on
Posttraumatic Stress Disorder
Laura A. Bajor, DO, Ana Nectara Ticlea, MD, and David N. Osser,
MD
Background: This project aimed to provide an organized, sequential, and evidence-supported
approach to the pharmacotherapy of posttraumatic stress disorder (PTSD), following the format of
previous efforts of the Psychopharmacology Algorithm Project at the Harvard South Shore Program.
Method: A comprehensive literature review was conducted to determine the best pharmacological
choices for PTSD patients and to update the last published version (1999) of the algorithm. We
focused on optimal pharmacological interventions to address the prominent symptoms of PTSD, with
additional attention to the impact that common comorbidities have on treatment choices.
Results: We found that SSRIs and SNRIs are not as effective as previously thought, and that
awareness of their long-term side effects has increased. New evidence suggests that addressing
fragmented sleep and nightmares can improve symptoms (in addition to insomnia) that are
frequently seen with PTSD (e.g., hyperarousal, reexperiencing). Prazosin and trazodone are
emphasized at this initial step; if significant PTSD symptoms remain, an antidepressant may be tried.
For PTSD-related psychosis, an antipsychotic may be added. In resistant cases, two or three
antidepressants may be used in sequence. Following that, or with partial improvement and residual
symptomatology, augmentation may be tried; the best options are antipsychotics, clonidine,
topiramate, and lamotrigine.
Conclusion: This heuristic may be helpful in producing faster symptom resolution, fewer side effects,
and increased compliance. (Harv Rev Psychiatry 2011;19:240–258.)
INTRODUCTION
There has been considerable interest in finding effective psychopharmacological
strategies for treating posttraumatic stress disorder (PTSD). It is assumed that
biological treatment may have an important role, given the abnormalities in
neurotransmitter, neuroendocrine, and neuroanatomical systems that have been
identified in patients with PTSD. 1 – 3
In this article the authors present a heuristic for selecting medication
treatments for PTSD. This version updates a previous PTSD algorithm from the
Psychopharmacology Algorithm Project at the Harvard South Shore Program
(PAPHSS). 4 It was also influenced by the International Psychopharmacology
Algorithm Project PTSD algorithm, to which one of the authors (DNO)
contributed as a consultant. 5
Although psychosocial interventions are effective for many patients with
PTSD, 6 this algorithm focuses on medication usage and is meant to be applied if
and when the prescribing clinician and patient determine that medication may be
appropriate. We did not evaluate the efficacy of psychotherapy and when it
should be offered, though we acknowledge that some guidelines consider
psychosocial interventions as a first-line treatment for PTSD. 7 – 9
At present, the only medications that the Food and Drug Administration
(FDA) has approved for PTSD are the selective serotonin reuptake inhibitors
(SSRIs) sertraline and paroxetine. These medications are widely recommended
and used in clinical practice. In this review, we focus on the quality of the
evidence for the efficacy of SSRIs and other medications used to treat PTSD.
Recent systematic reviews have questioned whether standard medication
treatments (e.g., SSRIs) produce results that are clinically robust and whether it
is time to revisit the usual sequence of medication choices. A novel approach
may be justifiable, at least for certain subpopulations of PTSD patients.7 , 10 , 11
Method
The PAPHSS method of algorithm development has been described in previous
publications. 12 – 14 These algorithms model the cognitive process involved in a
psychopharmacology consultation, with focus on the evidence base. Each is
structured as a series of questions about the patient’s diagnosis and past
treatment history. If the patient has not been tried on one of the medications that
is best supported by the evidence pertaining to the clinical circumstances, the
algorithm suggests trying that medication. The evidence is cited and appraised,
and other options that might be considered are also discussed. When the
evidence for treatment at a “node” is inadequate or contradictory, this situation is
acknowledged, and any recommendations offered are more tentative and
flexible. For more treatment-resistant patients (higher-numbered nodes), there is
greater uncertainty, more focus on treatment of residual symptoms, and more
deference to the prescriber’s clinical experience. The PAPHSS proposes that, as
a core value, consideration of the scientific evidence is necessary, but not
sufficient, for clinical decision making. The prescriber’s clinical experience can
support or contradict the research data and should contribute to treatment
decisions.
Since PTSD is a chronic illness, and the treatment selected is likely to be
continued over an extended period, factors such as short- and long-term side-
effect profiles and the risks for drug/drug interactions are weighed strongly in
deciding whether and at what point in treatment to include a medication.
After reviewing the previous (1999) PAPHSS algorithm, as well as other
algorithms and guidelines, the authors conducted literature searches in PubMed
to identify studies and reviews published since 1999. Proposed
psychopharmacological agents for PTSD were entered in Boolean (AND)
searches with the keywords “posttraumatic stress disorder.” Resultant studies in
English were selected. Other studies or reviews referenced in the selected
articles were also examined. The algorithm was updated based on 103 studies
and reviews published since 1999 identified in this manner.
Demographics, Symptom Clusters, and Tailoring of Treatment
Approaches
The criteria for PTSD in the Diagnostic and Statistical Manual of Mental
Disorders (4th ed.) (DSM-IV) include the symptom clusters of reexperiencing,
avoidance, and hyperarousal. 15 These symptom clusters may differ in their
responses to psychopharmacological treatment. It is less clear whether these
differences depend on the nature of the trauma—for example, combat veterans
versus survivors of rape or domestic abuse. Recently traumatized individuals
may respond better than those with distant trauma, such as Vietnam veterans. 16 ,
17 The evidence also suggests that SSRIs may be more effective with female
civilian survivors of sexual or domestic violence.16 , 17 It is not clear, however,
whether these differences are due to gender, age at initial traumatization,
possible influence of compensation for combat veterans with PTSD, or other
characteristics. Unfortunately, the available evidence is insufficient to support
targeting treatments based on these variables. The evidence base on
psychopharmacological treatment of child and adolescent PTSD is also scant and
devoid of positive controlled studies. 18
Flowchart for the Algorithm
A summary and overview of the algorithm appears in Figure 1 . Each numbered
“node” represents a decision point delineating patient populations ranging from
treatment naive to highly resistant. The questions, evidence analysis, and
reasoning that support the recommendations at each node will be presented
below .
Figure 1. Flowchart of the algorithm for posttraumatic stress disorder. Nodes are indicated in bold.
NODE 1: DOES THE PATIENT MEET DSM-IV
NODE 1: DOES THE PATIENT MEET DSM-IV
CRITERIA FOR POSTTRAUMATIC STRESS
DISORDER?
First, confirm a diagnosis based on DSM-IV criteria, and note any co-occurring
psychiatric and medical symptoms and diagnoses that may be important,
including substance abuse, depression, bipolar disorder, dissociative symptoms,
anger, impulsivity, and psychosis. In treating female patients of childbearing
age, the potential impact of medication on pregnancy should also be considered.
Table 1 provides a brief overview of treatment considerations for these
situations. A more thorough description of this important material is beyond the
scope of this review, but the reader is encouraged to consult the associated
references.
Table 1 | Comorbidity and Other Features in PTSD and How They Affect
the Algorithm
Comorbidity Considerations Recommendations
Substance abuse Comorbidity of substance abuse is very high in
PTSD patients4
PTSD patients are at increased risk of abusing
prescription medications 19
Algorithm recommendations do not apply to
patients who are actively abusing substances4
Screen for substance abuse
in PTSD patients
Avoid benzodiazepines
Ideally, a patient should be
clean & sober at least a
week before attempting to
apply this algorithm 20
Bipolar disorder Lifetime risk for PTSD approximately double in
patients with bipolar disorder, who may be
exposed to more trauma & have fewer resources
& social supports 21
SSRIs & other antidepressants may pose risks of
destabilizing the bipolar disorder 13
Treat nightmares &
disturbed awakenings with
prazosin
Be more reluctant to use
antidepressants for patient
dually diagnosed with
bipolar disorder & PTSD
than in the standard
algorithm
Psychosis Psychotic symptoms in PTSD patients could
indicate a comorbid psychotic disorder or could
be part of the PTSD 22
Consider skipping node 2
(sleep management)
If primary psychosis, treat
first with an antipsychotic
Major depressive
disorder
History of major depression increases risk of
developing PTSD, & PTSD diagnosis increases
risk of depression 23
Dysregulation of HPA axis may cause above
associations 2 , 24 , 25
Responsiveness to antidepressants is diminished
in PTSD patients with comorbid depression in
some studies 26 – 28
Children/adolescents with PTSD show more
variability in response to antidepressants than
those with only depression 29
Screen for depression in
PTSD patients
Use antidepressants earlier
in the algorithm but know
that prognosis is guarded
Know that patients with
both diagnoses may not
respond to antidepressants
as well as those with only
PTSD respond
If psychotic depression, treat
with antidepressant &
antipsychotic12
Dissociation Associated with more traumatic events & more
serious PTSD pathology 30
Paroxetine found slightly better than placebo in
one study with small n & high dropout rates 31
Some recommend psychotherapy as first-line
treatment for the dissociative symptoms of PTSD
32
Screen for dissociative
symptoms
Know that dissociation
indicates more serious
pathology & less predictable
response to
pharmacotherapy
Consider psychotherapy to
address these specific
symptoms
Pregnancy Physiological changes of pregnancy (e.g.,
decreased drug-protein binding, enhanced hepatic
metabolism & renal clearance, & delayed gastric
emptying) may affect drug levels in ways that are
difficult to predict 33
Medications with teratogenic risks should be
avoided during the first trimester, particularly
weeks 3 through 933
Paroxetine is only SSRI categorized by FDA as
“Category D” due to reports of cardiac septal
malformations33
Valproate has severe teratogenic effects33
Expect altered drug effects
in pregnant patients, &
monitor them more closely
Avoid paroxetine & valproic
acid
Smoking Rates of smoking were increased in veterans with
PTSD returning from Iraq & Afghanistan 34 , 35
Bupropion was found to be
effective for smoking-
cessation efforts in one
study of patients with
study of patients with
chronic PTSD 36
One study found smoking-
cessation efforts to be more
successful in PTSD patients
if smoking was addressed by
the patients’ psychiatric
team rather than by referral
to separate clinic34
FDA, Food and Drug Administration; SSRI, selective serotonin reuptake inhibitor; VA, Department of
Veterans Affairs.
NODE 2: IS SLEEP DISTURBED?
Mounting evidence has implicated sleep impairment as a core symptom in PTSD
and a primary source of distress and dysfunction for patients with this disorder.
37 , 38 It is therefore proposed that sleep problems be assessed initially and
reassessed after each algorithm step if they persist and overall response remains
unsatisfactory.38 For many patients, sleep deprivation may exacerbate core
daytime PTSD symptoms (hypervigilance, avoidance, reexperiencing), and these
symptoms may improve when sleep improves. 39 Another justification for
treating sleep difficulties first is the availability of prazosin, a
psychopharmacology option that targets impaired sleep in PTSD patients and
that has demonstrated substantially larger effect sizes than medications
commonly thought to be effective for the general symptom profile in PTSD
(SSRIs and serotonin-norepinephrine reuptake inhibitors [SNRIs]). To our
knowledge, none of the previous guidelines or algorithms has placed sleep
evaluation and treatment first, before the use of an SSRI.
Sleep disturbances common in PTSD include the following: hyperarousal
linked to difficulties initiating or maintaining sleep; trauma-related nightmares;
awakenings without nightmare recollection; and prolonged sleep latency. 40 , 41
Increased noradrenergic activity during sleep and while trying to fall asleep is
thought to be an important mechanism.41 – 43 Notably, SSRIs can sometimes
exacerbate these symptoms.39 , 44 , 45
Other causes of insomnia may contribute to the sleep difficulties of patients
with PTSD. These include sleep apnea, restless leg syndrome, periodic limb
movements of sleep, sleep hygiene issues, nicotine withdrawal, and medical
problems associated with sleep fragmentation (e.g., pain and nocturia). Caffeine,
though frequently employed as a method of coping with daytime symptoms of
sleep deprivation secondary to PTSD and other causes of insomnia, can at times
become a major independent contributor. Assessment of these factors is essential
in the sleep evaluation before applying the algorithm recommendations.
Node 2a
If the patient has PTSD-related nightmares or disturbed arousals, we recommend
consideration of a trial of prazosin as the first-line medication treatment.
Prazosin is a generic alpha-1 adrenergic antagonist previously used to treat
hypertension and symptoms of benign prostatic hyperplasia. Murray Raskind
and colleagues at the University of Washington reasoned that alpha antagonists
might be effective for the hyperarousal symptoms of PTSD. They selected
prazosin for study as it is the only commercially available alpha-1 agent that
crosses the blood-brain barrier, with the consequence that it would be the most
likely to have activity in the brain. To date, they have conducted three
randomized, placebo-controlled studies. 42 , 43 , 46 Efficacy was demonstrated for
trauma-related nightmares, overall quality of sleep, and, to some extent, general
PTSD symptoms in patients with either military and civilian trauma. All studies
found large effect sizes (Cohen’s d > 1.0) on the various measures of sleep
impairment. These results are summarized in Table 2 .
Prazosin was well tolerated in these studies. Hypotension risks were
minimized by slowly titrating the dose upward over several weeks, allowing
tolerance to the blood pressure effects to develop. Details of the dosing protocols
are provided in Table 2 and may be used as guidelines for clinical use. In the
largest study, 2 of 20 (10%) dropped out due to subjective dizziness possibly
related to blood pressure. Both studies by Raskind and colleagues42 , 43 involved
male veterans, whereas the study by Taylor and colleagues46 involved civilian
females. Though the reason is unclear, the dosage requirements for men and
women differed, with the male veterans often requiring 10 mg or more,
compared to the mean of 3 mg needed by women.
In a more recent observational study with mostly male veterans in a
Department of Veterans Affairs (VA) setting (n = 62), the mean dose of prazosin
after initial titration was 3 mg, which increased to 6 mg after up to six years of
follow-up. 47 This dose is much lower than in the two controlled studies and may
reflect clinicians’ unawareness of the doses used in those studies. The rate of
dropout due to hypotension at these doses was less than 2%.
Infrequent side effects include dizziness, drowsiness, headache, constipation,
loss of appetite, fatigue, nasal congestion, dry eyes, and priapism. Noncardiac
chest pain has occurred, but cardiac ischemia must be ruled out. 48 If the patient
is hypertensive, coordination with the primary care clinician is advised.
Thompson and colleagues39 showed in a small chart review study of 22
combat veterans that disturbed awakenings without nightmare recollection were
also significantly reduced (p < 0.01) following treatment with prazosin.
Although this finding needs to be confirmed in randomized, controlled trials
(RCTs), the study suggests that it would be reasonable to employ prazosin in
patients with these awakenings.
The study data currently available for prazosin are limited. It should be
emphasized that the studies were mostly small, that they were done mostly by
one group, and that the RCTs did not use monotherapy in previously untreated
patients. Furthermore, dosing with prazosin is somewhat complex. Though the
effect sizes with prazosin were large, it has been observed that small studies can
generate higher effect sizes; such results should be interpreted with caution. 49
Nevertheless, we are proposing the consideration of prazosin for first-line use for
patients with prominent nightmares and related sleep disturbances.
In support of this recommendation, we would first cite again the exceptional
effect size relative to placebo of around 1.0 for significant improvement in sleep.
As we will be showing later, all other medications, whether used as first-line
(e.g., SSRIs) or as add-on interventions for treatment-resistant patients, fail to
achieve even close to this effect size for PTSD symptoms. Next, we have
emphasized the importance of sleep impairment in PTSD and the central role
that it may have in the pathology of this disorder—and to that may be added the
medical risks of leaving sleep problems untreated. 50 Finally, the acceptable side-
effect profile of prazosin and low dropout rate that has been found in the studies
to date have a favorable appearance compared to the SSRIs, with their common
unacceptable sexual side effects and the high dropout rates that meta-analyses
have noted.
Table 2 | Effect of Prazosin on Sleep and PTSD Symptoms in Three
Placebo-Controlled, Randomized Trials
CAPS, Clinician-Administered PTSD Scale.
Clearly, we need larger studies with prazosin, and we need to know if alpha-1
adrenergic agents can be effective for the full spectrum of PTSD symptoms.
Some studies are under way: one involving 320 veterans across 13 VA medical
centers, and another studying 120 active-duty soldiers at Fort Lewis,
Washington. These studies are expected to be completed in late 2012. In the
interim, our view is that the current evidence is sufficiently strong to consider
employing this agent as a first-line intervention.
Other alpha-1 blocking agents such as doxazosin (4–8 mg/day) and terazosin
(3–7 mg/day) may have similar effects on PTSD symptoms, according to brief
reports of 12 and 20 patients, respectively. 51 , 52 Although these products
apparently do not cross the blood-brain barrier, the investigators propose that
reduction of peripheral adrenergic activity, including tachycardia, may
secondarily attenuate central nervous system manifestations of hyperarousal.
This hypothesis requires further investigation.
If sleep has improved to an acceptable level, the patient may be maintained on
prazosin. The long-term observational follow-up study of prazosin use in 62
patients for up to six years mentioned above found that almost 50% of patients
took prazosin until the end of the study period, usually without adding other
medications for PTSD.47
Node 2a, Continued: The Use of Trazodone
If prazosin fails to improve insomnia, or if it improves nightmares but without
eliminating problems with sleep onset—and if other causes unrelated to PTSD
have been addressed—then it may be worth considering a trial of low-dose
trazodone (see Figure 1 ). It can be added or substituted, depending on whether
prazosin is perceived to offer benefit.
Trazodone, a sedating antidepressant, has shown some effectiveness for sleep
difficulties in PTSD patients in open-label studies. 53 It was the most widely
prescribed medication used for hypnotic purposes in the United States in 2005. 54
Excess sedation, dizziness, and orthostasis occur frequently, and syncope
occasionally. In males, priapism is a concern. 55 Milder erectile stimulation is
apparently much more common; before the advent of medications such as
sildenafil, trazodone was recommended for patients with erectile dysfunction. 56
Trazodone has recently been described as an “ideal hypnotic agent.” It has
triple sleep-promoting actions (at the 5-HT2A, alpha-1, and H1 receptors), a
short half-life, and a low risk of dependence. 57 Although it has not received
FDA approval for primary insomnia, in a placebo-controlled RCT of trazodone
50 mg and zolpidem 10 mg in 278 patients with primary insomnia, the two
medications had similar efficacy at two weeks, and both had a low incidence of
adverse effects. The study was sponsored by the manufacturer of zolpidem. 58
If trazodone is used, side effects should be actively reviewed and monitored.
Since other medications can cause priapism, including prazosin and
phosphodiesterase inhibitors (e.g., sildenafil), combining trazodone with these
agents demands extra caution regarding this side effect. The combination of
trazodone and prazosin may also produce additive problems with blood pressure.
Trazodone is usually started at 50 mg at bedtime, with instructions to reduce to
25 mg if too sedating. The dosage of trazodone for sleep has ranged from 12.5 to
300 mg.
Node 2b
If the patient presents with difficulty falling asleep but not with nightmares or
nocturnal hyperarousal, trazodone may again be considered after identifying and
managing other contributing factors. Since prazosin is generally nonsedating, it
may be less useful in this situation. At this early point in the algorithm,
trazodone might work well enough to eliminate the need for further
pharmacotherapy for a patient with sleep-onset difficulties, but the evidence for
its use in these circumstances is much less compelling than for the use of
prazosin in patients with nightmares.
Trazodone may also be a good choice for patients who request a sleep aid for
the short term while waiting for medications (e.g., SSRIs) targeting general
symptoms of PTSD to take effect. Trazodone does appear to have efficacy for
SSRI-induced insomnia and nightmares, as demonstrated in two small, placebo-
controlled RCTs and some open-label studies.53 , 55 , 59 , 60 If, during any
subsequent steps of the algorithm when SSRIs and SNRIs are employed,
insomnia/nightmares either fail to improve or emerge de novo, the addition of
trazodone should be considered.
Other Medications for Insomnia?
If prazosin and trazodone are not effective or not tolerated in nodes 2, 2a, and
2b, other medications with hypnotic properties may be considered—and are
often used in clinical practice. The authors did not find sufficient evidence to
support their use at this early point in the algorithm. We will comment briefly on
several.
The tricyclic antidepressants (TCAs) imipramine and amitriptyline have some
evidence of usefulness in PTSD. 61 , 62 However, their side effects, especially at
full doses, include anticholinergic, cardiac, and seizure risks. TCAs are also
undesirable in suicidal patients, who might overdose on them.
Doxepin is a TCA that has recently been studied in large, placebo-controlled
RCTs as a treatment for primary insomnia in very low doses of 1–6 mg; one
study included geriatric patients. 63 It was found to be safe and effective for
transient or chronic insomnia and received FDA approval as a hypnotic in March
2010. It has been marketed at these doses under the new brand name Silenor, but
it will still be available as a generic capsule in doses as low as 10 mg. Its
mechanism of action at these doses appears to be histamine H1 blockade.63 It
may not provide any advantage over sedating antihistamines such as
diphenhydramine or hydroxyzine. Tolerance to the sedative effects of
antihistamines has been shown to occur quickly, making them impractical for the
long-term use usually required in PTSD. 64
Benzodiazepines (BZs) are frequently used by clinicians for sleep problems in
PTSD. However, in the only placebo-controlled RCT with a BZ (n = 10),
alprazolam demonstrated no efficacy for core PTSD symptoms. 65 When used in
PTSD patients who have problems with substance use, BZs have a high potential
for abuse.19 As with the use of antidepressants in bipolar disorder, the use of BZs
in patients with PTSD (with or without substance abuse) represents an area of
significant difference between common practice and guideline
recommendations.5 , 8 , 66 In both cases, clinicians may perceive that patients
improve in the short term while not suspecting placebo effects and without
anticipating the potential for harm over the long term. BZs might be considered
when a past history of clear response without significant abuse or misuse is
present.4 If the patient has a history of substance abuse, one possibility is to
prescribe a small quantity to test the patient’s ability to use appropriately.
Recently, eszopiclone, a GABA-A/benzodiazepine receptor agonist, was
administered for insomnia associated with PTSD in 24 patients, mostly women
with civilian trauma and no history of substance abuse. Efficacy was
demonstrated over three weeks in this placebo-controlled RCT. Further research
on the use of this class of agents is warranted. 67
Quetiapine is also widely prescribed for sleep in PTSD. However, a review of
reports of using quetiapine for sleep in various patient populations concluded
that the benefits did not justify the risks and that it should not be used as a first-
line treatment for insomnia. 68 Notably, the weight gain from quetiapine is not
dose related and can occur even at low doses. 69 , 70 A recent observational study
mentioned earlier compared results with quetiapine and prazosin for PTSD in a
VA setting between 2002 and 2005 (n = 62 on prazosin; n = 175 on
quetiapine).47 Quetiapine at a low mean dose of 64 mg was much more likely
than low-dose prazosin (3 mg) to be discontinued due to intolerable side effects
(35% vs. 18%, p = 0.008). Sedation and metabolic effects were the most
common reasons for discontinuing quetiapine. The authors’ concluding
recommendation was that “prazosin be used first-line for treating nighttime
PTSD symptoms in veterans.” One RCT of low to moderate doses of quetiapine
monotherapy versus placebo for PTSD with prominent insomnia has been
presented in poster format. 71 Some uncontrolled evidence also suggests that
quetiapine be added to SSRI therapy after the latter has proved unsatisfactory.47 ,
72 These reports will be discussed at a later node in the algorithm—in particular,
when we consider augmentation strategies for SSRIs.
Other hypnotics (e.g., zolpidem) and other sedating psychotropic agents (e.g.,
gabapentin) are occasionally used in clinical practice for PTSD-related sleep
problems, but the evidence base for them is too small to consider them in this
algorithm as options for initial treatment.
NODE 3: HAVE YOU GIVEN A TRIAL OF AN
SSRI?
If the patient does not have prominent sleep disturbance, or if prazosin or
trazodone was not tolerated or only partially effective for residual PTSD
symptoms such as hyperarousal, reexperiencing, and avoidance, the next step in
the algorithm would generally be to consider an SSRI trial. The evidence
supporting the use of SSRIs is weak, however, which is one reason that they are
not at the top of this algorithm for patients with prominent insomnia. Also, as
noted earlier, SSRIs often fail to treat insomnia associated with PTSD, can
sometimes aggravate it,59 and can produce intolerable sexual dysfunction. 73
Several recent comprehensive reviews and meta-analyses focus on using
SSRIs for PTSD. The first was a Cochrane Review. 74 Overall, the authors found
a number needed to treat (NNT) of about 5, which is reasonable. The calculated
NNT was based on the number of patients across all studies found to be
“responders” to medication. “Response” was defined for purposes of that review
as having either a final rating of “much improved” or “improved” as measured
by the Clinical Global Impression of Improvement (CGI-I) or, for a small
number of studies, similar outcomes on the Duke Global Rating for PTSD or on
other validated scales. The authors noted, however, that many of the studies
were flawed because of relatively small numbers, low effect sizes, and short trial
periods. Positive clinical outcomes were less convincing because of high dropout
rates (27% to 40%).26 , 28 , 75 , 76 Also, problems were also noted with tolerability.
A separate concern was that many trial subjects came from primary care
populations that are “less sick” than patients seen in a psychiatric setting.
Another major review of PTSD treatment data, published in 2008, was
commissioned by the VA and conducted by an eight-expert panel from the
Institute of Medicine of the U.S. National Academy of Sciences.11 This review
examined data from 14 SSRI studies conducted between 1991 and 2007. Seven
of these studies were deemed to be “weakly informative with respect to efficacy
because of study limitations.” The committee reached the overall conclusion that
“the evidence is inadequate to determine the efficacy of SSRIs in PTSD.”
Another detailed meta-analysis was conducted by the National Institute for
Clinical Excellence (NICE), part of the British National Health Service.7 That
review, which employed a more intensive and statistically rigorous analysis than
many qualitative reviews of this literature, also raised concern that SSRIs might
be significantly less effective than commonly thought for the treatment of PTSD.
The NICE analysis examined data for the SSRIs citalopram, fluoxetine,
paroxetine, and sertraline, as well as for amitriptyline, brofaromine, imipramine,
mirtazapine, olanzapine, phenelzine, risperidone, and venlafaxine. Data from
unpublished studies were included when obtainable from pharmaceutical
companies.
The NICE guidelines proposed definitions of levels of efficacy that could be
considered “clinically meaningful” or “clinically important.” Setting a
conservative standard, an effect size compared to placebo of a standard mean
difference (SMD) of 0.5 or better was considered “clinically meaningful,” and
an SMD of 0.8 or more was considered “clinically important.” They found that
none of the SSRIs were beneficial for PTSD symptoms at an effect size of 0.5
and thus that the benefits were not clinically meaningful. Furthermore, reported
effect sizes were considered to be overestimated because of the use of intent-to-
treat analyses with last-observation-carried-forward in studies that had high
dropout rates.
Some details of the NICE data on individual SSRIs will be briefly reviewed.
Paroxetine was evaluated in four RCTs, two of which were unpublished. One
was a placebo-controlled study by Marshall and colleagues in 2001 that reported
positive outcomes using the Clinician-Administered PTSD Scale (CAPS).28 The
specific PTSD symptom clusters of reexperiencing, hyperarousal, and
numbing/avoidance were included. Marshall and colleagues replicated those
results in a second RCT in 2007.31
The NICE meta-analysis of these paroxetine studies found that efficacy on the
CAPS (effect size = 0.42) and on the Davidson Trauma Scale (DTS) (0.41)
approached the 0.5 benchmark for clinical meaningfulness. In one unpublished
study, however—a maintenance trial carried out in patients who responded to
paroxetine in a 12-week acute study and then were assigned to either placebo or
continuation of paroxetine for 24 weeks—there was no efficacy and actually a
trend in favor of placebo on the CAPS (effect size = 0.19). This surprising result
suggests that something may have been irregular about the patient sample of this
unpublished study.
Sertraline , the other FDA-approved SSRI, was studied in four large RCTs,
two with positive results and two showing no efficacy. Three are published.
Brady and colleagues75 showed positive drug-versus-placebo differences for
three of four primary outcome measures (CAPS, CGI of change, and CGI of
severity) in a population of mostly women with sexual and other civilian trauma.
Davidson and colleagues26 used a similar design and population, and found
sertraline to be statistically superior to placebo using four primary outcome
measures. In the RCT by Friedman and colleagues,17 however, which involved
chronically ill combat veterans, sertraline produced no efficacy versus placebo
as measured by the CAPS, CGI, or Impact of Event Scale. The fourth study,
which is unpublished but was included in the NICE meta-analysis discussed
earlier,7 found no efficacy—possibly related, it was speculated, to the chronicity
of symptoms, gender, or the type of trauma that subjects endured.
In the NICE meta-analysis of these sertraline data,7 it was found that sertraline
was “unlikely” to be beneficial by self-report measures of the DTS or the Impact
of Event Scale, because of very small effect sizes of 0.18 and 0.06, respectively.
The effect size on the CAPS (0.26) was rated as “inconclusive.”
After evaluating the sertraline studies, licensing authorities in England
approved sertraline only for women with PTSD. In the United States the FDA
approved sertraline for PTSD patients of both genders. However, the FDA
imposed a fine on the corporate sponsor of the trial by Friedman and colleagues17
for withholding the study’s negative data for almost ten years.
Fluoxetine was the subject of three major studies, with mixed results. 77 – 79
Two of the studies, which involved RCTs of 12 weeks followed by a 24-week
maintenance phase, showed fluoxetine to be effective and well tolerated for the
initial 12-week period and for the relapse-prevention phase. Subjects were
mostly combat veterans, though some had civilian trauma, and the overall effect
size for fluoxetine was about 0.4. The largest study, however—involving 411
civilian women—found fluoxetine to be equivalent to placebo on the CAPS.79
An earlier, smaller study found no efficacy for fluoxetine in older, chronically ill
combat veterans.16 The NICE meta-analysis of fluoxetine, which looked at the
above studies and some unpublished data, found the overall evidence for
fluoxetine “inconclusive” on the DTS or CAPS (effect size = 0.28). They found
no efficacy (effect size = 0.02) on the self-report measure of the Treatment
Outcome PTSD Scale.7
Citalopram has been employed in one published RCT and several open-label
studies. In an open trial (n = 38, mostly children and adolescents), citalopram
improved total CAPS-2 scores and subscale ratings for reexperiencing,
hyperarousal, and avoidance. 80 English and colleagues 81 conducted an eight-
week, open-label study of citalopram in eight combat veterans. They found
improvement on the CAPS, Hamilton Rating Scale for Anxiety, and CGI
(among others) at week 4 but not at week 8. Tucker and colleagues76 conducted a
double-blind study of citalopram versus sertraline versus placebo for PTSD
patients (n = 25, 23, and 10, respectively). Using an intent-to-treat analysis, the
authors found significant improvement in total symptoms of PTSD measured by
the CAPS, as well as for all three symptom clusters and sleep time, in all three
groups, including placebo.
Robert and colleagues 82 published an open-label study with escitalopram in
25 patients, finding significant improvement for the CAPS-C
(avoidance/numbing) and CAPS-D (hyperarousal) subscales, but only trend
improvement for the CAPS-B (reexperiencing) subscale.
Alternatives to SSRIs at Node 3
As noted, side effects such as sexual dysfunction may make SSRIs unacceptable
to some patients. Options that might be considered at node 3 include bupropion,
mirtazapine, and certain antipsychotics. Nefazodone also has few sexual side
effects and some evidence of efficacy in PTSD, but due to the risk of liver
toxicity, it is not considered until later in the algorithm. Venlafaxine has efficacy
for PTSD, but it has sexual side effects, and for other reasons (to be discussed) it
seems better as a second-line option.
Bupropion showed some promise in an open-label trial in 17 combat veterans,
but those results were not confirmed in an eight-week, placebo-controlled RCT
in 30 patients with mixed civilian and military trauma. 83 , 84 Some patients had
bupropion added to an SSRI. A trend toward better outcomes was evident in
younger patients and those on monotherapy. More research is needed to
determine if bupropion is effective for PTSD.
The evidence for using mirtazapine is more favorable, although its desirability
is limited by the risk of weight gain. Bahk and colleagues 85 published a small
study (n = 15) of the effectiveness and tolerability of mirtazapine in an eight-
week trial in Korean patients with chronic PTSD. The dosing regimen was
flexible, and patients were evaluated at four and eight weeks on several rating
scales. At eight weeks, scores on all scales showed significant improvement. The
medication was well tolerated. An open-label study by Chung and colleagues in
2004, 86 also in Korean veterans, compared mirtazapine to sertraline. Both were
well tolerated and seemed effective.
Davidson and colleagues 87 conducted a placebo-controlled, double-blind RCT
of mirtazapine in 29 patients, with impressive results. The dose ranged up to 45
mg per day for eight weeks, with the DTS used as the primary outcome measure.
Rates of response were 65% and 20% for mirtazapine and placebo, respectively
(NNT = 2.2). The medication was well tolerated.
A long-term (24-week) study of mirtazapine was published by Kim and
colleagues in 2005. 88 Twelve of 15 participants completed the study. The results
suggested that mirtazapine might be effective for continuation treatment.
Certain antipsychotics are another alternative to SSRIs at node 3. For
example, as noted at node 2, some clinicians use quetiapine as a monotherapy,
first-line treatment for the global symptoms of PTSD, although the published
evidence to support this practice is minimal. As noted earlier, the side effect
risks are considerable, making the product appear unsuitable for early selection
in the algorithm.
Node 3 Conclusion
The FDA has approved the SSRIs sertraline and paroxetine for the treatment of
PTSD. Paroxetine has the best evidence of efficacy but has more problems with
sexual dysfunction, constipation, sedation, drug interactions, withdrawal
syndrome, and weight gain than the other SSRIs.66 The pregnancy risk rating of
D is an issue with women of childbearing potential. Though the evidence
supporting sertraline is weaker, especially in male combat veterans, it has fewer
side effects than paroxetine. It may be reasonable to consider non-FDA-
approved citalopram: although the subject of fewer and less rigorous studies in
relation to PTSD, citalopram’s efficacy in other anxiety disorders and in major
depression suggests that its benefit in treating PTSD might be comparable to that
of other SSRIs. It was thought to have the fewest side effects within the SSRI
class. 89 However, the FDA just issued a Drug Safety Communication saying that
the dose should not exceed 40 mg daily due to QTc prolongation risks.
According to most sources, an adequate trial of an SSRI for treating a PTSD
patient would run 4 to 6 weeks, although sometimes up to 12 weeks are required.
Some patients show a partial response to SSRIs or a response that is limited to
certain symptom domains in PTSD. Patients who partially respond but are still
improving should be continued until the benefits reach a plateau. If improvement
stalls for two or three weeks, consider raising the dose or switching to another
option (see node 4). Augmentation may be considered (see nodes 3a and 5a) if
both clinician and patient are convinced that the partial improvement was not a
placebo effect and not attributable to other aspects of the treatment such as
psychotherapy—which can be difficult to evaluate. Before proceeding with
augmentation, keep in mind the preceding discussion indicating that SSRIs
outperform placebo in controlled trials much less than generally assumed.
“Augmenting” a likely placebo effect with another medication should be
avoided. Also, augmentation introduces risks of increased side effects and drug
interactions, reduced compliance due to complexity of regimens, and increased
cost. In this algorithm, augmentation for partial response is considered most
appropriate at nodes 3a and 5a. A switch is considered at node 4. See Figure 1 .
Node 3a: Does the Patient Have PTSD-Related Psychosis?
PTSD-related psychotic symptoms are often present in PTSD patients. 90
Symptoms include phenomena referable to the original trauma—for example,
hearing soldiers scream, experiencing visual hallucinations of an enemy, or other
combat-related themes. Unrelated—for example, paranoid—delusions can also
occur. Delusions related to PTSD are non-bizarre and not associated with
disorganized thought or flat or inappropriate affect, and are not related to
substance abuse or withdrawal. They do not occur only during dissociative
flashbacks. 91 Patients with these psychotic symptoms can be considered one
subgroup of PTSD patients for whom early augmentation may be justified. For
this purpose, atypical antipsychotics are the medication of choice.
A preliminary study of risperidone (mean dose = 2.5 ± 1.25 mg/day) as an
augmentation of antidepressants in 40 combat veterans with chronic PTSD-
related psychotic symptoms demonstrated a significant decrease in psychotic
symptoms and an improvement in reexperiencing symptoms. 92 A more recent,
placebo-controlled RCT of risperidone augmentation for SSRI-resistant civilians
with psychotic PTSD found improvement in the positive symptoms and paranoia
subscales of the Positive and Negative Symptom Scale. 93
Open-label studies support the addition of quetiapine and olanzapine, but not
the first-generation neuroleptic fluphenazine, for antidepressant-resistant
psychotic combat veterans with PTSD.22 , 94 , 95 The quetiapine study involved
patients resistant to SSRIs and other medications who were admitted to an
inpatient unit for the trial.22 Without a placebo control it is impossible to exclude
that the positive outcome (on all three dimensions of PTSD symptoms) was due
to the effects of hospitalization. We could not find any reports of aripiprazole
augmentation in patients with PTSD-related psychosis.
Thus, if the patient does not respond satisfactorily to an antidepressant and has
PTSD-related psychosis, it seems reasonable to add an antipsychotic. The
evidence base points to risperidone since it has one published, placebo-
controlled RCT with favorable results. Quetiapine is widely used, has some
evidence as an augmentation in nonpsychotic PTSD, 96 and might also be tried
here. If the patient responds well to addition of an antipsychotic, and the SSRI
had minimal benefit, gradually removing the SSRI should be considered to
determine if it was necessary for the improvement.
NODE 4: HAVE YOU TRIED A SECOND SSRI,
SNRI, OR MIRTAZAPINE?
If the patient is not psychotic and was nonresponsive to the initial SSRI chosen
in node 3, several prime options are available: trying a different SSRI, an SNRI
(especially venlafaxine), or an antidepressant with different dual actions
(mirtazapine, evidence for which was discussed under node 3).
Venlafaxine was initially thought less likely to be effective in PTSD because
of its noradrenergic component, given that PTSD is characterized by excessive
noradrenergic activity. 97 , 98 An early RCT in combat veterans employing the
strong norepinephrine reuptake-blocking tricyclic desipramine (n = 18) found no
efficacy. 99 However, two large, placebo-controlled RCTs have been conducted
to evaluate the efficacy of venlafaxine ER in PTSD, and both demonstrated
some efficacy.
One of these venlafaxine studies involved 329 outpatients, mostly female,
from international sites. 100 Only 12% had combat-related trauma. In this 24-
week trial, CAPS scores improved five points more on venlafaxine than on
placebo (p = 0.06). Mean daily maximum dose of venlafaxine ER was 222 mg.
Reexperiencing and avoidance symptoms improved, but hyperarousal did not,
possibly due to the impact of the noradrenergic component of venlafaxine.
Overall effect sizes were small and similar to those found in the short-term SSRI
studies even after almost six months of treatment.
The second study was a 12-week comparison of venlafaxine ER, sertraline,
and placebo in a similar population of 538 patients, with CAPS scores again
used as the primary outcome measure. 101 Remission rates at week 12 were 30%
with venlafaxine, 24% with sertraline, and 20% with placebo. Mean daily
maximum doses with venlafaxine and sertraline were 225 mg and 151 mg,
respectively. Venlafaxine demonstrated statistically significant benefits over
placebo (p < 0.05), but again, effect sizes were generally small on secondary
outcome measures (particularly patient satisfaction and quality of life). Sertraline
response did not differ from placebo on most measures, consistent with the
unimpressive results with sertraline discussed earlier, in node 3. Both
medications were similarly tolerated, with 10% attrition from side effects.
In a separate pooled analysis, the authors of these two studies attempted to
differentiate response by gender and by trauma type. 102 No consistent predictors
were found despite the opportunity presented by the large number of subjects.
Venlafaxine offered no benefit for insomnia or nightmares. 103
Thus, venlafaxine is a reasonable option as a second-choice pharmacotherapy,
but the evidence base (despite the better response rate than sertraline in one
study) seems to suggest no reason to prefer it to SSRIs for first-line use. It was
ineffective for hyperarousal and sleep disturbance. Cardiovascular safety issues
might affect certain vulnerable patients.101
NODE 5: HAVE YOU TRIED A THIRD
MEDICATION AMONG SSRIs, SNRIs,
MIRTAZAPINE, OR NEFAZODONE?
If two adequate monotherapy regimens among the SSRIs, SNRIs, or mirtazapine
have been tried with no response to either, a third trial seems reasonable. The
options may now include nefazodone, which is limited to third-line due to its
liver toxicity. Fatal hepatotoxicity has been estimated to occur in about one in
250,000 patients. 104 Despite the rarity of this complication, nefazodone was
removed from European formularies in 2003 but remains available in the United
States as a generic. The usual side-effect profile of nefazodone actually makes it
rather desirable, given the lack of weight gain or sexual side effects, less
sedation than trazodone, and low risk of priapism.
Evidence to support the efficacy of nefazodone for PTSD includes two RCTs
(one placebo-controlled) and several open-label trials. 105 – 107 The placebo-
controlled RCT, with 41 patients, found benefits on the CAPS, with an
impressive effect size of 0.6 (p = 0.04).107 The other RCT was less impressive: it
was a comparator study of the effectiveness of nefazodone and sertraline in a 12-
week, randomized, double-blind study involving 37 patients, using the CAPS,
CGI, and DTS measures. 108 It found no significant difference between groups on
any outcome measure, including PTSD cluster symptoms, depression, sleep, and
quality of life over time. In an analysis of six open-label trials involving 105
patients, Hidalgo and colleagues 109 found that 46% had an improvement of at
least 30% on the CAPS.
Although small (n = 10), a nefazodone study conducted by Hertzberg and
colleagues 110 , 111 is of interest because subjects were followed for three to four
years. Originally conducted as a 12-week study,110 long-term follow-up was
described in 2002.111 The dose was 400–600 mg, and ten of ten participants were
rated as “much improved” on the CGI at 12 weeks. After three years of
monitoring, seven of ten were still “much improved,” while two were minimally
improved and one was worse than his original baseline.
Another interesting nefazodone case series involved 19 treatment-resistant
combat veterans with PTSD. Zisook and colleagues 112 administered doses of
100–600 mg per day for 12 weeks to patients who had failed three previous
medication trials. Improvements were noted in intrusive thoughts, avoidance,
hyperarousal, sleep, sexual function, and depression. The reduction in PTSD
symptoms, as measured by the CAPS, was 32%. Side effects were typically mild
and included headaches, dry mouth, and gastrointestinal disturbance.
Node 5a: If No Response or Partial Response, Consider
Augmentation (Depending on Residual Symptoms) or Try Other
Monotherapies
If the patient failed to respond to the previous interventions, or if the response
was partial, not explained by placebo effect, and still unsatisfactory in some
respects, various options are available: mood stabilizers (gabapentin,
lamotrigine, levetiracetam, tiagabine, topiramate, and valproate), antipsychotics
(aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone), anti-
adrenergic agents (alpha-1 antagonists, alpha-2 blockers, and beta-blockers), and
monoamine oxidase inhibitors (MAOIs). The supporting evidence ranges from
unconvincing to fairly robust.
Some of these treatments appear useful for all of the symptom clusters of
PTSD (avoidance, hyperarousal, reexperiencing), whereas others have evidence
that they target one or more clusters. As noted earlier, the general principle is
that one should try to minimize polypharmacy by critically evaluating partial
response and determining if improvement was due to real effects of the
medication or to a nonspecific response to other concomitantly administered
treatments (including psychotherapy) or to changed circumstances (including
hospitalization). If either of the latter is suspected, consider switching rather than
augmenting. It must be kept in mind, however, that the constellation of PTSD
manifestations is currently thought to include multiple symptom domains with
potentially different responses to medication, suggesting that some patients will
need more than one agent. We will briefly review some of the options,
considering strength of evidence and how the choice might be influenced by
comorbid psychiatric or medical problems. Patient preference and formulary
availability/cost will also affect choice. Medications are not listed in order of
preference, and the list is not complete. The flowchart in Figure 1 organizes
these medications by their target symptom clusters, consistent with the evidence
to be described below.
Anticonvulsants. In a 1991, open-label trial of valproic acid conducted at the
Seattle Veterans Affairs Medical Center involving 16 Vietnam veterans with
PTSD, 10 improved, mainly in symptoms of hyperarousal. 113 More recently, two
placebo-controlled RCTs of divalproex have been reported. The larger study,
published in 2008, involved 85 U.S. military veterans. It was conducted at the
Tuscaloosa Veterans Affairs Medical Center and supported by the manufacturer.
The subjects received a mean dose of 2,300 mg daily, which produced a mean
average plasma level of 82 mg/L. 114 For total CAPS scores and for two of the
CAPS symptom clusters (reexperiencing, avoidance), the divalproex group
showed slightly less improvement than the placebo group. For the hyperarousal
cluster, the study and control groups had the same final scores. Depression,
anxiety, and CGI of severity likewise showed no differentiation between the
study and control groups, with the quantity of improvement similar to that seen
in the open-label trial. The other RCT, published in 2009 and conducted at the
Ralph A. Johnson VA Medical Center in Charleston, South Carolina,
randomized 29 combat veterans to divalproex or placebo and also found no
advantages for divalproex. In fact, the placebo group did significantly better for
the avoidance symptom cluster and on changes in CGI of severity. Given that all
three of these studies involved monotherapy with male combat veterans, it
remains to be seen whether this drug might prove more effective for use with
veterans in an adjunctive role or when used either as monotherapy or adjunctive
therapy for civilian males or for females.
In a double-blind, placebo-controlled study of lamotrigine for PTSD, 14
patients with different kinds of trauma were randomized 2:1 to either lamotrigine
or placebo. 115 Over eight weeks the medication was titrated to a maximum of
500 mg per day (as tolerated). The study found nonsignificant, but possibly
promising, improvement in reexperiencing and avoidance/numbing symptoms
with lamotrigine in comparison to placebo.
Two negative studies of topiramate for PTSD have been published. In a
double-blind, placebo-controlled RCT, 38 subjects with non-combat-related
PTSD were studied on doses up to 400 mg per day. 116 Overall results showed a
nonsignificant decrease in total CAPS scores. However, the treatment group did
have significant reductions in symptoms of reexperiencing and on a secondary
global outcome measure. The second study was a seven-week, double-blind,
placebo-controlled RCT in 40 subjects, all male veterans in a residential PTSD
treatment program. 117 The experimental group received flexible-dose topiramate
and had a high dropout rate (40% vs. 10% for placebo recipients). The authors
found no significant treatment effects, but the high dropout rate may have been a
factor in this outcome.
In an observational study, levetiracetam was administered to 23 civilian
patients with treatment-resistant PTSD, with the medication used adjunctively in
19 of those cases. 118 Outcome was evaluated retrospectively with several rating
instruments, including the CGI. At a mean dose of 2000 mg for 10 weeks,
patients improved significantly on all measures. Fifty-six percent responded,
26% remitted, and the medication was well tolerated.
One small, open-label study and one large, multicenter, double-blind RCT of
tiagabine have been published. In the former, 29 outpatients were treated for 12
weeks. 119 Responders (n = 18) were later entered into a double-blind
maintenance study and randomly assigned to continue on tiagabine or placebo.
During the extension phase, the placebo-treated patients did not relapse, but the
tiagabine patients made further improvements. In the RCT, 232 patients were
randomized to tiagabine or placebo for 12 weeks. 120 The experimental group
received up to 16 mg daily of tiagabine. No efficacy was found for the
anticonvulsant.
Antipsychotics. Risperidone has been evaluated in four small, placebo-
controlled RCTs in nonpsychotic patients (civilians and veterans) with PTSD 121 ,
122 and in a recent, larger-scale, placebo-controlled RCT studying 247 veterans
who had served in combat zones. 123 Many of these patients were “treatment-
resistant,” and in most, the risperidone was added to other medications. It
seemed to have some efficacy on the reexperiencing and hyperarousal symptom
clusters, although the effects were small. There was no effect shown for
avoidance.
In two open-label trials, quetiapine administered as an adjuvant was shown to
improve all three clusters of PTSD symptoms and also sleep disturbance.72 , 124
One double-blind, placebo-controlled RCT of quetiapine monotherapy in 80
patients with “chronic PTSD” (94% male, mean age = 52) has been completed
and is under review, but some results were provided in a poster.96 Patients were
all U.S. combat veterans, and 30% had PTSD-related psychotic features. The
doses ranged from 50 to 800 mg per day, with a mean of 258 mg.
Reexperiencing and hyperarousal improved significantly (p = 0.002 and p =
0.03, respectively), but as with risperidone, the avoidance symptom cluster did
not (p = 0.56). A separate analysis was not provided for the psychotic and
nonpsychotic patients. Thus, it is unclear if these results best apply here or at
node 3a.
Aripiprazole has been investigated in three uncontrolled studies of PTSD
patients from mixed populations, including civilians and veterans. Medication
was used as monotherapy in two of these studies 125 , 126 and as an adjunct to
various other treatments in the third.95 Aripiprazole monotherapy was found
effective over 12 weeks in an open-label trial in 22 combat veterans at a mean
dose of 13 mg.125 CAPS scores improved (p = .01). Another case series of 32
civilian patients from Brazil experienced good results at a mean dose of 10 mg
daily.126 CAPS scores improved from a mean of 83 at baseline to 51 at the
endpoint 16 weeks later (p = .001). All studies reported significant improvement
in reexperiencing and avoidance/numbing, but marginal benefit for hyperarousal.
Doses generally started at 5 mg.
Based on two small studies, the use of olanzapine has minimal support. 127 , 128
In a case series ziprasidone was reported to be effective in nonpsychotic PTSD.
129
The benefits of atypical antipsychotics must be weighed against their side
effects, including weight gain, metabolic syndrome, and cardiac risk.69 Ray and
colleagues, 130 in a large epidemiological survey, found that patients treated with
antipsychotics had about double the rate of sudden cardiac death compared to
non-treated controls who had similar psychiatric diagnoses and metabolic
syndrome symptoms. The relative risk ratio of death was 2.26 (95% CI, 1.88–
2.72) with atypical antipsychotics, and it was dose related.130 The mechanism of
death was thought likely to be arrhythmias, perhaps involving QTc
prolongations. The authors of this study advised a “sharp reduction” in using
these agents in populations for which the evidence of efficacy is limited. There is
growing concern that antipsychotics should not be used as primary or adjunctive
agents in treating PTSD unless other options with comparable effectiveness and
better safety have already been tried. 131
Medications Targeting Central Noradrenergic Dysregluation. Studies with
the alpha-1 adrenergic antagonist prazosin were reviewed earlier. Alpha-2
agonists (clonidine and guanfacine) and beta-adrenergic antagonists have also
been used for PTSD, with mixed results.
Two studies, one a placebo-controlled RCT, investigated clonidine . Kinzie 132
studied the combination of imipramine and clonidine in 9 traumatized
Cambodian refugees with concurrent PTSD and major depression. PTSD global
symptoms (CAPS) improved in 6 patients, nightmares improved in 7 patients,
and hyperarousal in 4 patients. Avoidance behavior showed no improvement. In
the RCT, 18 patients (17 female) with borderline personality disorder, all of
whom had prominent hyperarousal symptoms on the CAPS, were treated with
clonidine, up to 0.45 mg in divided doses, for two weeks. 133 Most were on other
medications, which were maintained, but benzodiazepines were not allowed.
Hyperarousal improved significantly versus placebo (p = 0.003), irrespective of
PTSD comorbidity. Sleep also improved across all subjects.
Guanfacine , a longer-acting alpha-2 agonist, was administered in two recent
RCTs, both with negative outcomes. Neylan and colleagues 134 treated 63
chronically ill U.S. veterans with guanfacine at a mean daily dose of 2.4 mg at
bedtime (achieved with weekly 0.5 mg increases) or placebo for eight weeks.
Most were on one or more other medications. Analysis showed no separation of
guanfacine and placebo on the CAPS, the Impact of Events Scale, general mood,
or subjective quality of sleep. In a smaller study, Davis and colleagues 135
administered guanfacine or placebo to combat veterans for eight weeks while
continuing their antidepressants. No improvement was shown on the CAPS or
DTS.
Beta-blockers have not received substantial study in chronic PTSD. Several
studies have explored the use of propranolol immediately after a trauma to
prevent the onset of PTSD. 136 – 139 The findings are variable, and more research
is needed before this treatment can be recommended.
Four RCTs have examined the short-term benefits of monoamine-oxidase
inhibitors in PTSD due to a variety of traumas. Two involved phenelzine.62 , 140
In the first, a comparison of phenelzine (n = 19), imipramine (n = 23), and
placebo (n = 18), there was significant improvement with both antidepressants
compared to placebo, but more so with the MAOI.62 The dropout rate was about
50%, however, making interpretation difficult. The other phenelzine study was
small and showed no benefit.140 The other two MAOI trials involved
brofaromine, a non-selective MAOI not available in the United States. 141 , 142
Both found no efficacy.
COMPARISON TO OTHER ALGORITHMS AND
GUIDELINE RECOMMENDATIONS:
The present algorithm for selecting psychopharmacology treatment for PTSD
differs in some respects from earlier versions of the PAPHSS algorithm and
other published algorithms and guidelines. The 1999 version of the PAPHSS
algorithm recommended initial use of trazodone for managing sleep disturbance,
including nightmares, with low-dose doxepin a second choice for patients not at
high risk for suicide, seizures, or cardiac events.4 That algorithm was similar to
the present version (and different from other guidelines at that time) in proposing
efforts to manage PTSD-related sleep problems before the introduction of an
SSRI or other antidepressants. The most recent (2005) NICE guidelines
recommended paroxetine and mirtazapine as first-line pharmacotherapy and
discouraged sertraline.7 Similarly, the International Psychopharmacology
Algorithm Project’s 2005 algorithm recommended an SSRI, SNRI, or
mirtazapine, whereas the American Psychiatric Association practice guideline
(2004) also endorsed SSRIs as first-line treatment.5 , 143 However, the
association’s March 2009 “Guideline Watch” for PTSD noted that more recent
studies “suggest that SSRIs may no longer be recommended with the same level
of confidence for veterans with combat-related PTSD.”10 It was also noted that
prazosin is “among the most promising advances,” though without any
indication as to when it should be used.
Table 3 | Characteristics of Other Algorithms and Guidelines for the
Treatment of PTSD
Psychopharmacology Algorithm
Project at Harvard South Shore
Program4
1999 Early use of hypnotic agent for sleep, trazodone
first-line, followed by SSRI for persistent daytime
PTSD symptoms
2005 SSRIs in PTSD are reviewed & shown to have a
The United Kingdom’s National
Institute for Clinical Excellence7
2005 SSRIs in PTSD are reviewed & shown to have a
more modest effect size then commonly
considered
Psychotherapy recommended as first-line
treatment
Canadian clinical practice guidelines
145
2005 First-line: one agent among fluoxetine,
paroxetine, sertraline, & venlafaxine XR
Second-line: mirtazapine, fluvoxamine,
phenelzine, & moclobemide, plus adjunctive
olanzapine or risperidone
The International Psychopharmacology
Algorithm Project5
2005 Once diagnosis of PTSD established, SSRI trial
recommended as first-line pharmacological
intervention, followed by venlafaxine &
mirtazapine trials
The International Society of Traumatic
Stress Studies6
2008 SSRIs recommended as first-line intervention,
followed by augmentation with atypical
antipsychotics
Prazosin considered “promising”
APA Guidelines Watch10 2009 Concludes new studies suggest SSRIs are less
effective than previously assumed
Prazosin considered a promising option for sleep
disturbance in PTSD
VA/DoD clinical practice guideline for
managing posttraumatic stress 146
2010 Strongest recommendation is for SSRIs & SNRIs
but suggests “some benefit” for prazosin,
mirtazapine, & adjunctive atypical antipsychotics
Recommends consideration of prazosin for
nightmares as adjunctive treatment if trazodone &
other hypnotics are insufficient
APA, American Psychiatric Association; DoD, Department of Defense; SNRI, serotonin-norepinephrine
reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; VA,
Veterans Administration.
The 2008 assessment by the National Academy of Sciences made no
psychopharmacology recommendations; it found the evidence “inadequate to
determine efficacy” for all classes of drugs reviewed.11 See Table 3 for a
summary of these and other algorithms and guidelines, with comments on their
essential features.
FINAL COMMENT
This heuristic will serve clinicians by offering a summary and interpretation of
the current evidence base pertinent to psychopharmacological practice.
Nevertheless, despite development of this and other algorithms and guidelines,
the treatment of PTSD remains a challenge for physicians and patients. More
needs to be learned about the pathophysiology of this chronic, disabling
condition and about the comorbidities with which it often presents.
Improvements in our understanding of genetics, the neurobiological
underpinnings of PTSD, and mechanisms related to each symptom cluster
promise to add refinements to the current treatment strategy.
Declaration of interest: The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of the article.
REFERENCES
1. Germain A, Buysse DJ, Nofzinger E. Sleep-specific mechanisms underlying posttraumatic stress
disorder: integrative review and neurobiological hypotheses. Sleep Med Rev 2008;12:185–95.
2. Rasmusson AM, Vythilingam M, Morgan CA 3rd. The neuroendocrinology of posttraumatic stress
disorder: new directions. CNS Spectr 2003;8:651–6, 665–7.
3. Wang Z, Neylan TC, Mueller SG, et al. Magnetic resonance imaging of hippocampal subfields in
posttraumatic stress disorder. Arch Gen Psychiatry 2010;67:296–303.
4. Osser DN, Renner JA, Bayog R. Algorithms for the pharmacotherapy of anxiety disorders in patients
with chemical abuse and dependence. Psychiatr Ann 1999;29:285–301.
5. Davidson J, Bernik M, Connor KM, Friedman MJ, Jobson KO, Yoshiharo K. A new treatment
algorithm for posttraumatic stress disorder. Psychiatr Ann 2005;35:887–98.
6. Foa EB, Keane TM, Friedman MJ, Cohen JA. Effective treatments for PTSD: practice guidelines from
the International Society for Traumatic Stress Studies. 2nd ed. New York: Guilford, 2008.
7. National Collaborating Centre for Mental Health. Post-traumatic stress disorder: the management of
PTSD in adults and children in primary and secondary care. London; Leicester, UK: Gaskell and the
British Psychological Society, 2005.
9. Bisson J, Andrew M. Psychological treatment of post-traumatic stress disorder (PTSD). Cochrane
Database Syst Rev 2005;(2):CD003388.
10. Benedek DM, Friedman MJ, Zatzick D, Ursano RJ. Practice guideline for the treatment of patients
with acute stress disorder and post-traumatic stress disorder. Arlington, VA: American Psychiatric
Publishing, 2009.
11. Committee on Treatment of Post-traumatic Stress Disorder, Institute of Medicine. Treatment of post-
traumatic stress disorder: an assessment of the evidence. Washington, DC: National Academies,
2008.
2008.
12. Hamoda HM, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: an update on psychotic depression. Harv Rev Psychiatry 2008;16: 235–47 .
13. Ansari A, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: an update on bipolar depression. Harv Rev Psychiatry 2010;18:36–55.
14. Osser DN, Dunlop LR. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: an update on generalized social anxiety disorder. Psychopharm Rev 2010;45:91–8.
15. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed., text
rev. Washington, DC: American Psychiatric Press, 2000.
16. van der Kolk BA, Dreyfuss D, Michaels M, et al. Fluoxetine in posttraumatic stress disorder. J Clin
Psychiatry 1994;55:517–22.
17. Friedman MJ, Marmar CR, Baker DG, Sikes CR, Farfel GM. Randomized, double-blind comparison
of sertraline and placebo for posttraumatic stress disorder in a Department of Veterans Affairs
setting. J Clin Psychiatry 2007;68:711–20.
18. Strawn JR, Geracioti TD Jr. Noradrenergic dysfunction and the psychopharmacology of
posttraumatic stress disorder. Depress Anxiety 2008;25:260–71.
19. Chilcoat HD, Breslau N. Posttraumatic stress disorder and drug disorders: testing causal pathways.
Arch Gen Psychiatry 1998;55:913–7.
20. Mason BJ, Kocsis JH, Ritvo EC, Cutler RB. A double-blind, placebo-controlled trial of desipramine
for primary alcohol dependence stratified on the presence or absence of major depression. JAMA
1996;275:761–7.
21. Otto MW, Perlman CA, Wernicke R, Reese HE, Bauer MS, Pollack MH. Posttraumatic stress
disorder in patients with bipolar disorder: a review of prevalence, correlates, and treatment strategies.
Bipolar Disord 2004;6:470–9.
22. Kozaric-Kovacic D, Pivac N. Quetiapine treatment in an open trial in combat-related post-traumatic
stress disorder with psychotic features. Int J Neuropsychopharmacol 2007;10:253–61.
23. Breslau N, Davis GC, Peterson EL, Schultz LR. A second look at comorbidity in victims of trauma:
the posttraumatic stress disorder-major depression connection. Biol Psychiatry 2000;48:902–9.
24. Gill J, Vythilingam M, Page GG. Low cortisol, high DHEA, and high levels of stimulated TNF-
alpha, and IL-6 in women with PTSD. J Trauma Stress 2008;21:530–9.
25. Rasmusson AM, Wu R, Paliwal P, Anderson GM, Krishnan-Sarin S. A decrease in the plasma
DHEA to cortisol ratio during smoking abstinence may predict relapse: a preliminary study.
Psychopharmacology (Berl) 2006;186:473–80.
26. Davidson JR, Rothbaum BO, van der Kolk BA, Sikes CR, Farfel GM. Multicenter, double-blind
comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Arch Gen
Psychiatry 2001;58:485–92.
27. Brady KT, Clary CM. Affective and anxiety comorbidity in post-traumatic stress disorder treatment
trials of sertraline. Compr Psychiatry 2003;44:360–9.
28. Marshall RD, Beebe KL, Oldham M, Zaninelli R. Efficacy and safety of paroxetine treatment for
chronic PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry 2001;158:1982–8.
29. Lewis CC, Simons AD, Nguyen LJ. Impact of childhood trauma on treatment outcome in the
treatment for adolescents with depression study (TADS). J Am Acad Child Adolesc Psychiatry
2010;49:132–40.
2010;49:132–40.
30. Brand BL, Classen CC, McNary SW, Zaveri P. A review of dissociative disorders treatment studies.
J Nerv Ment Dis 2009;197:646–54.
31. Marshall RD, Lewis-Fernandez R, Blanco C, et al. A controlled trial of paroxetine for chronic PTSD,
dissociation, and interpersonal problems in mostly minority adults. Depress Anxiety 2007;24:77–84.
32. Steiner H, Carrion V, Plattner B, Koopman C. Dissociative symptoms in posttraumatic stress
disorder: diagnosis and treatment. Child Adolesc Psychiatr Clin N Am 2003;12:231–49, viii.
33. Menon SJ. Psychotropic medication during pregnancy and lactation. Arch Gynecol Obstet
2008;277:1–13.
34. Kirby AC, Hertzberg BP, Collie CF, et al. Smoking in help seeking veterans with PTSD returning
from Afghanistan and Iraq. Addict Behav 2008;33:1448–53 .
35. Cook J, Jakupcak M, Rosenheck R, Fontana A, McFall M. Influence of PTSD symptom clusters on
smoking status among help-seeking Iraq and Afghanistan veterans. Nicotine Tob Res 2009;11:1189–
95.
36. Hertzberg MA, Moore SD, Feldman ME, Beckham JC. A preliminary study of bupropion sustained-
release for smoking cessation in patients with chronic posttraumatic stress disorder. J Clin
Psychopharmacol 2001;21:94–8.
37. Spoormaker VI, Montgomery P. Disturbed sleep in posttraumatic stress disorder: secondary symptom
or core feature? Sleep Med Rev 2008;12:169–84.
38. Belleville G, Guay S, Marchand A. Impact of sleep disturbances on PTSD symptoms and perceived
health. J Nerv Ment Dis 2009;197:126–32.
39. Thompson CE, Taylor FB, McFall ME, Barnes RF, Raskind MA. Nonnightmare distressed
awakenings in veterans with posttraumatic stress disorder: response to prazosin. J Trauma Stress
2008;21:417–20.
40. Neylan TC, Marmar CR, Metzler TJ, et al. Sleep disturbances in the Vietnam generation: findings
from a nationally representative sample of male Vietnam veterans. Am J Psychiatry 1998;155:929–
33.
41. Mellman TA, Knorr BR, Pigeon WR, Leiter JC, Akay M. Heart rate variability during sleep and the
early development of posttraumatic stress disorder. Biol Psychiatry 2004;55: 953–6.
42. Raskind MA, Peskind ER, Kanter ED, et al. Reduction of nightmares and other PTSD symptoms in
combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry 2003;160:371–3.
43. Raskind MA, Peskind ER, Hoff DJ, et al. A parallel group placebo controlled study of prazosin for
trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol
Psychiatry 2007;61:928–34.
44. Lamarche LJ, De Koninck J. Sleep disturbance in adults with posttraumatic stress disorder: a review.
J Clin Psychiatry 2007;68:1257–70.
45. Kobayashi I, Boarts JM, Delahanty DL. Polysomnographically measured sleep abnormalities in
PTSD: a meta-analytic review. Psychophysiology 2007;44:660–9.
46. Taylor FB, Martin P, Thompson C, et al. Prazosin effects on objective sleep measures and clinical
symptoms in civilian trauma posttraumatic stress disorder: a placebo-controlled study. Biol
Psychiatry 2008;63:629–32.
47. Byers MG, Allison KM, Wendel CS, Lee JK. Prazosin versus quetiapine for nighttime posttraumatic
stress disorder symptoms in veterans: an assessment of long-term comparative effectiveness and
stress disorder symptoms in veterans: an assessment of long-term comparative effectiveness and
safety. J Clin Psychopharmacol 2010;30:225–9.
48. Nuzhat SS, Osser DN. Chest pain in a young patient treated with prazosin for PTSD. Am J
Psychiatry 2009;166: 618–9.
49. Contopoulos-Ioannidis DC, Gilbody SM, Trikalinos TA, Churchill R, Wahlbeck K, Ioannidis J.
Comparison of large versus smaller trials for mental-health interventions. Am J Psychiatry
2005;162:578–84.
50. Troxel WM, Buysse DJ, Matthews KA, et al. Sleep symptoms predict the development of the
metabolic syndrome. Sleep 2010;33:1633–40.
51. Chung. Effect of terazosin on posttraumatic nightmares. Poster (No. 356) presented at the annual
meeting of the American Psychiatric Association, San Diego, CA, May 2007.
52. De Jong J, Wauben P, Huijbrechts I, Oolders H, Haffmans J. Doxazosin treatment for posttraumatic
stress disorder. J Clin Psychopharmacol 2010;30:84–5.
53. Hertzberg MA, Feldman ME, Beckham JC, Davidson JR. Trial of trazodone for posttraumatic stress
disorder using a multiple baseline group design. J Clin Psychopharmacol 1996;16:294–8.
54. Leshner HI, Bagdhoyan HA, Bennett SJ, Caples SM, DeRubeis RJ, Glynn RJ. NIH State-of-the-
Science Conference Statement on manifestations and management of chronic insomnia in adults.
NIH Consens State Sci Statements 2005;22(2):1–30.
55. Warner MD, Dorn MR, Peabody CA. Survey on the usefulness of trazodone in patients with PTSD
with insomnia or nightmares. Pharmacopsychiatry 2001;34:128–31.
56. Sadock BJ, Sadock VA. Trazodone. In: Kaplan and Sadock’s pocket handbook of psychiatric drug
treatment. New York: Lippincott Williams & Wilkins, 2001:237–40 .
57. Stahl SM. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr 2009;14:536–46.
58. Walsh JK. Subjective hypnotic efficacy of trazodone and zolpidem in DSM III-R primary insomnia.
Hum Psychopharmacol 1998;13:191–8.
59. Kaynak H, Kaynak D, Gozukirmizi E, Guilleminault C. The effects of trazodone on sleep in patients
treated with stimulant antidepressants. Sleep Med 2004;5:15–20.
60. Nierenberg AA, Adler LA, Peselow E, Zornberg G, Rosenthal M. Trazodone for antidepressant-
associated insomnia. Am J Psychiatry 1994;151:1069–72.
61. Davidson J, Kudler H, Smith R, et al. Treatment of posttraumatic stress disorder with amitriptyline
and placebo. Arch Gen Psychiatry 1990;47:259–66.
62. Kosten TR, Frank JB, Dan E, McDougle CJ, Giller EL Jr. Pharmacotherapy for post-traumatic stress
disorder using phenelzine or imipramine. J Nerv Ment Dis 1991;179:366–70.
63. Scharf M, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly
patients with primary insomnia: a randomized, double-blind, placebo-controlled crossover study. J
Clin Psychiatry 2008;69:1557–64.
64. Richardson GS, Roehrs TA, Rosenthal L, Koshorek G, Roth T. Tolerance to daytime sedative effects
of H1 antihistamines. J Clin Psychopharmacol 2002;22:511–5.
65. Braun P, Greenberg D, Dasberg H, Lerer B. Core symptoms of posttraumatic stress disorder
unimproved by alprazolam treatment. J Clin Psychiatry 1990;51:236–8.
66. Baker DG, Nievergelt CM, Risbrough VB. Post-traumatic stress disorder: emerging concepts of
pharmacotherapy. Expert Opin Emerg Drugs 2009;14:251–72.
67. Pollack MH, Hoge EA, Worthington JJ. Eszopiclone for the treatment of posttraumatic stress
disorder and associated insomnia: a randomized, double-blind, placebo-controlled trial. J Clin
Psychiatry 2011;72:892–7.
68. Wine JN, Sanda C, Caballero J. Effects of quetiapine on sleep in nonpsychiatric and psychiatric
conditions. Ann Pharmacother 2009;43:707–13.
69. Simon V, van Winkel R, De Hert M. Are weight gain and metabolic side effects of atypical
antipsychotics dose dependent? A literature review. J Clin Psychiatry 2009;70:1041–50.
70. Williams SG, Alinejad NA, Williams JA, Cruess DF. Statistically significant increase in weight
caused by low-dose quetiapine. Pharmacotherapy 2010;30:1011–5.
71. Hamner MB, Canive J, Robert S, Calais LA, Villarreal G, Durkalski V. Quetiapine monotherapy in
chronic posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial. Paper
presented at the annual meeting of the American Psychiatric Association, San Francisco, CA, May
2009.
72. Hamner MB, Deitsch SE, Brodrick PS, Ulmer HG, Lorberbaum JP. Quetiapine treatment in patients
with posttraumatic stress disorder: an open trial of adjunctive therapy. J Clin Psychopharmacol
2003;23:15–20.
73. Cascade E, Kalali AH, Kennedy SH. Real-world data on SSRI antidepressant side effects. Psychiatry
(Edgmont) 2009;6:16–8.
74. Stein DJ, Ipser J, McAnda N. Pharmacotherapy of posttraumatic stress disorder: a review of meta-
analyses and treatment guidelines. CNS Spectr 2009;14:25–31.
75. Brady K, Pearlstein T, Asnis GM, et al. Efficacy and safety of sertraline treatment of posttraumatic
stress disorder: a randomized controlled trial. JAMA 2000;283:1837–44.
76. Tucker P, Potter-Kimball R, Wyatt DB, et al. Can physiologic assessment and side effects tease out
differences in PTSD trials? A double-blind comparison of citalopram, sertraline, and placebo.
Psychopharmacol Bull 2003;37:135–49.
77. Martenyi F, Brown EB, Zhang H, Prakash A, Koke SC. Fluoxetine versus placebo in posttraumatic
stress disorder. J Clin Psychiatry 2002;63:199–206.
78. Martenyi F, Soldatenkova V. Fluoxetine in the acute treatment and relapse prevention of combat-
related post-traumatic stress disorder: analysis of the veteran group of a placebo-controlled,
randomized clinical trial. Eur Neuropsychopharmacol 2006;16:340–9.
79. Martenyi F, Brown EB, Caldwell CD. Failed efficacy of fluoxetine in the treatment of posttraumatic
stress disorder: results of a fixed-dose, placebo-controlled study. J Clin Psychopharmacol
2007;27:166–70 .
80. Seedat S, Stein DJ, Emsley RA. Open trial of citalopram in adults with post-traumatic stress disorder.
Int J Neuropsychopharmacol 2000;3:135–40.
81. English BA, Jewell M, Jewell G, Ambrose S, Davis LL. Treatment of chronic posttraumatic stress
disorder in combat veterans with citalopram: an open trial. J Clin Psychopharmacol 2006;26:84–8.
82. Robert S, Hamner MB, Ulmer HG, Lorberbaum JP, Durkalski VL. Open-label trial of escitalopram in
the treatment of posttraumatic stress disorder. J Clin Psychiatry 2006;67: 1522–6.
83. Canive JM, Clark RD, Calais LA, Qualls C, Tuason VB. Bupropion treatment in veterans with
posttraumatic stress disorder: an open study. J Clin Psychopharmacol 1998;18:379–83.
Becker ME, Hertzberg MA, Moore SD, Dennis MF, Bukenya DS, Beckham JC. A placebo-
84. Becker ME, Hertzberg MA, Moore SD, Dennis MF, Bukenya DS, Beckham JC. A placebo-
controlled trial of bupropion SR in the treatment of chronic posttraumatic stress disorder. J Clin
Psychopharmacol 2007;27:193–7.
85. Bahk WM, Pae CU, Tsoh J, et al. Effects of mirtazapine in patients with post-traumatic stress
disorder in Korea: a pilot study. Hum Psychopharmacol 2002;17:341–4.
86. Chung MY, Min KH, Jun YJ, Kim SS, Kim WC, Jun EM. Efficacy and tolerability of mirtazapine
and sertraline in Korean veterans with posttraumatic stress disorder: a randomized open label trial.
Hum Psychopharmacol 2004;19:489–94.
87. Davidson JR, Weisler RH, Butterfield MI, et al. Mirtazapine vs. placebo in posttraumatic stress
disorder: a pilot trial. Biol Psychiatry 2003;53:188–91.
88. Kim W, Pae CU, Chae JH, Jun TY, Bahk WM. The effectiveness of mirtazapine in the treatment of
post-traumatic stress disorder: a 24-week continuation therapy. Psychiatry Clin Neurosci
2005;59:743–7.
89. Preskorn SH. Outpatient management of depression: a guide for the practitioner. 3rd ed. West Islip,
NY: Professional Communications, 2009.
90. David D, Kutcher GS, Jackson EI, Mellman TA. Psychotic symptoms in combat-related
posttraumatic stress disorder. J Clin Psychiatry 1999;60:29–32.
91. Moskowitz A, ed. Psychosis, trauma, and dissociation. Oxford: Wiley & Sons, 2009.
92. Hamner MB, Faldowski RA, Ulmer HG, Frueh BC, Huber MG, Arana GW. Adjunctive risperidone
treatment in posttraumatic stress disorder: a preliminary controlled trial of effects on comorbid
psychotic symptoms. Int Clin Psychopharmacol 2003;18:1–8.
94. Pivac N, Kozaric-Kovacic D, Muck-Seler D. Olanzapine versus fluphenazine in an open trial in
patients with psychotic combat-related post-traumatic stress disorder. Psychopharmacology (Berl)
2004;175:451–6.
95. Robert S, Hamner MB, Durkalski VL, Brown MW, Ulmer HG. An open-label assessment of
aripiprazole in the treatment of PTSD. Psychopharmacol Bull 2009;42:69–80.
96. Hamner MB, Canive J, Robert S, Calais LA, Villarreal G, Durkalski V. Quetiapine monotherapy in
chronic posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial. Paper
presented at the annual meeting of the American Psychiatric Association, San Francisco, CA, May
2009.
97. Southwick SM. Noradrenergic alterations in posttraumatic stress disorder. Ann N Y Acad Sci
1997;821:125–41.
98. Murphy SE, Yiend J, Lester KJ, Cowen PJ, Harmer CJ. Short term serotonergic but not
noradrenergic antidepressant administration reduces attentional vigilance to threat in healthy
volunteers. Int J Neuropsychopharmacol 2009;12:169–79.
99. Reist C, Kauffmann CD, Haier RJ, et al. A controlled trial of desipramine in 18 men with
posttraumatic stress disorder. Am J Psychiatry 1989;146:513–6.
100. Davidson J, Baldwin D, Stein DJ, et al. Treatment of posttraumatic stress disorder with venlafaxine
extended release: a 6-month randomized controlled trial. Arch Gen Psychiatry 2006;63:1158–65.
101. Davidson J, Rothbaum BO, Tucker P, Asnis G, Benattia I, Musgnung JJ. Venlafaxine extended
release in posttraumatic stress disorder: a sertraline- and placebo-controlled study. J Clin
Psychopharmacol 2006;26:259–67 .
102. Rothbaum BO, Davidson JR, Stein DJ, et al. A pooled analysis of gender and trauma-type effects
on responsiveness to treatment of PTSD with venlafaxine extended release or placebo. J Clin
Psychiatry 2008;69:1529–39.
103. Stein DJ, Pedersen R. Onset of activity and time to response on individual CAPS-SX17 items in
patients treated for posttraumatic stress disorder with venlafaxine ER: a pooled analysis. Int J
Neuropsychopharmacol 2009;12:23–31.
104. Gelenberg AJ. Nefazedone hepatotoxicity: black box warning. Biol Ther Psychiatry 2002;25:2.
105. Davis LL, Nugent AL, Murray J, Kramer GL, Petty F. Nefazodone treatment for chronic
posttraumatic stress disorder: an open trial. J Clin Psychopharmacol 2000;20:159–64.
106. Garfield DA, Fichtner CG, Leveroni C, Mahableshwarkar A. Open trial of nefazodone for combat
veterans with posttraumatic stress disorder. J Trauma Stress 2001;14:453–60.
107. Davis LL, Jewell ME, Ambrose S, et al. A placebo-controlled study of nefazodone for the
treatment of chronic posttraumatic stress disorder: a preliminary study. J Clin Psychopharmacol
2004;24:291–7.
108. McRae AL, Brady KT, Mellman TA, et al. Comparison of nefazodone and sertraline for the
treatment of posttraumatic stress disorder. Depress Anxiety 2004;19:190–6.
109. Hidalgo R, Hertzberg MA, Mellman T, et al. Nefazodone in post-traumatic stress disorder: results
from six open-label trials. Int Clin Psychopharmacol 1999;14:61–8.
110. Hertzberg MA, Feldman ME, Beckham JC, Moore SD, Davidson JR. Open trial of nefazodone for
combat-related posttraumatic stress disorder. J Clin Psychiatry 1998;59:460–4.
111. Hertzberg MA, Feldman ME, Beckham JC, Moore SD, Davidson JR. Three- to four-year follow-up
to an open trial of nefazodone for combat-related posttraumatic stress disorder. Ann Clin
Psychiatry 2002;14:215–21.
112. Zisook S, Chentsova-Dutton YE, Smith-Vaniz A, et al. Nefazodone in patients with treatment-
refractory posttraumatic stress disorder. J Clin Psychiatry 2000;61:203–8.
114. Davis LL, Davidson JR, Ward LC, Bartolucci A, Bowden CL, Petty F. Divalproex in the treatment
of posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial in a veteran
population. J Clin Psychopharmacol 2008;28:84–8.
115. Hertzberg MA, Butterfield MI, Feldman ME, et al. A preliminary study of lamotrigine for the
treatment of posttraumatic stress disorder. Biol Psychiatry 1999;45:1226–9.
116. Tucker P, Trautman RP, Wyatt DB, et al. Efficacy and safety of topiramate monotherapy in civilian
posttraumatic stress disorder: a randomized, double-blind, placebo-controlled study. J Clin
Psychiatry 2007;68:201–6.
117. Lindley SE, Carlson EB, Hill K. A randomized, double blind, placebo-controlled trial of
augmentation topiramate for chronic combat-related posttraumatic stress disorder. J Clin
Psychopharmacol 2007;27:677–81.
118. Kinrys G, Wygant L, Pardo T, Melo M. Levetiracetam for treatment-refractory posttraumatic stress
disorder. J Clin Psychiatry 2006;67:211–4.
disorder. J Clin Psychiatry 2006;67:211–4.
119. Connor KM, Davidson JR, Weisler RH, Zhang W, Abraham K. Tiagabine for posttraumatic stress
disorder: effects of open-label and double-blind discontinuation treatment. Psychopharmacology
(Berl) 2006;184:21–5.
120. Davidson JR, Brady K, Mellman TA, Stein MB, Pollack MH. The efficacy and tolerability of
tiagabine in adult patients with post-traumatic stress disorder. J Clin Psychopharmacol 2007;27:85–
8.
121. Pae CU, Lim HK, Peindl K, et al. The atypical antipsychotics olanzapine and risperidone in the
treatment of posttraumatic stress disorder: a meta-analysis of randomized, double-blind, placebo-
controlled clinical trials. Int Clin Psychopharmacol 2008;23:1–8.
122. Monnelly EP, Ciraulo DA, Knapp C, Keane T. Low-dose risperidone as adjunctive therapy for
irritable aggression in posttraumatic stress disorder. J Clin Psychopharmacol 2003;23:193–6.
123. Krystal J, Rosenheck R, Cramer J. Adjunctive risperidone treatment for antidepressant-resistant
symptoms of chronic military service-related PTSD. JAMA 2011;306: 493–502 .
124. Ahearn EP, Mussey M, Johnson C, Krohn A, Krahn D. Quetiapine as an adjunctive treatment for
post-traumatic stress disorder: an 8-week open-label study. Int Clin Psychopharmacol 2006;21:29–
33.
125. Villarreal G, Calais LA, Canive JM, Lundy SL, Pickard J, Toney G. Prospective study to evaluate
the efficacy of aripiprazole as a monotherapy in patients with severe chronic posttraumatic stress
disorder: an open trial. Psychopharmacol Bull 2007;40:6–18.
126. Mello MF, Costa MC, Schoedl AF, Fiks JP. Aripiprazole in the treatment of posttraumatic stress
disorder: an open-label trial. Rev Bras Psiquiatr 2008;30:358–61.
127. Butterfield MI, Becker ME, Connor KM, Sutherland S, Churchill LE, Davidson JR. Olanzapine in
the treatment of post-traumatic stress disorder: a pilot study. Int Clin Psychopharmacol
2001;16:197–203.
128. Stein MB, Kline NA, Matloff JL. Adjunctive olanzapine for SSRI-resistant combat-related PTSD:
a double-blind, placebo-controlled study. Am J Psychiatry 2002;159:1777–9.
130. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of
sudden cardiac death. N Engl J Med 2009;360:225–35.
131. Pies R. Should psychiatrists use atypical antipsychotics to treat nonpsychotic anxiety? Psychiatry
(Edgmont) 2009;6:29–37.
132. Kinzie JD, Leung P. Clonidine in Cambodian patients with posttraumatic stress disorder. J Nerv
Ment Dis 1989;177:546–50.
133. Ziegenhorn AA, Roepke S, Schommer NC, et al. Clonidine improves hyperarousal in borderline
personality disorder with or without comorbid posttraumatic stress disorder: a randomized, double-
blind, placebo-controlled trial. J Clin Psychopharmacol 2009;29:170–3.
134. Neylan TC, Lenoci M, Samuelson KW, et al. No improvement of posttraumatic stress disorder
symptoms with guanfacine treatment. Am J Psychiatry 2006;163:2186–8.
135. Davis LL, Ward C, Rasmusson A, Newell JM, Frazier E, Southwick SM. A placebo-controlled trial
of guanfacine for the treatment of posttraumatic stress disorder in veterans. Psychopharmacol Bull
2008;41:8–18.
2008;41:8–18.
136. Pitman RK, Sanders KM, Zusman RM, et al. Pilot study of secondary prevention of posttraumatic
stress disorder with propranolol. Biol Psychiatry 2002;51:189–92.
137. Vaiva G, Ducrocq F, Jezequel K, et al. Immediate treatment with propranolol decreases
posttraumatic stress disorder two months after trauma. Biol Psychiatry 2003;54:947–9.
138. Stein MB, Kerridge C, Dimsdale JE, Hoyt DB. Pharmacotherapy to prevent PTSD: results from a
randomized controlled proof-of-concept trial in physically injured patients. J Trauma Stress
2007;20:923–32.
139. Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK. Effect of post-retrieval
propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in
post-traumatic stress disorder. J Psychiatr Res 2008;42:503–6.
140. Shestatzky M, Greenberg D, Lerer B. A controlled trial of phenelzine in posttraumatic stress
disorder. Psychiatry Res 1988;24:149–55.
141. Baker DG, Diamond BI, Gillette G, et al. A double-blind, randomized, placebo-controlled, multi-
center study of brofaromine in the treatment of post-traumatic stress disorder. Psychopharmacology
(Berl) 1995;122:386–9.
142. Katz RJ, Lott MH, Arbus P, et al. Pharmacotherapy of posttraumatic stress disorder with a novel
psychotropic. Anxiety 1994;1:169–74.
143. American Psychiatric Association. Practice guideline for the treatment of patients with acute stress
disorder and posttraumatic stress disorder. Arlington, VA: APA, 2004.
144. Foa EB, Davidson JR, Frances A. The expert consensus guidelines: treatment of posttraumatic
stress disorder. J Clin Psychiatry 1999;60 (suppl 16).
145. Canadian Psychiatric Association. Clinical practice guidelines. Management of anxiety disorders.
Can J Psychiatry 2006; 51(8 suppl 2):9S–91S.
146. United States Department of Veterans Affairs; United States Department of Defense. Clinical
practice guideline for management of post-traumatic stress. Washington, DC: Veterans Health
Administration, DoD, 2010.
Prazosin: Still First Line for PTSD Patients With Prominent
Insomnia
Since the publication of the algorithm, there have been two more studies of
prazosin versus placebo for veterans with combat-related trauma and
posttraumatic stress disorder (PTSD). 1 , 2 One of these (n = 67) showed a
robust advantage of prazosin over placebo, and the second, larger and
multicentered, (n = 304 distributed over 13 Veterans Hospital sites) found
no advantage for prazosin. There was also a small placebo-controlled study
with 20 subjects in a civilian population, 85% female, with mild-to-
moderate levels of suicidality, and half of the patients had comorbid major
depression. This study found an advantage for placebo over prazosin for
insomnia and nightmares. 3 Added to the three small placebo-controlled
studies reviewed in the algorithm paper, there are, therefore, now six
studies, four in veterans or soldiers of which three were positive and two
among civilians of which one was positive.
In the 2013 Department of Veterans Affairs (VA) study, subjects took
prazosin at night and in the morning, and there was robust improvement on
all primary and secondary outcome measures on sleep, nightmares, global
functioning, and hyperarousal—similar to the previous three studies from
Raskind et al. A total of 64% responded to prazosin versus 27% on placebo,
a number needed to treat (NNT) of 2.7. However, in the much larger 2018
study, there were no differences from placebo despite similar dosing to the
2013 study. The authors and editorialists discussed possible explanations
for these negative results. Subjects were relatively stable socially,
economically, and clinically compared to those in previous studies. None of
the previous studies excluded patients who were unstable in these respects.
If patients were on trazodone and getting some benefit from it, they could
not participate unless they were willing to stop it. Trazodone helps many
PTSD patients fall asleep even if it is not as helpful for staying asleep and
preventing nightmares, while prazosin (a nonsedative) is not particularly
helpful for initial insomnia. It should also be noted that prazosin had been
prescribed in these VA hospitals for years, and perhaps the best candidates
for it had already been treated. It was also noted that patients had low
baseline blood pressure, suggesting they had a PTSD subtype that was less
adrenergically driven. A study of previous patient samples found that
higher pretreatment blood pressure was associated with greater PTSD
symptom reduction with prazosin. 4 Clinicians are advised to pay attention
to this possible predictor.
It seems reasonable to conclude that response to prazosin is
heterogeneous and precision medicine needs to be elaborated by future
studies to enable prediction of responders. However, meanwhile, the
medication had four positive studies with robust effect sizes. There clearly
are responders out there and it seems an important contributor to the
armamentarium of medications that could be considered. The evidence base
on prazosin may be contrasted with that of sertraline, a Food and Drug
Administration (FDA)-approved medication treatment for PTSD commonly
recommended at the top of guidelines, such as those of the Veterans
Administration. 5 This medication has had at least seven placebo-controlled
studies in PTSD, several of them unpublished but discussed in a National
Institute of Clinical Excellence (NICE) review, 6 but only two have been
positive. As we indicated in the 2011 review, the licensing agency in
England approved sertraline only for women with PTSD due to
unsatisfactory results in male veterans. Also, even in the best sertraline
studies, it had a small effect size—much smaller than what was found in the
positive prazosin studies.6 A recent review of PTSD psychopharmacology
concluded that sertraline is “best avoided” in combat veterans. 7 Also, there
has been much discussion of a 2019 study in veterans comparing sertraline
to prolonged exposure therapy and to their combination. 8 All groups
improved equally, but there was no control group on just placebo and some
nonspecific supportive therapy. Given, as noted above, that previous studies
have not found efficacy versus placebo for sertraline in this population, this
study raises more questions than provides answers about treatment choices.
Another large 2019 study in a civilian population compared sertraline and
prolonged exposure (again, without placebo control), and there were
advantages found for the exposure therapy. 9
How should the aggregate evidence on prazosin, including the clinical
experience of many prescribers, be interpreted, in comparison with the
evidence on selective serotonin reuptake inhibitors (SSRIs)? We think it
favors prazosin despite the small numbers of patients studied, and we are
retaining prazosin at the top of the algorithm for patients with prominent
insomnia. This includes the great majority of patients with PTSD. The sleep
disturbances typically involve nightmares, but some patients have disturbed
awakenings without recalling nightmares, and clinicians should be sure to
ask about those. They may wake up one or more times a night feeling
anxious, perspiring profusely, hyperventilating, or experiencing
tachycardia. It is usually difficult to return to sleep and they may have to
get up and pace about, watch TV, play video games, or otherwise distract
themselves to calm down before they can return to sleep. Also, many
patients have night terrors (phenomena witnessed by a bed partner or
roommate during which the patient is talking, yelling, fighting, kicking, or
otherwise appearing to be in distress—but nothing is recalled by the patient
upon awakening). All of these are candidates for treatment with prazosin
and related medications targeting alpha adrenergic mechanisms.
Prazosin is often underdosed, resulting in a negative outcome. 10 It seems
reasonable to use the dosing in the largest study with a positive outcome.1
The dosing protocol was somewhat complex, and it takes time and, often, a
series of outpatient visits to administer effectively and address side effects.
For example, the patient may already be on one or more antihypertensives,
and introducing prazosin may bring on light-headedness or low blood
pressure. Negotiation with the prescriber of the antihypertensive regimen is
advised to determine which agent should be lowered or eliminated to allow
for the titration of the prazosin.
The dosing protocol for men was:
1 mg HS × 2 nights
2 mg for 5 nights
4 mg for 7 nights
6 mg for 7 nights
10 mg for 7 nights
15 mg for 7 nights
20 mg maximum at bedtime
Median final bedtime dose was 15.6 mg.
The day dose was: (usually taken about 10 AM to avoid any overlap with
night dose—use cell phone to set up reminder)
Week 2: 1 mg
Weeks 3–4: 2 mg
Weeks 5–6: 5 mg
Women seem to need lower doses, for reasons that have not been fully
explained. For women, the protocol was:
1 mg at bedtime for 2 nights
2 mg for 12 nights
4 mg for 7 nights
6 mg for 7 nights
10 mg maximum at bedtime
Median final bedtime dose was 7 mg
Midmorning dose
Weeks 2–3: 1 mg
Weeks 4–5: 2 mg
These increases may need to be slowed or modified depending on side
effects. One should not prescribe this protocol and expect the patient to
follow it precisely without consultation along the way. A check-in with the
patient is advised every week or two. To get the most out of prazosin, it is
very important to begin with a discussion about expectations. The person
with nightmares every night and who gets 3 hours of sleep a night is not
going to transition to no nightmares and 7–8 hours of restful, restorative
sleep in a week or two. The process will be gradual and may take weeks or
months as the dose is slowly increased as tolerated. Some patients
experience worsening of nightmares after the first few doses, though this
could be due to traumatic triggers coincidentally occurring at this point
rather than a medication effect. The patient should be prepared for this
possibility and urged to keep taking it and (if otherwise tolerated) progress
to the higher doses, at which point usually this problem will fade. The first
sign of actual improvement may be that the nightmares will become less
severe or the time required to recover from them and return to sleep will
shorten. Next, the frequency of nightmares should reduce, though disturbed
awakenings without nightmare recollection may continue even when
patients no longer remember any nightmares. The doses of prazosin should
still be increased as in the protocols, attempting to reach goals of no
nightmares or disturbed awakenings and longer total sleep time. It can be
very helpful to give patients a handout with these instructions or a copy of
the Raskind et al. study.1
Some patients may need, and tolerate, doses higher than in the Raskind
and colleagues. protocol. There are case reports in the literature of patients
being raised to 30 and even 45 mg at bedtime safely with good outcome. 11
Since the 2011 PTSD algorithm publication, there is the first placebo-
controlled trial of doxazosin XL as an alternative to prazosin. 12 We had
mentioned an open-label trial suggesting effectiveness, but in this study
with crossover design, eight patients had trials on placebo and on active
medication. Results were positive on one of the two primary outcome
measures (the PTSD Checklist—Military version). Like prazosin,
doxazosin is an alpha-1 adrenergic antagonist, but its half-life is 15–19
hours compared to the 2–3 hours half-life of prazosin. These properties may
render it less prone to hypotensive and other side effects. Previous studies
suggested that doxazosin does not cross the blood–brain barrier, or does so
only minimally. However, the authors provided evidence that it does have
central effects.12 Clinical experience has been accumulating with doxazosin
for PTSD, and some clinicians prefer it over prazosin because of
impressions of better tolerability. Dosing is similar.
Comorbidities and How They Affect the Algorithm
There is one pertinent new study that may be relevant for patients with
comorbid alcohol use disorder and PTSD. 13 At doses up to 300 mg daily,
topiramate reduced alcohol cravings, alcohol consumption, and also PTSD
symptoms, especially hyperarousal complaints. However, patients should
be warned about the significant risk of symptomatic kidney stones, which is
about 2.1%, with the highest rates occurring in patients on 300 mg daily or
more or who have a previous history of kidney stones. 14
Under the heading of women of child-bearing potential, a new large
study confirms that paroxetine deserves the D rating it had from the FDA
because of atrial septal defects. 15 Fluoxetine also turned up as having a
similar rate in this observational study.
Many patients with PTSD report anxiety. Clinicians may diagnose this
anxiety as coming from comorbid anxiety disorders like generalized anxiety
disorder, social anxiety disorder, or panic disorder. Medications with an
evidence base for treating those disorders may therefore be tried. However,
more careful evaluation often reveals that these apparent comorbid anxiety
symptoms are actually coming from the PTSD. The triggers for these
anxiety symptoms may be events that are similar to or remind the patient of
previous traumatic experiences. Often one finds PTSD patients who are on
medications such as benzodiazepines, hydroxyzine, gabapentin, and
buspirone. They were put on these medications to treat anxiety symptoms.
But if the symptoms are coming from PTSD, one may not see significant
benefit: none of these has any important evidence base supporting
effectiveness in PTSD.
Considerations for Helping Patients With Initial Insomnia
The discussion in the original paper still holds. Quetiapine,
benzodiazepines, and sedating tricyclics are not recommended. A newer
study adds to the reasons to avoid benzodiazepines: they may reduce the
short- and long-term effectiveness of exposure-mediated psychotherapies
commonly used for PTSD. 16
Considerations for First- and Second-Line Pharmacotherapy
Choices if Symptoms Remain Significant After Addressing
Sleep Disturbance
The discussion and recommendations in the original paper still hold. There
have been some new data on mirtazapine usage. There has been one
randomized controlled trial in mostly civilian subjects (N-29) and five
open-label studies, recently summarized in a critical review. 17 The potential
advantages of mirtazapine are that it could be more sedating than SSRIs
and it has low sexual side effects. The disadvantage is the weight gain, and
also since it has alpha-adrenergic stimulating properties it might, like
venlafaxine, also not be beneficial for (or might worsen) hyperarousal
symptoms of PTSD. The studies to date have not evaluated this. There is
also one study of mirtazapine as an augmentation strategy in 36 civilian
patients with PTSD, added to sertraline (mean dose 120 mg). 18 There was
no difference from adding placebo in the primary outcome measures, and
sexual side effects were not reduced. However, a secondary outcome
showed that at 24-week follow-up, 39% of the mirtazapine patients remitted
versus only 11% of those with added placebo. It seems that mirtazapine
should stay where it is as a second-line option and could be considered to
be somewhat promising as an augmentation.
Recommendations for Treatment-Resistant Patients (Node 5a
of the Algorithm)
These, as well, appear reasonably current as written. There was a new
placebo-controlled study of topiramate that was positive. 19 The two
previous randomized trials, from 2007, were not impressive. However, Yeh
and colleagues treated 70 civilian patients in Brazil for 12 weeks and the
reduction on the Clinician-Administered PTSD Scale (CAPS) in the
topiramate group was 58 points versus a 32-point improvement on placebo
(p = 0.008). There was improvement in reexperiencing (which is where we
recommended it) and also in avoidance symptoms. Hence topiramate may
be added to the options for prominent avoidance symptoms though with
consideration of the side-effect risks including kidney stones, mentioned
earlier.
Regarding the use of second-generation antipsychotics (SGAs) as
augmentations or monotherapies for PTSD at node 5a, there are some new
studies. Some had thought that the large 2011 VA Cooperative study of
risperidone as adjunctive therapy to SSRIs, discussed in the algorithm
publication, which did not find any benefit on global severity of PTSD, was
the “nail in the coffin” 20 for a major role for SGAs. There was actually a
small effect on hyperarousal, and this is why we listed risperidone as an
option for residual symptoms in this domain. However, a new study of the
SGA quetiapine as monotherapy versus placebo for PTSD appeared in
2016. 21 A total of 80 subjects were randomized for 12 weeks, and there
were positive results for both hyperarousal and reexperiencing symptoms,
and in multiple other domains of secondary outcomes. Doses could be
titrated up to 800 mg daily, and the mean dose was about 250 mg.
Improvement at end point, though greater than placebo, was modest, and
patients were left with significant residual symptoms and “additional
psychopharmacological or psychotherapeutic interventions would need to
be considered.”21 One always has to wonder, in quetiapine placebo-
controlled studies, if the blind was successful; it might be very easy for
patients to guess if they were randomized to quetiapine because of the
strong sedative effects and the appetite stimulation. Metabolic side effects,
though not thoroughly measured in this short-term study, did seem modest.
However, considering benefits and risks, it would seem that this study
would not justify changing the previous placement of quetiapine in the
algorithm, namely as a third-line option at node 5a, in the list of choices to
consider for patients with residual hyperarousal or reexperiencing
symptoms.
There was also a recent small placebo-controlled trial of ziprasidone as
an augmentation of SSRIs in PTSD. 22 After unsatisfactory response to
sertraline or paroxetine, 24 patients were randomized for 8 weeks. About
44% completed the ziprasidone trial while 64% completed the placebo
treatment. There were no efficacy differences.
In conclusion, SGAs still deserve to be at node 5a as a third-line option
because of their modest effectiveness and significant side effects, compared
to the antidepressants.
Are There Any New Options to Be Considered That Were Not
Reviewed in 2011?
Cannabis and derivatives (e.g., cannabidiol) have received much publicity
as possible treatments for PTSD. It is one of more than 50 indications for
“medical marijuana” that are approved by various State governments.
Cannabis is legal in 36 states and 10 states allow recreational use, but there
is no regulation of the quality or purity of these products. Patients are vocal
in reporting that they feel more relaxed or may sleep better after taking
these products. Many report that it is the only thing that is reliably helpful
for their sleep and anxiety symptoms, compared with what we prescribe.
Notably, nicotine users say the similar things: it is their coping strategy of
choice for just about every stress, or even their “only pleasure in life.”
Others say the same things about benzodiazepines. So, here is a rhetorical
question: What do these substances have in common? What PTSD patients
do not seem to appreciate is that after the relaxation wears off, they need it
again and again, and overall the course of their PTSD seems adversely
effected, especially anger management, according to limited evidence that
is available. 23 More research is needed.
Transcranial magnetic stimulation (TMS) has received considerable
interest as a treatment for PTSD. A meta-analysis of nine studies found an
impressive effect size of −0.88 on reducing PTSD symptoms using high-
frequency application of the magnet over the right dorsolateral prefrontal
cortex. 24 More recent TMS work has focused on the theta-burst technique
(iTMS) that delivers intensive pulses for 3 minutes over 10 days rather than
the 37 minutes over 6 weeks in the standard TMS protocol, but iTMS is
hard to deliver accurately to the desired areas. 25 A recent study with iTMS
in 50 PTSD subjects found no statistical improvement versus sham at 2
weeks, though the difference appeared clinically meaningful. 26 One-month
(unblinded) outcomes were better, with effect size on improvement in
social and occupational functioning reaching 0.93. TMS delivered by
evolving devices and techniques is among the most promising new
treatments for PTSD, but further studies are needed before enough is
known to propose it as a standard recommendation.
REFERENCES
1. Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with
nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry
2013;170:1003–10.
2. Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in
military veterans. N Engl J Med 2018;378:507–17.
3. McCall WV, Pillai A, Case D, et al. A pilot, randomized clinical trial of bedtime doses of
prazosin versus placebo in suicidal posttraumatic stress disorder patients with nightmares. J Clin
Psychopharmacol 2018;38:618–21.
4. Raskind MA, Millard SP, Petrie EC, et al. Higher pretreatment blood pressure is associated with
greater posttraumatic stress disorder symptom reduction in soldiers treated with prazosin. Biol
Psychiatry 2016;80:736–42.
6. National Institute for Clinical Excellence. Post-traumatic stress disorder: the management of
PTSD in adults and children and secondary care. London, UK: Gaskell and the British
Psychological Society, 2005.
7. Akiki TJ, Abdallah CG. Are there effective psychopharmacologic treatments for PTSD? J Clin
Psychiatry 2018;80.
8. Rauch SAM, Kim HM, Powell C, et al. Efficacy of prolonged exposure therapy, sertraline
hydrochloride, and their combination among combat veterans with posttraumatic stress disorder:
a randomized clinical trial. JAMA Psychiatry 2019;76:117–26.
9. Zoellner LA, Roy-Byrne PP, Mavissakalian M, Feeny NC. Doubly randomized preference trial
of prolonged exposure versus sertraline for treatment of PTSD. Am J Psychiatry 2019;176:287–
96.
10. Alexander B, Lund BC, Bernardy NC, Christopher ML, Friedman MJ. Early discontinuation
and suboptimal dosing of prazosin: a potential missed opportunity for veterans with
posttraumatic stress disorder. J Clin Psychiatry 2015;76:e639–44.
11. Koola MM, Varghese SP, Fawcett JA. High-dose prazosin for the treatment of post-traumatic
stress disorder. Ther Adv Psychopharmacol 2014;4:43–7.
12. Rodgman C, Verrico CD, Holst M, et al. Doxazosin XL reduces symptoms of posttraumatic
stress disorder in veterans with PTSD: a pilot clinical trial. J Clin Psychiatry 2016;77:e561–5.
13. Batki SL, Pennington DL, Lasher B, et al. Topiramate treatment of alcohol use disorder in
veterans with posttraumatic stress disorder: a randomized controlled pilot trial. Alcohol Clin
Exp Res 2014;38:2169–77.
14. Dell’Orto VG, Belotti EA, Goeggel-Simonetti B, et al. Metabolic disturbances and renal stone
promotion on treatment with topiramate: a systematic review. Br J Clin Pharmacol
2014;77:958–64.
15. Reefhuis J, Devine O, Friedman JM, Louik C, Honein MA. Specific SSRIs and birth defects:
Bayesian analysis to interpret new data in the context of previous reports. BMJ (Clinical
Research Ed) 2015;351:h3190 .
16. Rosen CS, Greenbaum MA, Schnurr PP, Holmes TH, Brennan PL, Friedman MJ. Do
benzodiazepines reduce the effectiveness of exposure therapy for posttraumatic stress
disorder? J Clin Psychiatry 2013;74:1241–8.
17. McGrane IR, Shuman MD. Mirtazapine therapy for posttraumatic stress disorder: implications
of alpha-adrenergic pharmacology on the startle response. Harv Rev Psychiatry 2018;26:36–
41.
18. Schneier FR, Campeas R, Carcamo J, et al. Combined mirtazapine and SSRI treatment of
PTSD: a placebo-controlled trial. Depress Anxiety 2015;32:570–9.
19. Yeh MS, Mari JJ, Costa MC, Andreoli SB, Bressan RA, Mello MF. A double-blind
randomized controlled trial to study the efficacy of topiramate in a civilian sample of PTSD.
CNS Neurosci Ther 2011;17:305–10.
20. Stein MB. Adjusting to traumatic stress research. Am J Psychiatry 2016;173:1165–6.
21. Villarreal G, Hamner MB, Canive JM, et al. Efficacy of quetiapine monotherapy in
posttraumatic stress disorder: a randomized, placebo-controlled trial. Am J Psychiatry
2016;173:1205–12.
22. Hamner MB, Hernandez-Tejada MA, Zuschlag ZD, Agbor-Tabi D, Huber M, Wang Z.
Ziprasidone augmentation of SSRI antidepressants in posttraumatic stress disorder: a
randomized, placebo-controlled pilot study of augmentation therapy. J Clin Psychopharmacol
2019;39:153–7.
23. Mammen G, Rueda S, Roerecke M, Bonato S, Lev-Ran S, Rehm J. Association of cannabis
with long-term clinical symptoms in anxiety and mood disorders: a systematic review of
prospective studies. J Clin Psychiatry 2018;79.
24. Cirillo P, Gold AK, Nardi AE, et al. Transcranial magnetic stimulation in anxiety and trauma-
related disorders: a systematic review and meta-analysis. Brain Behav 2019;9:e01284.
25. McDonald WM, van Rooij SJH. Targeting PTSD. Am J Psychiatry 2019;176:894–6.
26. Philip NS, Barredo J, Aiken E, et al. Theta-burst transcranial magnetic stimulation for
posttraumatic stress disorder. Am J Psychiatry 2019;176:939–48.
* I thank Laura A. Bajor, D.O. for her contributions to this update on the PTSD algorithm.
The Psychopharmacology Algorithm Project at
the Harvard South Shore Program: An
Algorithm for Adults with Obsessive-
Compulsive Disorder
Ashley M. Beaulieu , DO a , Edward Tabasky , MD b , and
David N. Osser , MDa ,*
Abstract: A previous algorithm for the pharmacological treatment of obsessive-
compulsive disorder was published in 2012. Developments over the past 7 years
suggest an update is needed. The authors conducted searches in PubMed, focusing on
new studies and reviews since 2012 that would support or change previous
recommendations. We identified exceptions to the main algorithm, including pregnant
women and women of child-bearing potential, the elderly, and patients with common
medical and psychiatric co-morbidities. Selective serotonin reuptake inhibitors (SSRIs)
are still first-line. An adequate trial requires a period at typical antidepressant doses
and dose adjustments guided by a plasma level to evaluate for poor adherence or ultra-
rapid metabolism. If the response is inadequate, consider a trial of another SSRI this
time possibly taken to a very high dose. Clomipramine could be an alternative. If the
response to the second trial remains inadequate, the next recommendation is to
augment with aripiprazole or risperidone. Alternatively, augmentation with novel
agents could be selected, including glutamatergic (memantine, riluzole, topiramate, n-
acetylcysteine, lamotrigine), serotonergic (ondansetron), and anti-inflammatory
(minocycline, celecoxib) agents. A third option could be transcranial magnetic
stimulation. Lastly, after several of these trials, deep brain stimulation and cingulotomy
have evidence for a role in the most treatment-refractory patients.
INTRODUCTION
Obsessive-compulsive disorder (OCD) is a common, chronic
neuropsychiatric disorder that causes significant psychosocial
impairment (Fineberg et al., 2015 ). It is characterized by recurrent and
persistent obsessions and/or compulsions that the individual feels
driven to perform (American Psychiatric Association, 2013 ). OCD
equally affects males and females and has a lifetime prevalence of
1.6% worldwide (Stein et al., 2012 ). Seeking treatment is often
delayed (Stein et al., 2012 ), and is associated with a poorer outcome,
whereas effective pharmacological treatment improves quality of life
(Fineberg et al., 2015 ).
Treatments for OCD include cognitive-behavioral therapy (which
may be first-line especially for patients with prominent compulsive
behaviors), medication, and their combination (Foa et al., 2005 ).
Selective serotonin reuptake inhibitors (SSRIs) are considered the
first-line pharmacological treatment for patients with OCD, but these
medications are effective in only 40–60% of patients (Stein et al.,
2012 ). Evidence-informed psychopharmacology algorithms can guide
clinicians in choosing appropriate medication options beyond the first-
line options for OCD (Burchi et al., 2018 ). In this article, we present
an updated version of a previously published OCD algorithm to which
one of the authors (DNO) contributed (Stein et al., 2012 ).
Since 1995 the Psychopharmacology Algorithm Project at the
Harvard South Shore Program (PAPHSS) has been creating evidence-
informed treatment algorithms. Eight peer-reviewed PAPHSS
algorithms have been published and can also be accessed through a
publicly available website (www.psychopharm.mobi ).
The PAPHSS algorithms focus on psychopharmacological
treatment, but psychotherapeutic and other non-pharmacological
treatments for OCD are important. Family counseling or cognitive
behavioral therapy incorporating exposure and response prevention
could be first-line or integrated with pharmacotherapy at any point
(Burchi et al., 2018 ; Heyman et al., 2006 ). If and when medication is
considered desirable, this algorithm is meant to suggest the best
supported and safest options for the first and subsequent medication
trials, taking into consideration the common psychiatric and medical
comorbidities that might alter the selection process.
METHODS
The methods used in developing new and revised PAPHSS algorithms
have been described previously (Abejuela and Osser, 2016 ; Ansari
and Osser, 2010 ; Bajor et al., 2011 ; Giakoumatos and Osser, 2019 ;
Hamoda and Osser, 2008 ; Mohammad and Osser, 2014 ; Osser and
http://www.psychopharm.mobi
Dunlop, 2010 ; Osser et al., 2013 ).
In brief, the authors conducted literature searches using PubMed
with key words obsessive-compulsive disorder, algorithm,
management, and psychopharmacology, focusing on new randomized
controlled trials (RCTs), reviews, meta-analyses, and other guidelines
published since the last OCD algorithm to which current authors
contributed (Stein et al., 2012 ).
The authors considered efficacy, tolerability, and safety as the main
factors for determining the order of recommended pharmacological
treatments. All recommendations to retain or change the previously
published algorithm were based on the body of evidence reviewed and
conclusions agreed upon by the three authors. The peer review process
that follows submission of the article also adds validation to the
recommendations in this and other PAPHSS algorithms. If the
interpretations of the pertinent evidence, and subsequent
recommendations, are plausible to reviewers, then they are retained.
When differences of opinion occur, the authors make modifications to
achieve consensus with the reviewers or examine the relevant
evidence further in order to present additional support for their
interpretation.
While the algorithm is intended to provide flexible decision-making
guidance based on the evidence, clinicians must also consider the
unique aspects of each patient’s case.
RESULTS
Flow chart for the algorithm
An overview of the algorithm appears in Fig. 1 . Each “node”
represents a clinical scenario where a treatment choice must be made.
The steps in the algorithm progress through initial treatments at the
beginning to highly treatment-resistant scenarios at the end. The
evidence and reasoning that support the recommendations at each
node will be presented below.
Figure 1. Flow chart for the algorithm for pharmacotherapy of OCD.
Node 1: Diagnosis of OCD
The treatment recommendations of this algorithm apply only to
patients that have been diagnosed with OCD based on the American
Psychiatric Association Diagnostic and Statistical Manual of Mental
Disorders, edition 5 (DSM-5) criteria (American Psychiatric
Association, 1994 ). These criteria have undergone only very minor
changes since the DSM-IV criteria (American Psychiatric Association,
1994 ) that were in use from 1994 to 2013 when the great majority of
psychopharmacology studies of OCD were conducted. The changes
mostly clarify previous texts and reorganize where the disorder is
found in the manual. It is reasonable to consider the results of studies
utilizing the older criteria to apply to patients meeting the present
criteria.
Once a diagnosis has been made based on DSM-5 criteria, it is also
important to consider any co-occurring psychiatric or medical
diagnoses or other circumstances that may be particularly important,
such as bipolar disorder and women of childbearing potential. Table 1
provides a brief summary of how these comorbidities and other
considerations would modify the basic algorithm.
Table 1 | Comorbidity and Other Features in Obsessive
Compulsive Disorder and How They Affect the Algorithm
Comorbidity and
other
circumstances
Considerations Recommendations
Cardiac
arrhythmias
TCAs may cause cardiac arrhythmias
due to their effects on cardiac sodium
and potassium channels (Thanacoody
and Thomas, 2005 ).
Try SSRIs before TCAs
(clomipramine).
EKG monitoring of TCA-treated
patients is a more accurate way to
detect cardiac toxicity than plasma
level monitoring.
Sertraline appears to be safe in patients
at risk of arrhythmia following
myocardial infarction (Glassman et al.,
2002 ).
We do not recommend citalopram or
escitalopram because of concerns about
QTc prolongation (Beach et al., 2013
Bird et al., 2014 ).
Gastrointestinal
bleeding
SSRIs increase hemorrhage risk.
Gastrointestinal bleeding can be
increased 9-fold by SSRIs combined
with NSAIDS (Anglin et al., 2014 ;
Paton and Ferrier, 2005 ).
Adding proton pump inhibitors such as
omeprazole decreases the risk to only
slightly above controls not on SSRIs
(Paton and Ferrier, 2005 ).
Paton and Ferrier, 2005 ).
Older adults
(greater than 65
years of age)
SSRIs may increase risk of bleeding;
however, in a Cochrane metaanalysis
of post-stroke patients, bleeding risk
was non-significant (Mead et al., 2013
).
SSRIs are associated with higher rates
of hyponatremia secondary to SIADH
in older adults (De Picker et al., 2014 ).
SSRIs, TCAs, and other antidepressant
classes have been associated with
increased risk of falls, particularly in
frail older women (Naples et al., 2016
).
Consider side effect profiles of
antidepressant medications prior to
initiation or titration in elderly adults.
In patients with intolerable
hyponatremia secondary to SSRI use,
consider mirtazapine (De Picker et al.,
2014 ).
Escitalopram has fewer drug
interactions than fluoxetine or
fluvoxamine and less QTc prolongation
than citalopram, so it might be
considered but QTc should be
monitored as the dose goes higher.
Women of child-
bearing potential
and pregnant
women
Severity of OCD is mostly unchanged
in pregnancy and postpartum.
Predictors of severity of OCD included
younger age at delivery and delivery by
C-section (House et al., 2016 ),
suggesting that increased surveillance
during pregnancy and postpartum may
be indicated.
There were no differences in neonatal
outcomes including birth weight, birth
length, estimated gestational age at
delivery, or NICU admissions between
patients with OCD and those without
OCD, and severity of OCD in women
who were adequately treated with
pharmacotherapy, suggesting that
neither disease nor treatment of OCD
during pregnancy pose a direct risk to
the neonate (House et al., 2016 ).
Alternatively, late exposure to SSRIs
(after 20th week of pregnancy) has
been associated with increased risk of
prematurity, low body weight, neonatal
complications (Addis and Koren, 2000
) and persistent pulmonary
hypertension of the newborn in other
studies (Kieler et al., 2012 ). Some of
these could be due to confounding by
indication.
The risk to the newborn of maternal
treatment may be out-weighed by the
impact of uncontrolled OCD symptoms
on the patient (House et al., 2016 ).
Avoid paroxetine (D rating due to atrial
septal defect risk) (Reefhuis et al.,
2015 ). If the patient is already on
paroxetine, consider risks involved
with switching.
Consider CBT.
Treatment choices are a collaborative
decision with the patient.
Bipolar disorder Antidepressants may shift euthymic CBT and psychoeducation are strongly
Bipolar disorder Antidepressants may shift euthymic
patients with bipolar disorder toward a
manic phase (Sahraian et al., 2017 ).
CBT and psychoeducation are strongly
recommended as a necessary part of
treatment.
Among antidepressants, tricyclics
(clomipramine) should particularly be
avoided because of higher mania
switch rates (Pacchiarotti et al., 2013
If other antidepressants such as SSRIs
are used, they should be added to a
mood stabilizer. Even then, their use is
associated with a significant increase in
[hypo]manic switches on one-year
followup (McGirr et al., 2016 ). Of
perhaps greater concern, if the bipolar
disorder is rapid cycling, adding an
antidepressant triples the rate of
recurrent depressions compared with
not starting one, according to the
STEP-BD study (El-Mallakh et al.,
2015 ).
Memantine 20 mg/day showed promise
as an effective adjunctive agent in
reducing OCD symptoms in manic
patients with bipolar I disorder
(Sahraian et al., 2017 ).
Schizophrenia Obsessive-compulsive symptoms
(OCS) occur in the course of many
patients with schizophrenia
(Schirmbeck et al., 2019 ) and also can
be a new-onset side effect of second
generation antipsychotics (SGAs) in
these patients, most often with
clozapine, due to mechanisms that are
unclear (Grillault Laroche and
Gaillard, 2016 ). In addition, some
patients with OCD have psychotic
symptoms (Cederlof et al., 2015 ) and
such patients may be at risk for
developing schizophrenia (Meier et al.,
2014 ). Schizotypal personality, a
condition genetically linked to
schizophrenia, can present with OCS as
well (De Haan, 2015 ).
CBT and psychoeducation are strongly
recommended as a necessary part of
treatment if the patient has the capacity
to cognitively process and cooperate
with the procedures. Use of SSRI
antidepressants added to the
antipsychotic for these symptoms is
reasonable if there is no history of
mania (as in schizoaffective disorder).
If there is a mania history, review the
suggestions for bipolar-related
disorders. For treating OCS due to
clozapine, first check a plasma level
(Meyer, 2019 ). If it is above usual
therapeutic levels, consider lowering
the dose to see if the OCS are dose-
related and the antipsychotic benefits
can be retained. Next, consider treating
with sertraline which has the least drug
interactions and would be preferred
over fluvoxamine (especially),
fluoxetine, and paroxetine. When
adding an SSRI to other SGAs, other
interactions may need to be considered.
interactions may need to be considered.
Node 2: Start with an SSRI (fluoxetine, fluvoxamine,
sertraline)
After making the diagnosis of OCD based on DSM-5 criteria and
considering the comorbidities and conditions in Table 1 that might
change the basic algorithm, the next step is to initiate a trial of an
SSRI (fluoxetine, fluvoxamine, or sertraline) for 8–12 weeks. All three
of these options are U.S. Food and Drug Administration (FDA)
approved for OCD and are considered first-line. There have been
multiple large multi-center studies of each and the details of those
studies have been reviewed elsewhere and need not be repeated here
(Fineberg and Gale, 2005 ; Fineberg et al., 2015 ). However, a few
comments pertinent to their first-line selection follow.
Fluoxetine has been found effective in at least some studies at 20,
40, and 60 mg daily at 12–13 week end points, but with greater
effectiveness with increasing dose (Tollefson et al., 1994 ). We will
have more to say on this later.
Fluvoxamine (100–300 mg/day) is effective. In one study at a mean
dose of 271 mg, 63% of the fluvoxamine CR group versus 46% of the
placebo group were responders (defined as a Yale-Brown Obsessive-
Compulsive Symptoms score (YBOCS) decrease of ≥ 25%).
Fluvoxamine was the first SSRI approved for OCD in the United
States. As a result, it is often thought of as a better medication for
treating OCD than other SSRIs, but there is no evidence to suggest it is
any more effective. Fluvoxamine has significant drug interactions
through its inhibition of Cytochrome CYP 1A2, 2C9, C219, and 3A4
metabolizing enzymes that are important to consider (Oesterheld, 1999
).
Sertraline was tested in an RCT (50 mg, 100 mg, 200 mg) and all
doses were equally effective for OCD symptoms (Greist et al., 1995 ).
In the double-blind phase of a long term 80-week trial (n = 223),
sertraline was more effective than placebo in preventing: dropout due
to relapse or insufficient clinical response (9% versus 24%,
respectively) and acute exacerbation of symptoms (12% versus 35%)
(Koran et al., 2002 ). Ninan et al. (2006) studied non-responders after
16 weeks of receiving sertraline 50–200 mg/day. They were
randomized to receive an additional 12 weeks of high-dose sertraline
(250–400 mg/day) or continue on 200 mg daily. Responder rates
(defined as a decrease in YBOCS score of ≥ 25% and a Clinical
Global Impression of Improvement (CGI-I) rating ≤ 3) were
numerically higher for the high-dose sertraline group versus the 200
mg/day group (52% vs. 34%), although this was not statistically
significant (Ninan et al., 2006 ).
Paroxetine is also FDA-approved for the treatment of OCD but is
not recommended as a first-line treatment option due having more side
effects than the others. It causes more weight gain (Fava et al., 2000 ;
Uguz et al., 2015 ), sedation, and constipation (Marks et al., 2008 ). It
also has strong drug-drug interactions due to inhibition at cytochrome
P450 2D6. It is particularly prone to produce discontinuation
symptoms if stopped abruptly or doses are missed (Marks et al., 2008
). Paroxetine is the only SSRI with a category D rating in pregnancy
(see Table 1 ).
Citalopram and escitalopram are not FDA-approved but they are
effective for OCD (Montgomery et al., 2001 ; Stein et al., 2007 ).
Citalopram can cause QTc prolongation with doses of 40 mg and
above (Beach et al., 2013 ), and escitalopram causes moderate dose-
dependent QTc prolongation at approved doses (Bird et al., 2014 ) (see
reference 2). Above the maximum dose of 20 mg/day, QTc was
prolonged more than the control moxifloxacin. Therefore, we prefer to
avoid citalopram and escitalopram because higher doses are often
needed.
In summary, the first SSRI trial could be either sertraline,
fluoxetine, or fluvoxamine. Unfortunately, SSRIs do have many side
effects and these need to be discussed with patients. Perhaps the most
disturbing are the sexual side effects and these usually do not diminish
over time (Serretti and Chiesa, 2009 ). Some medical considerations
related to these side effects are presented in Table 1 .
Considering these side effects, it is recommended to carefully
evaluate whether improvement on an SSRI was medication-related and
not due to other reasons. As noted above, placebo response rates can
be as high as 46%. This can be accomplished by trials off the
medication when patients are well and have supports in place.
As noted, some evidence suggests that higher doses (and for a
longer time) than usually used for depression may be necessary for
maximum results (Bloch et al., 2010 ; Ninan et al., 2006 ; Pampaloni
et al., 2010 ). However, over 20 years ago, the Expert Consensus Panel
for OCD recommended that patients be treated with moderate doses at
first and only increased to high doses after a period of assessment at
regular doses (March, 1997 ). This still seems reasonable. The
informative fixed-dose study by Tollefson et al. (1994) showed very
little difference in benefit in the first three weeks of treatment with
fluoxetine at any dose (20 mg, 40 mg, or 60 mg) or placebo in mean
YBOCS total score (Tollefson et al., 1994 ). At 5 weeks, all the doses
start separating from placebo. Then, there appears to be a decision
point at about week 7, when the fluoxetine 60 mg dose begins
separating slightly from the 40 mg dose. It therefore seems reasonable
to recommend that, to minimize unnecessary dose escalation and
associated increased side effects, clinicians wait a minimum of 7
weeks before increasing beyond the moderate dose, if the response is
inadequate.
There may be three possible outcomes as one proceeds with the
moderate dose of the selected SSRI; an adequate response, a partial
but inadequate response, or no response. If there is an adequate
response, continue with maintenance treatment for at least 1–2 years
and then consider tapering to evaluate if the improvement was a
placebo effect. Earlier drug discontinuation can be followed by a high
likelihood of symptom recurrence (Ravizza et al., 1996 ). If there is a
partial but inadequate response, or no response, the next step is to get a
plasma SSRI level to check for nonadherence or rapid metabolizers.
This adds “precision medicine” to the case, checking to see if the
medication is bioavailable, and it could also help explain problematic
side effects (Grunder, 2018 ). If the plasma level is zero, the patient is
most likely non-adherent, so this should be discussed with the patient
to see if the problem can be corrected. If adherence appears
satisfactory but the plasma level is low, the patient may be a rapid
metabolizer of that SSRI. Seven percent of Caucasians and 3% of
other ethnicities can be ultrarapid metabolizers of some SSRIs
(Bertilsson et al., 1993 ). Genetic testing could confirm this. The
testing could then indicate which SSRI would be metabolized
normally (Brandl et al., 2014 ). SSRIs do not have therapeutic levels
for treating OCD (Koran et al., 1996 ) but the laboratory will provide
the usual range of levels associated with a given dose.
Once adherence is confirmed, the next step is to increase the dose
(if tolerated) to the maximum FDA-recommended dose for OCD (e.g.,
fluoxetine 80 mg, fluvoxamine 300 mg, or sertraline 200 mg daily) for
8–12 weeks and recheck the plasma SSRI level. A meta-analysis
showed that patients obtain only a 9 or 7% greater decline in OCD
symptoms on high-dose SSRI compared to low and medium dose
SSRI treatment, respectively (Bloch et al., 2010 ). Therefore,
expectations for the results of this increase should be realistic and
weighed against any possible associated additional harms.
Are there other antidepressants that could be considered for
initial treatment of OCD?
Bupropion, trazodone, venlafaxine, and duloxetine have received
study in OCD but the evidence is not convincing for priority in the
algorithm (Balachander et al., 2019 ; Denys et al., 2003 ; Phelps and
Cates, 2005 ; Pigott et al., 1992 ; Sansone and Sansone, 2011 ; Vulink
et al., 2005 ).
Mirtazapine is a dual neurotransmitter action agent that has the
benefit of fewer sexual side effects than SSRIs and SNRIs, and its
sedative effects could be useful for anxiety and insomnia. There is one
small study of 30 participants who received open-label high-dose
mirtazapine 60 mg daily for 12 weeks. It suggested that mirtazapine
may be superior to placebo in treating OCD, but the study needs
replication (Koran et al., 2005 ). Of perhaps greater interest regarding
mirtazapine, there is a single-blind study of 49 OCD patients (never
previously treated) comparing initiating them on citalopram 40–80
mg/day plus mirtazapine 15–30 mg/day versus citalopram plus
placebo (Pallanti et al., 2004 ). Raters were not blind to the treatment
group, undermining confidence in the findings, but over the first 4
weeks the results with the combined treatment were significantly
better (p < 0.001) on YBOC scores. However, by 12 weeks there was
no significant difference. It appeared that mirtazapine accelerated the
response to the SSRI, though it did not ultimately produce a greater
response. Accelerating response would be highly desirable given the
discussions above about how long it takes for the SSRIs to achieve
their maximum effects. However, it could come at the cost of
mirtazapine side effects like weight gain – unless the mirtazapine
could be removed after the acceleration and the OCD results
maintained. It seems that these findings should be replicated in an
appropriately-designed double-blind placebo-controlled study before it
should become routine practice to add mirtazapine (Schule and
Laakmann, 2005 ). However, it may be reasonable to explain this
option to patients and the evidence behind it, and give it consideration.
Node 3: Try another SSRI (preferable) or clomipramine
If the patient fails to achieve an adequate improvement on the first
SSRI trial, the next recommendation is to try another SSRI from the
three first-line options, or consider the tricyclic clomipramine.
Clomipramine is effective for OCD and was the first medication
approved by the FDA for OCD in the United States (Thoren et al.,
1980 ). Some meta-analyses have concluded that clomipramine has
slightly greater efficacy than the SSRIs, but direct comparisons have
found no differences (Fineberg and Gale, 2005 ; Stein et al., 2012 ).
Moreover, early studies with clomipramine may have employed
particularly medication-responsive subjects (Fineberg and Gale, 2005
). Mostly in Europe, clomipramine has also been used IV to produce a
faster response (Koran et al., 1994 ). Since clomipramine has many
more side effects than SSRIs especially seizures, cardiotoxicity,
weight gain, anticholinergic effects, particularly strong sexual
dysfunction, and overdose lethality, the general preference is to try
another SSRI for the second trial. Controlled studies, however, have
not been done to evaluate whether patients who failed one adequate
SSRI trial would respond to a second SSRI trial versus other
medication options like augmentation strategies. The Expert
Consensus group estimated a 40% likelihood of a significant response
to a second SSRI trial (March, 1997 ). Notably, other disorders that
can be treated with SSRIs such as major depression can respond to a
different SSRI after failure on a first (Rush et al., 2006 ). SSRIs differ
somewhat in their neurotransmitter-based activities. Furthermore, the
side effects for patients are probably greater when adding the most-
studied augmenting medications (second generation antipsychotics),
compared with trying a different SSRI.
As in the first SSRI trial, there are three potential outcomes; an
adequate response in which the maintenance dose would be continued,
a partial but inadequate response, or no response. Again, plasma levels
should be checked for nonadherence and rapid metabolizers. Once
adherence is confirmed, the dose should then be increased if tolerated,
to the maximum recommended dose. However, node 3 differs from
node 2 in that if the response is inadequate or there is no response, and
the plasma level has been adjusted to typical levels, consideration
could be given for pushing the dose of the second SSRI beyond that
recommended in the manufacturer’s package insert. This suggestion is
based on limited evidence. As described earlier, Ninan et al. (2006)
found that among acute phase non-responders, continuation treatment
with high-dose (250–400 mg) sertraline sometimes gave greater and
more rapid improvement in OCD symptoms compared to continuing
the maximal-labeled dose of sertraline (200 mg). This suggests that
some patients who do not respond with doses up to 200 mg/day of
sertraline may benefit from higher doses. However, these patients did
not have baseline sertraline plasma levels before the dose increases. In
this algorithm, this would have occurred, and dose adjustments made.
It is unclear if the benefits seen in Ninan et al. (2006) could occur in
patients raised to above normal plasma levels, and it is unclear if the
side effect burden would be increased in such cases. However, if
typical levels have been well tolerated, it seems reasonable to consider
a dose increase as in Ninan et al. (2006) . There were, in fact,
somewhat higher rates of tremor and agitation seen on the higher
doses. In the next step in the algorithm (node 4) the recommendation
is to augment with SGAs, which have significant side effect profiles
and, often, marginal benefits. Therefore, it may be a safer and possibly
effective option for some patients to try an SSRI dose above the FDA
maximum.
Other antidepressant options to consider for node 3:
Venlafaxine was mentioned earlier and has evidence of comparable
effectiveness to a second SSRI. However, it has more side effects
including hypertension especially at high doses, higher overdose
lethality risk, and greater gastrointestinal problems (Giakoumatos and
Osser, 2019 ).
Node 4: Augment the SSRI with a second-generation
antipsychotic
If there is no or a partial but inadequate response to the second SSRI,
options could include a third SSRI or clomipramine, or an
augmentation strategy. The latter have received much more study and
there are some positive findings. Among the augmentations, the most
evidence has accumulated with SGAs, and, of those, the results favor
choosing aripiprazole or risperidone. Antipsychotic augmentation has
been associated with significant improvement in approximately one
third of patients (Diniz et al., 2011 ). Other augmentations and
treatment strategies are discussed in nodes 5 and 6, and prescribers
should look over those options as well before making a decision at this
point since they may appear better suited to the individual patient.
Risperidone (0.5 mg/day) and aripiprazole (10 mg/day or possibly
lower) have the most evidence of short-term benefit (Veale et al., 2014
). In this meta-analysis, there were 5 small studies involving low-dose
risperidone, with a total of 77 participants receiving risperidone and 89
participants receiving placebo. The risperidone group had a 3.9-point
reduction in overall mean YBOCS score, which was statistically
significant compared to the placebo. The number needed to treat
(NNT) for significant improvement was 4.65. There were 2
aripiprazole trials including a total of 41 participants on aripiprazole
and 38 on placebo. There was a 6.3-point improvement on YBOCS
outcome scores between the aripiprazole group and placebo, which
was statistically and clinically significant. Of note, 50% of participants
on the SGAs had a greater than 10% increase in body mass index
(BMI) compared to 15.2% with an elevated BMI in the SSRI plus
placebo group. The SGA group also had a higher fasting blood sugar.
These risks should be taken into consideration and discussed with the
patient before choosing an SGA as an augmentation strategy. Notably,
the benefits from the augmentation seemed to plateau at 4 weeks and
there was no further improvement after that. Therefore, if aripiprazole
or risperidone are used for treatment-resistant OCD, they should be
trialed for no longer than 4 weeks (and without other interventions) to
determine effectiveness. If a patient is determined to be a responder at
4 weeks, then another discussion should be had regarding the possible
long-term risks and need for regular monitoring of weight, blood
sugar, and lipid profile.
There is also one single-blind head-to-head comparison of
risperidone versus aripiprazole which found a greater response rate for
risperidone. Participants were placed on high doses of either sertraline,
fluoxetine, or paroxetine for 12 weeks, and those who did not achieve
an improvement of ≥ 35% on the YBOCS were considered refractory
and augmented for an additional 8 weeks with aripiprazole 15 mg/day
or risperidone 3 mg/day (Selvi et al., 2011 ). It was found that YBOCS
scores for both risperidone and aripiprazole significantly declined over
the 8 weeks, but risperidone showed a significantly greater response
rate of ≥ 35% on the YBOCS (72.2%, 13 patients) compared to
aripiprazole (50%, 8 patients). However, risperidone has a more severe
long-term side effect profile in terms of weight gain, sedation,
extrapyramidal effects and problems associated with
hyperprolactinemia including amenorrhea and sexual dysfunction
(Veale et al., 2014 ).
Of note, most of these SGA trials only last for 8–12 weeks, but
when deciding on a medication regimen, it should be taken into
consideration that OCD has a chronic relapsing and remitting pattern.
One long-term open-label study did not support the effectiveness of
SGA augmentation of SSRIs for treatment-resistant OCD. SSRI non-
responders who required atypical antipsychotic augmentation had
significantly higher total YBOCS scores both at initial assessment and
after one year of treatment (initial assessment = 29.3 ± 9.9, after 1 year
= 19.3 ± 6.8) compared to SSRI responders (at initial assessment =
25.8 ± 11.4, after 1 year = 13.7 ± 4.6) (Matsunaga et al., 2009 ).
Moreover, the SSRI + atypical antipsychotic group had significantly
more side effects.
Veale et al. (2014) found no evidence for the effectiveness of
quetiapine or olanzapine (Veale et al., 2014 ). In one study, quetiapine
as an augmentation of an SSRI was actually less effective than placebo
(Diniz et al., 2011 ). Notably, in the same study, clomipramine as an
augmenter was not different from adding placebo. Some clinicians
report from experience that combining an SSRI and clomipramine is
an effective augmentation strategy, but the evidence does not support
that impression. Haloperidol has some evidence of efficacy as an
augmenter; however, it is not recommended due to increased risk of
long-term adverse effects with the use of first-generation
antipsychotics including tardive dyskinesia (Veale et al., 2014 ).
Node 5: Novel agents
If there is still an inadequate response, augmentation with novel agents
can be considered. As noted in node 4, they might be preferred over
the recommended SGAs if the side effects of the SGAs would be
unacceptable.
The benefit from some of these novel agents, including memantine,
riluzole, topiramate, n-acetylcysteine, lamotrigine and ketamine,
theoretically occurs via modulation of glutamatergic pathways. Of
these, memantine seems particularly promising based on a small
amount of evidence. In one RCT, participants with a YBOCS score of
21 or higher were started on fluvoxamine 100–200 mg/day for 8
weeks, and randomly assigned to also receive memantine 20 mg/day
(n = 19) or placebo (n = 19). By the end of the trial 89% of the
memantine group compared to 32% of the placebo group achieved
remission (YBOCS score ≤ 16) (Ghaleiha et al., 2013 ). Side effects
were not different between the two groups. Another RCT (n = 29)
demonstrated that, compare to patients with adjuvant placebo, patients
who received adjuvant memantine 5–10 mg/day in addition to
standard SSRI or clomipramine medication, improved significantly
after 12 weeks and were more likely to achieve a full response (35%
or more in Y-BOCS reduction) and show a decline in CGI severity
over time. It was also found that adjuvant memantine not only affects
overall response rate, but also may accelerate monotherapy response
rate with a standard SSRI or clomipramine (Haghighi et al., 2013 ).
Riluzole is a glutamate-blocking agent approved for the treatment of
symptoms of amyotrophic lateral sclerosis. An 8-week RCT (n = 50)
investigated adding adjuvant riluzole 50 mg twice daily or placebo to
fluvoxamine 200 mg/day in patients with moderate to severe OCD.
Thirteen patients in the riluzole group achieved remission (YBOCS
score ≤ 16), versus 5 patients in the placebo group, which was
significantly different (Emamzadehfard et al., 2016 ).
Topiramate 50–400 mg/day (mean dose 177.8 mg/day) is another
inhibitor of glutamatergic function that has been studied in OCD.
When added as an adjuvant to participants’ stable SSRI doses, it was
shown to significantly reduce compulsion scores on the YBOCS by
5.38 points (versus 0.6 points in the placebo group), but not obsessions
or total YBOCS scores (Berlin et al., 2011 ). However, 28% of 18
subjects receiving topiramate discontinued due to adverse effects.
N-acetylcysteine (NAC) 2000 mg/day is also a glutamate-inhibiting
agent that has been studied as an augmenter. NAC or placebo were
added to fluvoxamine 200 mg/day in a 10-week double-blind RCT (n
= 22 participants in each group). NAC significantly reduced YBOCS
total scores and the obsession subscale compared to the control group
(Paydary et al., 2016 ).
Another trial investigated augmentation with lamotrigine 100 mg/
day or placebo in 33 subjects with persistent OCD symptoms despite
an adequate trial on an SSRI for at least 12 weeks. In this 16-week
double-blind placebo-controlled trial, significant improvement was
achieved on the YBOCS obsession, compulsion, total scores, as well
as CGI scores of the lamotrigine group in comparison to the placebo
group at the end of the study (Bruno et al., 2012 ). Thirty-five percent
of the lamotrigine group had a reduction of 35% or greater in YBOCS
total score, corresponding to a full response, while none of the patients
in the placebo group met response criteria of even 25% improvement
in YBOCS total score. Lamotrigine was well-tolerated in this trial.
Another 12-week study of lamotrigine by Khalkhali et al. (2016)
found that SSRI-resistant patients who received adjuvant lamotrigine
100 mg/day to their SSRI (n = 26) had a significant reduction in
obsessive and compulsive symptoms on the YBOCS total score and
subscores compared to SSRI + placebo (n = 27) (Khalkhali et al., 2016
).
Ketamine infusions (0.5 mg/kg over 40 min) were compared with
saline infusions in 15 patients with OCD (Rodriguez et al., 2013 ). In
further support of the proposed importance of glutamate mechanisms
in OCD, the ketamine subjects had a significant rapid reduction in
obsessions mid-infusion, 230 min post-infusion, and 1-week post-
infusion. Fifty percent of the ketamine group (n = 8) met treatment
response criteria (≥ 35% reduction in YBOCS score) at 1-week post-
infusion versus 0% of the placebo group (n = 7), suggesting
ketamine’s effects on OCD symptoms can last at least a week
(Rodriguez et al., 2013 ). The most common side effects included
increases in blood pressure and pulse, and dissociative symptoms
during the ketamine infusion. We mention ketamine because of current
interest in this product, but much more research is needed before it
should be used routinely for OCD.
Other novel agents may reduce OCD symptoms by different
mechanisms. Ondansetron is a serotonin-3 receptor antagonist used to
treat nausea. Patients with OCD symptoms receiving fluoxetine 20
mg/day were augmented with ondansetron 4 mg/day or placebo in an
8-week trial. Patients treated with ondansetron had significantly lower
YBOCS scores at weeks 2 and 8 compared to placebo (Soltani et al.,
2010 ). Another 8-week trial (n = 44) involved augmentation of
fluvoxamine 100–200 mg/day with either ondansetron 4 mg twice
daily or placebo over 8 weeks. It was found that the ondansetron group
showed a significant reduction in YBOCS total score from week 4 and
thereafter compared to the placebo, such that at the end of the trial, 14
(64%) patients in the ondansetron group versus 6 (27%) patients in the
placebo group achieved remission (YBOCS score ≤ 16) (Heidari et al.,
2014 ).
Agents that reduce neuroinflammation may also serve as effective
augmenters for patients with OCD. In one 10-week trial of
augmentation of fluvoxamine 100–200 mg/day with minocycline 100
mg twice daily versus augmentation with placebo (n = 47 in each
group), it was found that the minocycline group had a significantly
lower YBOCS total scores compared to the placebo group at the end
of the trial. The minocycline group also achieved higher remission,
partial, and complete response rates compared to placebo at the end of
the trial. Furthermore, there was a significantly shorter period of time
needed in the minocycline group than the placebo group for a partial
response to be achieved (Esalatmanesh et al., 2016 ).
In an 8-week trial investigating the anti-inflammatory agent
celecoxib as an adjunctive treatment of OCD, 27 patients were placed
on fluoxetine 20 mg/day plus celecoxib 200 mg twice daily, and 25
patients were placed on fluoxetine 20 mg/day plus placebo. It was
found that patients in the celecoxib group had significantly lower
YBOCS scores at the end of the study compared to placebo. Both
groups showed a decline in mean YBOCS scores during the trial, but
the celecoxib group started to decline sooner (by week 2) versus the
placebo group (week 4) (Sayyah et al., 2011 ).
These experimental agents are placed after the SGAs in this
algorithm due to the limited amount of evidence on each agent.
However, they do show some positive benefit and one could debate
whether they should be offered as a group at node 4. It is reasonable to
present these options at the same time as antipsychotics, as most of the
novel agents, except for ketamine and maybe topiramate, have fewer
side effects compared to SGAs.
Node 6: Non-invasive device based therapy
If SGAs and any novel agents selected are not effective, the next step
to consider is transcranial magnetic stimulation (rTMS). It is also
reasonable to offer this treatment option at the same time as the novel
agents to patients who might prefer this somatic therapy compared to
taking another medication. rTMS has received many studies. A recent
meta-analysis evaluated 15 RCTs with sham control as adjunctive
treatment for OCD. Most of the trials targeted the dorsolateral
prefrontal cortex. Active TMS was found to be significantly more
effective than sham, but had questionable clinical meaningfulness due
to the small effect size (2.94-point difference on YBOCS between
groups) (Trevizol et al., 2016 ). However, media reports of interesting
new data submitted to the FDA by the Brainsway “Deep” TMS
System involving a study of 100 patients suggested that 38%
responded with 30% reduction of YBOCS scores compared to an 11%
response rate on sham. The FDA approved the device in 2018. The
procedure is to apply the magnet for 25 min, 5 days a week for 6
weeks. The procedure costs over $10,000. An important additional
aspect of the treatment in this study was the provision of a brief
session just before each procedure in which patients were asked to
think about their obsessions and compulsions. Hence, it was really a
study of combined cognitive processing and magnetic stimulation.
None of the other 15 RCTs employed this method and it may account
for the (as yet unpublished) better results. It is unclear where this
costly procedure belongs in the algorithm at this time. More study is
needed. Also, nothing is known about what maintenance procedures
would be needed to sustain the benefit.
Traditional electroconvulsive therapy could be considered for OCD
patients who have severe comorbid depression that has not responded
to the antidepressant trials (Hanisch et al., 2009 ).
Node 7: Neurosurgery
Finally, deep brain stimulation (DBS) and ablative surgery have been
shown to be beneficial for severe and intractable OCD, but remain
experimental. A meta-analysis of 31 DBS trials showed that YBOCS
scores improved 45.1% in patients treated with DBS (Alonso et al.,
2015 ). It was also found that 60% of patients treated with DBS met
criteria for response to treatment (defined as a reduction of ≥ 35% on
YBOCS). DBS responders had a significantly older age at onset of
OCD than nonresponding patients (responders 17.1 years ± 7.9 vs non-
responders 13.7 years ± 6.9) and more frequently reported obsessions
and compulsions of sexual/religious content than non-responders (33%
of responders compared to 0% of non-responders) (Alonso et al., 2015
). Most responding patients also reported significant improvement in
quality of life. Severe adverse events were less common with DBS
than lesional neurosurgery (Alonso et al., 2015 ). Of note, the optimal
brain region is still being established.
There is one double-blind RCT of radiosurgery (gamma ventral
capsulotomy – GVC) of the anterior limb of the internal capsule, for
patients with intractable OCD, which showed that 2 out of 8 patients
(25%) in the active treatment group reached a response at 12 months
(defined as a 35% or greater reduction in YBOCS and “improved” or
“much improved” on the CGI-I) compared to 0 out of 8 patients in the
sham group. This finding suggests that patients who underwent GVC
may have benefited more than those who underwent sham surgery,
although the difference was not statistically significant. However, in
the open long-term follow-up phase, 3 additional patients in the active
treatment group responded at post-GVC month 24, raising the
response rate to 62.5% (Lopes et al., 2014 ). Furthermore, 2 out of 4
patients who received active treatment, after having been in the sham
group initially, became responders at post-GVC months 12 and 24. In
sum, of the 12 patients who ultimately received GVC, 7 (58.3%)
became responders. Review of open-label gamma capsulotomy trials
showed response rates of at least 55% in patients with severe
refractory OCD (Leveque et al., 2013 ; Ruck et al., 2008 ).
Capsulotomy is also effective in reducing OCD symptoms at long-
term follow-up (mean of 10.9 years after surgery), but has a
substantial risk of adverse effects, including problems with executive
function, apathy, and disinhibition, particularly in patients who
received high doses of radiation or underwent multiple surgical
procedures (Ruck et al., 2008 ).
DISCUSSION
This algorithm organizes the evidence systematically for practical
clinical application and can serve as a guide for clinicians in the
management of OCD. It stresses the importance of adequate trials of
SSRIs including adding the benefits of measuring plasma levels at
times before going on to less established or more side-effect-prone
augmentations or somatic procedures. Nevertheless, the treatment of
OCD still has many challenges. There is much to be learned about the
pathophysiology, genetics, and neurobiology of OCD that could
improve future treatment and algorithms.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to
influence the work reported in this paper.
Funding
This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.
REFERENCES
Abejuela, H.R., Osser, D.N., 2016. The psychopharmacology algorithm project at the Harvard
South Shore Program: an algorithm for generalized anxiety disorder. Harv. Rev.
Psychiatry 24 (4), 243–256.
Addis, A., Koren, G., 2000. Safety of fluoxetine during the first trimester of pregnancy: a
meta-analytical review of epidemiological studies. Psychol. Med. 30 (1), 89–94.
Alonso, P., Cuadras, D., Gabriels, L., Denys, D., Goodman, W., Greenberg, B.D., Jimenez-
Ponce, F., Kuhn, J., Lenartz, D., Mallet, L., Nuttin, B., Real, E., Segalas, C., Schuurman,
R., du Montcel, S.T., Menchon, J.M., 2015. Deep brain stimulation for obsessive-
compulsive disorder: a meta-analysis of treatment outcome and predictors of response.
PLoS ONE 10 (7), e0133591.
American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental
Disorders, IV ed. American Psychiatric Association, Washington, D.C.
American Psychiatric Association, 2013. Diagnostic and Statistical Manual of Mental
Disorders, 5th ed. American Psychiatric Publishing, Washington, D.C.
Anglin, R., Yuan, Y., Moayyedi, P., Tse, F., Armstrong, D., Leontiadis, G.I., 2014. Risk of
upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or
without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-
analysis. Am. J. Gastroenterol. 109 (6), 811–819.
Ansari, A., Osser, D.N., 2010. The psychopharmacology algorithm project at the Harvard
South Shore Program: an update on bipolar depression. Harv. Rev. Psychiatry 18 (1), 36–
55.
Bajor, L.A., Ticlea, A.N., Osser, D.N., 2011. The psychopharmacology algorithm project at
the Harvard South Shore Program: an update on posttraumatic stress disorder. Harv. Rev.
Psychiatry 19 (5), 240–258.
Balachander, S., Kodancha, P.G., Arumugham, S.S., Sekharan, J.T., Narayanaswamy, J.C.,
Reddy, Y.C.J., 2019. Effectiveness of venlafaxine in selective serotonin reuptake
inhibitor-resistant obsessive-compulsive disorder: experience from a specialty clinic in
India. J. Clin. Psychopharmacol. 39 (1), 82–85.
Beach, S.R., Celano, C.M., Noseworthy, P.A., Januzzi, J.L., Huffman, J.C., 2013. QTc
prolongation, torsades de pointes, and psychotropic medications. Psychosomatics 54 (1),
1–13.
Berlin, H.A., Koran, L.M., Jenike, M.A., Shapira, N.A., Chaplin, W., Pallanti, S., Hollander,
E., 2011. Double-blind, placebo-controlled trial of topiramate augmentation in treatment-
resistant obsessive-compulsive disorder. J. Clin. Psychiatry 72 (5), 716–721.
Bertilsson, L., Dahl, M.L., Sjoqvist, F., Aberg-Wistedt, A., Humble, M., Johansson, I.,
Bertilsson, L., Dahl, M.L., Sjoqvist, F., Aberg-Wistedt, A., Humble, M., Johansson, I.,
Lundqvist, E., Ingelman-Sundberg, M., 1993. Molecular basis for rational mega-
prescribing in ultrarapid hydroxylators of debrisoquine. Lancet 341 (8836), 63.
Bird, S.T., Crentsil, V., Temple, R., Pinheiro, S., Demczar, D., Stone, M., 2014. Cardiac
safety concerns remain for citalopram at dosages above 40 mg/day. Am. J. Psychiatry 171
(1), 17–19.
Bloch, M.H., McGuire, J., Landeros-Weisenberger, A., Leckman, J.F., Pittenger, C., 2010.
Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive
disorder. Mol. Psychiatry 15 (8), 850–855.
Brandl, E.J., Tiwari, A.K., Zhou, X., Deluce, J., Kennedy, J.L., Muller, D.J., Richter, M.A.,
2014. Influence of CYP2D6 and CYP2C19 gene variants on antidepressant response in
obsessive-compulsive disorder. Pharmacogen. J. 14 (2), 176–181.
Bruno, A., Mico, U., Pandolfo, G., Mallamace, D., Abenavoli, E., Di Nardo, F., D’Arrigo, C.,
Spina, E., Zoccali, R.A., Muscatello, M.R., 2012. Lamotrigine augmentation of serotonin
reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a double-blind,
placebo-controlled study. J. Psychopharmacol. 26 (11), 1456–1462.
Burchi, E., Hollander, E., Pallanti, S., 2018. From treatment response to recovery: a realistic
goal in OCD. Int. J. Neuropsychopharmacol. 21 (11), 1007–1013.
Cederlof, M., Lichtenstein, P., Larsson, H., Boman, M., Ruck, C., Landen, M., Mataix-Cols,
D., 2015. Obsessive-Compulsive disorder, psychosis, and bipolarity: a longitudinal cohort
and multigenerational family study. Schizophr. Bull. 41 (5), 1076–1083 .
De Haan, L., Schirmbeck, F., Zink, M., 2015. Obsessive-compulsive Symptoms in
Schizophrenia. Springer.
De Picker, L., Van Den Eede, F., Dumont, G., Moorkens, G., Sabbe, B.G., 2014.
Antidepressants and the risk of hyponatremia: a class-by-class review of literature.
Psychosomatics 55 (6), 536–547.
Denys, D., van der Wee, N., van Megen, H.J., Westenberg, H.G., 2003. A double blind
comparison of venlafaxine and paroxetine in obsessive-compulsive disorder. J. Clin.
Psychopharmacol. 23 (6), 568–575.
Diniz, J.B., Shavitt, R.G., Fossaluza, V., Koran, L., Pereira, C.A., Miguel, E.C., 2011. A
double-blind, randomized, controlled trial of fluoxetine plus quetiapine or clomipramine
versus fluoxetine plus placebo for obsessive-compulsive disorder. J. Clin.
Psychopharmacol. 31 (6), 763–768.
Emamzadehfard, S., Kamaloo, A., Paydary, K., Ahmadipour, A., Zeinoddini, A., Ghaleiha,
A., Mohammadinejad, P., Zeinoddini, A., Akhondzadeh, S., 2016. Riluzole in
augmentation of fluvoxamine for moderate to severe obsessive-compulsive disorder:
randomized, double-blind, placebo-controlled study. Psychiatry Clin. Neurosci. 70 (8),
332–341.
Esalatmanesh, S., Abrishami, Z., Zeinoddini, A., Rahiminejad, F., Sadeghi, M., Najarzadegan,
M.R., Shalbafan, M.R., Akhondzadeh, S., 2016. Minocycline combination therapy with
fluvoxamine in moderate-to-severe obsessive-compulsive disorder: a placebo-controlled,
double-blind, randomized trial. Psychiatry Clin. Neurosci. 70 (11), 517–526.
Fava, M., Judge, R., Hoog, S.L., Nilsson, M.E., Koke, S.C., 2000. Fluoxetine versus sertraline
and paroxetine in major depressive disorder: changes in weight with longterm treatment.
J. Clin. Psychiatry 61 (11), 863–867.
J. Clin. Psychiatry 61 (11), 863–867.
Fineberg, N.A., Gale, T.M., 2005. Evidence-based pharmacotherapy of obsessive-compulsive
K., Stein, D.J., Sareen, J., Brown, A., Sookman, D., 2015. Obsessive-compulsive disorder
(OCD): practical strategies for pharmacological and somatic treatment in adults.
Psychiatry Res. 227 (1), 114–125.
Foa, E.B., Liebowitz, M.R., Kozak, M.J., Davies, S., Campeas, R., Franklin, M.E., Huppert,
J.D., Kjernisted, K., Rowan, V., Schmidt, A.B., Simpson, H.B., Tu, X., 2005.
Randomized, placebo-controlled trial of exposure and ritual prevention, clomipramine,
and their combination in the treatment of obsessive-compulsive disorder. Am. J.
Psychiatry 162 (1), 151–161.
Ghaleiha, A., Entezari, N., Modabbernia, A., Najand, B., Askari, N., Tabrizi, M., Ashrafi, M.,
Hajiaghaee, R., Akhondzadeh, S., 2013. Memantine add-on in moderate to severe
obsessive-compulsive disorder: randomized double-blind placebo-controlled study. J.
Psychiatr. Res. 47 (2), 175–180.
Giakoumatos, C.I., Osser, D., 2019. The psychopharmacology algorithm project at the
Harvard South Shore Program: an update on unipolar nonpsychotic depression. Harv.
Rev. Psychiatry 27 (1), 33–52.
Glassman, A.H., O’Connor, C.M., Califf, R.M., Swedberg, K., Schwartz, P., Bigger Jr., J.T.,
Krishnan, K.R., van Zyl, L.T., Swenson, J.R., Finkel, M.S., Landau, C., Shapiro, P.A.,
Pepine, C.J., Mardekian, J., Harrison, W.M., Barton, D., McLvor, M., 2002. Sertraline
treatment of major depression in patients with acute MI or unstable angina. JAMA 288
(6), 701–709.
Greist, J.H., Jefferson, J.W., Kobak, K.A., Chouinard, G., DuBoff, E., Halaris, A., Kim, S.W.,
Koran, L., Liebowtiz, M.R., Lydiard, B., et al., 1995. A 1 year double-blind placebo-
controlled fixed dose study of sertraline in the treatment of obsessive-compulsive
disorder. Int. Clin. Psychopharmacol. 10 (2), 57–65.
Grillault Laroche, D., Gaillard, A., 2016. Induced Obsessive Compulsive Symptoms (OCS) in
schizophrenia patients under atypical 2 antipsychotics (AAPs): review and hypotheses.
Psychiatry Res. 246, 119–128.
Grunder, G., 2018. Editorial to consensus guidelines for therapeutic drug monitoring in
neuropsychopharmacology. Pharmacopsychiatry 51 (1-02), 5–6.
Haghighi, M., Jahangard, L., Mohammad-Beigi, H., Bajoghli, H., Hafezian, H., Rahimi, A.,
Afshar, H., Holsboer-Trachsler, E., Brand, S., 2013. In a double-blind, randomized and
placebo-controlled trial, adjuvant memantine improved symptoms in inpatients suffering
from refractory obsessive-compulsive disorders (OCD). Psychopharmacology (Berl) 228
(4), 633–640 .
Hamoda, H.M., Osser, D.N., 2008. The psychopharmacology algorithm project at the Harvard
South Shore Program: an update on psychotic depression. Harv. Rev. Psychiatry 16 (4),
235–247.
Hanisch, F., Friedemann, J., Piro, J., Gutmann, P., 2009. Maintenance electroconvulsive
therapy for comorbid pharmacotherapy-refractory obsessive-compulsive and
schizoaffective disorder. Eur. J. Med. Res. 14 (8), 367–368.
Heidari, M., Zarei, M., Hosseini, S.M., Taghvaei, R., Maleki, H., Tabrizi, M., Fallah, J.,
Akhondzadeh, S., 2014. Ondansetron or placebo in the augmentation of fluvoxamine
response over 8 weeks in obsessive-compulsive disorder. Int. Clin. Psychopharmacol. 29
(6), 344–350.
Heyman, I., Mataix-Cols, D., Fineberg, N.A., 2006. Obsessive-compulsive disorder. BMJ 333
Heyman, I., Mataix-Cols, D., Fineberg, N.A., 2006. Obsessive-compulsive disorder. BMJ 333
(7565), 424–429.
House, S.J., Tripathi, S.P., Knight, B.T., Morris, N., Newport, D.J., Stowe, Z.N., 2016.
Obsessive-compulsive disorder in pregnancy and the postpartum period: course of illness
and obstetrical outcome. Arch. Womens Ment. Health 19 (1), 3–10.
Khalkhali, M., Aram, S., Zarrabi, H., Kafie, M., Heidarzadeh, A., 2016. Lamotrigine
augmentation versus placebo in serotonin reuptake inhibitors-resistant obsessive-
compulsive disorder: a randomized controlled trial. Iran J. Psychiatry 11 (2), 104–114.
Kieler, H., Artama, M., Engeland, A., Ericsson, O., Furu, K., Gissler, M., Nielsen, R.B.,
Norgaard, M., Stephansson, O., Valdimarsdottir, U., Zoega, H., Haglund, B., 2012.
Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary
hypertension in the newborn: population based cohort study from the five Nordic
countries. BMJ 344, d8012.
Koran, L.M., Cain, J.W., Dominguez, R.A., Rush, A.J., Thiemann, S., 1996. Are fluoxetine
plasma levels related to outcome in obsessive-compulsive disorder? Am. J. Psychiatry
153 (11), 1450–1454.
Koran, L.M., Faravelli, C., Pallanti, S., 1994. Intravenous clomipramine for obsessive-
compulsive disorder. J. Clin. Psychopharmacol. 14 (3), 216–218.
Koran, L.M., Gamel, N.N., Choung, H.W., Smith, E.H., Aboujaoude, E.N., 2005. Mirtazapine
for obsessive-compulsive disorder: an open trial followed by doubleblind discontinuation.
J. Clin. Psychiatry 66 (4), 515–520.
Koran, L.M., Hackett, E., Rubin, A., Wolkow, R., Robinson, D., 2002. Efficacy of sertraline
in the long-term treatment of obsessive-compulsive disorder. Am. J. Psychiatry 159 (1),
88–95.
Leveque, M., Carron, R., Regis, J., 2013. Radiosurgery for the treatment of psychiatric
disorders: a review. World Neurosurg. 80 (3–4), e31–e39 S32.
March, J.S., 1997. The expert consensus guideline series: treatment of obsessive-compulsive
disorder. J. Clin. Psychiatry 58 (Suppl), 1–72.
Marks, D.M., Park, M.H., Ham, B.J., Han, C., Patkar, A.A., Masand, P.S., Pae, C.U., 2008.
Paroxetine: safety and tolerability issues. Expert Opin. Drug Saf. 7 (6), 783–794.
Matsunaga, H., Nagata, T., Hayashida, K., Ohya, K., Kiriike, N., Stein, D.J., 2009. A
longterm trial of the effectiveness and safety of atypical antipsychotic agents in
augmenting SSRI-refractory obsessive-compulsive disorder. J. Clin. Psychiatry 70 (6),
863–868.
McGirr, A., Vohringer, P.A., Ghaemi, S.N., Lam, R.W., Yatham, L.N., 2016. Safety and
efficacy of adjunctive second-generation antidepressant therapy with a mood stabiliser or
an atypical antipsychotic in acute bipolar depression: a systematic review and meta-
analysis of randomised placebo-controlled trials. Lancet Psychiatry 3 (12), 1138–1146.
Mead, G.E., Hsieh, C.F., Hackett, M., 2013. Selective serotonin reuptake inhibitors for stroke
recovery. JAMA 310 (10), 1066–1067 .
Meier, S.M., Petersen, L., Pedersen, M.G., Arendt, M.C., Nielsen, P.R., Mattheisen, M., Mors,
O., Mortensen, P.B., 2014. Obsessive-compulsive disorder as a risk factor for
schizophrenia: a nationwide study. JAMA Psychiatry 71 (11), 1215–1221.
schizophrenia: a nationwide study. JAMA Psychiatry 71 (11), 1215–1221.
Meyer, J.M., Stahl, S.M., 2019. The Clozapine Handbook. Cambridge University Press, New
York, NY.
Mohammad, O., Osser, D.N., 2014. The psychopharmacology algorithm project at the
Harvard South Shore Program: an algorithm for acute mania. Harv. Rev. Psychiatry 22
(5), 274–294.
Montgomery, S.A., Kasper, S., Stein, D.J., Bang Hedegaard, K., Lemming, O.M., 2001.
Citalopram 20 mg, 40 mg and 60 mg are all effective and well tolerated compared with
placebo in obsessive-compulsive disorder. Int. Clin. Psychopharmacol. 16 (2), 75–86.
Naples, J.G., Kotlarczyk, M.P., Perera, S., Greenspan, S.L., Hanlon, J.T., 2016. Non-tricyclic
and non-selective serotonin reuptake inhibitor antidepressants and recurrent falls in frail
older women. Am. J. Geriatr. Psychiatry 24 (12), 1221–1227.
Ninan, P.T., Koran, L.M., Kiev, A., Davidson, J.R.T., Rasmussen, S.A., Zajecka, J.M.,
Robinson, D.G., Crits-Christoph, P., Mandel, F.S., Austin, C., 2006. High-Dose sertraline
strategy for nonresponders to acute treatment for obsessive-compulsive disorder: a
multicenter double-blind trial. J. Clin. Psychiatry 67 (1), 15–22.
Oesterheld, J., Osser, D.N., 1999. Drug interactions in augmentation strategies for
pharmacotherapy of OCD. J. Pract. Psychiatry Behav. Health 5 (3), 179–183.
Osser, D.N., Dunlop, L.R., 2010. The psychopharmacology algorithm project at the Harvard
South Shore Program an update on generalized social anxiety disorder. Psychopharm.
Rev. 45 (12), 91–98.
Osser, D.N., Roudsari, M.J., Manschreck, T., 2013. The psychopharmacology algorithm
project at the Harvard South Shore Program: an update on schizophrenia. Harv. Rev.
Psychiatry 21 (1), 18–40.
Pacchiarotti, I., Bond, D.J., Baldessarini, R.J., Nolen, W.A., Grunze, H., Licht, R.W., Post,
R.M., Berk, M., Goodwin, G.M., Sachs, G.S., Tondo, L., Findling, R.L., Youngstrom,
E.A., Tohen, M., Undurraga, J., Gonzalez-Pinto, A., Goldberg, J.F., Yildiz, A., Altshuler,
L.L., Calabrese, J.R., Mitchell, P.B., Thase, M.E., Koukopoulos, A., Colom, F., Frye,
M.A., Malhi, G.S., Fountoulakis, K.N., Vazquez, G., Perlis, R.H., Ketter, T.A., Cassidy,
F., Akiskal, H., Azorin, J.M., Valenti, M., Mazzei, D.H., Lafer, B., Kato, T., Mazzarini,
L., Martinez-Aran, A., Parker, G., Souery, D., Ozerdem, A., McElroy, S.L., Girardi, P.,
Bauer, M., Yatham, L.N., Zarate, C.A., Nierenberg, A.A., Birmaher, B., Kanba, S., El-
Mallakh, R.S., Serretti, A., Rihmer, Z., Young, A.H., Kotzalidis, G.D., MacQueen, G.M.,
Bowden, C.L., Ghaemi, S.N., Lopez-Jaramillo, C., Rybakowski, J., Ha, K., Perugi, G.,
Kasper, S., Amsterdam, J.D., Hirschfeld, R.M., Kapczinski, F., Vieta, E., 2013. The
International Society for Bipolar Disorders (ISBD) task force report on antidepressant use
in bipolar disorders. Am. J. Psychiatry 170 (11), 1249–1262.
Pallanti, S., Quercioli, L., Bruscoli, M., 2004. Response acceleration with mirtazapine
augmentation of citalopram in obsessive-compulsive disorder patients without comorbid
depression: a pilot study. J. Clin. Psychiatry 65 (10), 1394–1399.
Pampaloni, I., Sivakumaran, T., Hawley, C.J., Al Allaq, A., Farrow, J., Nelson, S., Fineberg,
N.A., 2010. High-dose selective serotonin reuptake inhibitors in OCD: a systematic
retrospective case notes survey. J. Psychopharmacol. 24 (10), 1439–1445.
Paton, C., Ferrier, I.N., 2005. SSRIs and gastrointestinal bleeding. BMJ 331 (7516), 529–530.
Paydary, K., Akamaloo, A., Ahmadipour, A., Pishgar, F., Emamzadehfard, S., Akhondzadeh,
Phelps, N.J., Cates, M.E., 2005. The role of venlafaxine in the treatment of obsessive-
Phelps, N.J., Cates, M.E., 2005. The role of venlafaxine in the treatment of obsessive-
compulsive disorder. Ann. Pharmacother. 39 (1), 136–140.
Pigott, T.A., L’Heureux, F., Rubenstein, C.S., Bernstein, S.E., Hill, J.L., Murphy, D.L., 1992.
A double-blind, placebo controlled study of trazodone in patients with obsessive-
compulsive disorder. J. Clin. Psychopharmacol. 12 (3), 156–162 .
Ravizza, L., Barzega, G., Bellino, S., Bogetto, F., Maina, G., 1996. Drug treatment of
obsessive-compulsive disorder (OCD): long-term trial with clomipramine and selective
serotonin reuptake inhibitors (SSRIs). Psychopharmacol. Bull. 32 (1), 167–173.
Reefhuis, J., Devine, O., Friedman, J.M., Louik, C., Honein, M.A., 2015. Specific SSRIs and
birth defects: bayesian analysis to interpret new data in the context of previous reports.
BMJ 351, h3190.
Rodriguez, C.I., Kegeles, L.S., Levinson, A., Feng, T., Marcus, S.M., Vermes, D., Flood, P.,
Simpson, H.B., 2013. Randomized controlled crossover trial of ketamine in obsessive-
compulsive disorder: proof-of-concept. Neuropsychopharmacology 38 (12), 2475–2483.
Ruck, C., Karlsson, A., Steele, J.D., Edman, G., Meyerson, B.A., Ericson, K., Nyman, H.,
Asberg, M., Svanborg, P., 2008. Capsulotomy for obsessive-compulsive disorder: long-
term follow-up of 25 patients. Arch. Gen. Psychiatry 65 (8), 914–921.
Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W., Warden, D.,
Niederehe, G., Thase, M.E., Lavori, P.W., Lebowitz, B.D., McGrath, P.J., Rosenbaum,
J.F., Sackeim, H.A., Kupfer, D.J., Luther, J., Fava, M., 2006. Acute and longer-term
outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D
report. Am. J. Psychiatry 163 (11), 1905-1917.
Sahraian, A., Jahromi, L.R., Ghanizadeh, A., Mowla, A., 2017. Memantine as an adjuvant
treatment for obsessive compulsive symptoms in manic phase of bipolar disorder: a
randomized, double-blind, placebo-controlled clinical trial. J. Clin. Psychopharmacol. 37
(2), 246–249.
Sansone, R.A., Sansone, L.A., 2011. SNRIs pharmacological alternatives for the treatment of
obsessive compulsive disorder? Innov. Clin. Neurosci. 8 (6), 10–14.
Sayyah, M., Boostani, H., Pakseresht, S., Malayeri, A., 2011. A preliminary randomized
double-blind clinical trial on the efficacy of celecoxib as an adjunct in the treatment of
obsessive-compulsive disorder. Psychiatry Res. 189 (3), 403–406.
Schirmbeck, F., Konijn, M., Hoetjes, V., Zink, M., de Haan, L., For Genetic, R., 2019.
Obsessive-compulsive symptoms in psychotic disorders: longitudinal associations of
symptom clusters on between-and within-subject levels. Eur. Arch. Psychiatry Clin.
Neurosci. 269 (2), 245–255.
Schule, C., Laakmann, G., 2005. Mirtazapine plus citalopram has short term but not longer
term benefits over citalopram alone for the symptoms of obsessive compulsive disorder.
Evid. Based Ment. Health 8 (2), 42.
Selvi, Y., Atli, A., Aydin, A., Besiroglu, L., Ozdemir, P., Ozdemir, O., 2011. The comparison
of aripiprazole and risperidone augmentation in selective serotonin reuptake inhibitor-
refractory obsessive-compulsive disorder: a single-blind, randomised study. Hum.
Psychopharmacol. 26 (1), 51–57.
Serretti, A., Chiesa, A., 2009. Treatment-emergent sexual dysfunction related to
antidepressants: a meta-analysis. J. Clin. Psychopharmacol. 29 (3), 259–266.
Soltani, F., Sayyah, M., Feizy, F., Malayeri, A., Siahpoosh, A., Motlagh, I., 2010. A
doubleblind, placebo-controlled pilot study of ondansetron for patients with obsessive-
compulsive disorder. Hum. Psychopharmacol. 25 (6), 509–513.
Thoren, P., Asberg, M., Cronholm, B., Jornestedt, L., Traskman, L., 1980. Clomipramine
treatment of obsessive-compulsive disorder. I. A controlled clinical trial. Arch. Gen.
Psychiatry 37 (11), 1281–1285.
Tollefson, G.D., Rampey Jr., A.H., Potvin, J.H., Jenike, M.A., Rush, A.J., kominguez, R.A.,
Koran, L.M., Shear, M.K., Goodman, W., Genduso, L.A., 1994. A multicenter
investigation of fixed-dose fluoxetine in the treatment of obsessive-compulsive disorder.
Arch. Gen. Psychiatry 51 (7), 559–567 .
Trevizol, A.P., Shiozawa, P., Cook, I.A., Sato, I.A., Kaku, C.B., Guimaraes, F.B., Sachdev, P.,
Sarkhel, S., Cordeiro, Q., 2016. Transcranial magnetic stimulation for obsessive-
compulsive disorder: an updated systematic review and meta-analysis. J. ect 32 (4), 262–
266.
Uguz, F., Sahingoz, M., Gungor, B., Aksoy, F., Askin, R., 2015. Weight gain and associated
factors in patients using newer antidepressant drugs. Gen. Hosp. Psychiatry 37 (1), 46–48.
Veale, D., Miles, S., Smallcombe, N., Ghezai, H., Goldacre, B., Hodsoll, J., 2014. Atypical
antipsychotic augmentation in SSRI treatment refractory obsessive-compulsive disorder:
a systematic review and meta-analysis. BMC Psychiatry 14, 317.
Vulink, N.C., Denys, D., Westenberg, H.G., 2005. Bupropion for patients with obsessive-
compulsive disorder: an open-label, fixed-dose study. J. Clin. Psychiatry 66 (2), 228–230.
Pharmacologic Approach to the Psychiatric Inpatient
*
Arash Ansari, MD, David N. Osser, MD, Leonard S. Lai, MD, Paul
M. Schoenfeld, MD, and Kenneth C. Potts, MD
CHARACTERISTICS OF INPATIENT
TREATMENT
The role of inpatient psychiatric treatment has evolved in recent decades.
Psychopharmacologic advances have enabled more successful treatment of
major mental illnesses. The movement to deinstitutionalize psychiatric patients
and shift care to community-based agencies and the economic realities of the
health care marketplace have had major impact to reduce the length of stay.
Nevertheless, a recent study by the U.S. Health and Human Services Agency for
Healthcare Research and Quality 1 found that in 2004, 1.9 million out of 32
million admissions (6%) to US community hospitals were primarily for a mental
health or substance abuse diagnosis, while an additional 5.7 million admissions
(18%) also involved depression, bipolar disorder, schizophrenia, or other mental
health diagnoses or substance abuse-related disorders as a secondary diagnosis.
The top five diagnoses reported were mood disorders, substance abuse-related
disorders, delirium/dementia, anxiety disorders, and schizophrenia. The average
length of stay for a patient with a primary mental health or substance abuse
diagnosis was 8 days compared to 5 days for nonmental health-related
diagnoses.
Because of time limitations, the goals of inpatient psychiatry have shifted
from striving to achieve full remission to symptom alleviation through the
judicious use of psychotropic medication so that the stay can be brief. Patients
may therefore be discharged as long as they are evaluated to be unlikely to harm
themselves or others, even though only some of the most distressing symptoms
have improved, for example, agitation, anxiety, or insomnia. Medication
treatment plans focus on these symptoms with the understanding that the full
effect and benefit may not occur for several weeks. Psychosocial treatments such
as intensive short-term individual psychotherapy, group therapy, and milieu
interventions that apply the principles of psychodynamic, cognitive, behavioral,
and dialectic behavioral techniques are vital in helping patients reduce
problematic thoughts, behavior, feelings, and other responses to their stressors
and symptoms in the inpatient setting. As no patient exists in a vacuum, outreach
to families, significant others, and social supports to address possible acute
psychosocial precipitants will contribute to helping reduce the likelihood of a
relapse or a recurrence. Consultations with outpatient providers can be of critical
importance. The inpatient stay can often provide an opportunity to clarify how
the community treatment network can be made more efficient and responsive to
the patient’s needs.
FACTORS INFLUENCING
PHARMACOTHERAPY ON AN INPATIENT UNIT
Publicly and privately funded inpatient psychiatric treatment is usually
authorized for patients who present a danger to themselves or to others or who
have demonstrated that they are unable to care for themselves. Inpatient
treatment is monitored closely by mental health review agencies hired to ensure
that this most expensive level of psychiatric care is used effectively and
minimally in order to contain costs. Inpatient treatment teams must be vigilant
about the time limitations imposed on each admission. This is made more
difficult by the fact that the safety concerns that open the door to an inpatient
admission generally are often found to be complicated by a myriad of additional
reasons for which the patient has come to the attention of health care providers.
Thorough assessment and formulation of why the patient is in a crisis must be
done quickly and with a careful evaluation of which symptoms and contributing
factors are the most important to address. These factors can range from
noncompliance with treatment because of poor insight to limited treatment
access and to destabilizing forces such as homelessness and family or
relationship conflicts. Patients have comorbid medical illnesses or substance
abuse-related factors that confound and prevent successful outpatient
interventions. Therefore, the challenge for the inpatient multidisciplinary
treatment team is to be able to evaluate and stabilize the sickest patients in the
psychiatric care continuum in the shortest time possible.
In some cases, keeping the inpatient stay brief may be therapeutic, especially
in the more character-disordered where the inpatient treatment milieu may
encourage regressive behaviors.
GOAL OF INPATIENT TREATMENT AS
RELATED TO PHARMACOTHERAPY
The task of the psychiatrist is to alleviate some of the presenting symptoms. This
may mean the commencement of a new medicine or the resumption or
adjustment of a medication regimen that has been effective in the past. The
choices made have to enable prompt and effective symptom relief while the
patient is in the hospital and to be feasible for the outpatient treatment team to
continue in the community. Some medicines will be effective in the short run,
for example, benzodiazepines for anxiety, whereas other medicines such as
antidepressants are initiated with the expectation that in time a more definitive
effect will occur. In other situations, it may be preferable to withhold initiation
of pharmacologic treatment, such as when the presenting picture is complicated
by significant substance abuse that obscures determination of whether Axis I
pathology is primary or secondary. The opportunity to observe the initial
response to medication will also allow evaluation of side effects, such as excess
sedation or akathisia, which may preclude the use of that particular drug.
Close observations by the treatment team facilitate psychopharmacology
decisions dependent on symptoms rather than syndromal diagnoses. For
example, medicine may be given to target anxiety symptoms while it is
determined if the symptoms are part of a mood disorder or an independent
anxiety disorder.
It is important to explain to the patient and his or her family that the short
length of stay allowed does not commonly result in full remission. They need to
understand that the goal is to reduce troubling symptoms and to enable the
patient to feel safer, be in better behavioral control, and to be able to function
better with or without the assistance of others in the community. Often the
suicidal or homicidal ideation that prompted the admission will resolve soon
after admission because of the containment and structure of the supportive
inpatient milieu. The focus will then quickly shift to the crucial question of
whether the patient still requires inpatient level of care.
SELECTING TREATMENT
Selecting initial psychopharmacologic treatment for a newly admitted patient
can be a complicated process and is based on multiple considerations and
variables. Often the prescribing physician must weigh many of these variables
simultaneously and rapidly given the complicated psychiatric, medical, and
psychosocial presentations of most hospitalized patients. Ten factors that
influence choice of initial agent will be reviewed.
SYMPTOM CONTROL—THE AGITATED
PATIENT AND THE USE OF P.R.N. MEDICATION
The inpatient psychiatrist is faced with the challenge of making a provisional
diagnosis and an initial treatment plan for the patient. Sometimes this diagnosis
is based on very limited or even contradictory clinical and historical data. The
clinician must be aware that new information may come to light, and the
diagnoses may need to be modified. Recalling the guiding principles of “safety
first” and “do no harm” is frequently helpful.
It is important to identify and treat the most serious symptoms regardless of
diagnosis—these include violence, aggression, assault, self-harm, suicide,
disorganizing psychosis, agitation, and risk of dying from inanition or other
complications of poor oral intake and immobility (e.g., deep venous thrombosis
[DVT], aspiration pneumonia, and skin breakdown). A symptom-based approach
to psychopharmacologic treatment in an inpatient setting is therefore often
necessary. This section will focus on the treatment of the agitated patient and the
use of p.r.n. medication.
The Agitated Patient
A patient may become agitated at any time during the admission. Upon entry to
the hospital, factors include the effects of being confined, the change in
environment, and the loss of autonomy. A patient may become agitated later in
the admission, such as if too rapidly allowed out of a contained situation or
denied privileges. Nicotine-dependent patients can become extremely agitated if
not permitted to smoke when they want. Interestingly, a recent study found that
when units become smoke-free, incidents of agitation and restraint are markedly
reduced. 2
The violent, aggressive, or out-of-control patient can be very difficult to
manage. The risk of assault or of self-harm must be assessed and reassessed.
Prevention is the best approach, of course, with active treatment of any patient
who may be at risk.
Certainly, the intensive use of the structure of the inpatient milieu can be
instrumental in minimizing the need for medication. The containment of quiet
rooms and destimulation can reduce potentially stressful situations for the
patient, allowing time for a treatment plan to help an agitated patient.
However, there are situations where all the best efforts fail. Safety of the
patient or staff is at risk, and sometimes urgent medication is necessary. When a
rapid response is required, parenteral medication is indicated (although in less
acute situations oral medication should be considered). A combination of an
intramuscular typical antipsychotic and a benzodiazepine has been shown to be
more effective than either one used alone. 3 This combination can avoid the need
for an adjunctive dose of an anticholinergic; extrapyramidal symptoms (EPS) are
infrequent. The advantages are avoiding both additional injections and
anticholinergic toxicity. A common combination includes haloperidol 2 to 5 mg
along with lorazepam 1 to 2 mg intramuscularly (in the same syringe) given
every 30 to 60 minutes, up to three doses. Haloperidol is often considered first-
line because of its relative safety profile, the lack of an established ceiling dose,
and years of clinical experience. Other typical antipsychotics are less often used
in this situation and have become less available. Intramuscular chlorpromazine is
not recommended because of its high risk of hypotension. Intramuscular
droperidol should not be used in the emergency treatment of agitation because of
the increased risk of QTc prolongation with this agent.
The role of intramuscular atypical antipsychotics (i.e., ziprasidone,
olanzapine, aripiprazole) is less clear. The upper limit of dosing and risks of
drug interactions (e.g., QTc prolongation issues) may preclude ongoing use in an
agitated patient. Although these drugs are heavily promoted by their
manufacturers and many clinicians use them, the evidence base is unsatisfactory.
All have been compared with haloperidol alone, without lorazepam or
concomitant anticholinergic agents. 4 – 6 This gave the atypicals an unfair
advantage.
One alternative to consider is monotherapy with parenteral lorazepam. This
can be a valuable option when exposure to a typical antipsychotic is undesirable.
A usual dose may be 1 to 3 mg intramuscularly hourly up to three doses. Some
clinicians may be hesitant to use benzodiazepines with a substance-using patient.
However, its efficacy in treating agitation in an emergency may well outweigh
these concerns. Some clinicians are also concerned about the risk of
“disinhibition” or a paradoxical reaction. There are no clear risk factors for this,
and it appears to be rare. The risk of respiratory depression with repeated doses
of benzodiazepines should be taken into account, especially if the patient has
other sedating drugs on board, or has pulmonary insufficiency. As with all
medication, an elderly agitated patient may require significant dose reduction
and greater intervals between dosing.
Use of p.r.n. Medication
Use of p.r.n. Medication
The use of so-called p.r.n. medication (pro re nata —“as the thing is born”) is
common in inpatient psychiatry to treat a variety of symptoms, including
agitation (see preceding text), anxiety, breakthrough psychotic symptoms, and
insomnia. Judicious use of p.r.n. medication can be very helpful in evaluating the
need to change the standing medication plan. For example, the psychotic patient
who is not “held” by his standing medication and needs “extra” doses may need
a reevaluation of the standing medication dose.
However, there are also potential pitfalls. There is the risk of forming an
association, on the part of the patient, between an undesirable behavior and
taking an extra pill, thereby reinforcing drug-seeking behavior and
externalization of responsibility. On many units, the culture is to actively
encourage patients, if in distress, to ask for a p.r.n. medication. The astute
clinician then helps the patient identify the precipitating factor and solve the
problem, thereby fostering more of a sense of self-control on the part of the
patient.
The milieu effect of p.r.n. medication is important to consider. Asking for
extra medicine may be a patient’s way of communicating the need for more
contact, especially in a busy inpatient unit. The patient may then feel heard,
attended to, and held, even if medicine is not offered. The interaction allows for
more patient-staff contact. In addition, nursing staff often feel safer if p.r.n.
medication is “on the books” for a challenging patient. The placebo effect of
p.r.n. medication must not be overlooked.
The choice of a p.r.n. agent should take into account the relevant symptom
and the current medication list. Attention should be paid to the total daily dose
(standing plus p.r.n. available) so as to avoid exceeding maximum recommended
doses. When treating psychosis or mania, p.r.n. medication should ideally be the
same as the standing medication, so as to avoid the risks of polypharmacy,
including the risks of adverse (e.g., cardiac) effects. Adjunctive use of
benzodiazepines can be very helpful in psychotic patients.3
In patients with anxiety, short-acting or intermediate acting benzodiazepines
are often used. Although not approved by the U.S. Food and Drug
Administration (FDA), many clinicians use low-dose antipsychotics in these
patients, especially if substance abuse is an issue. Low-dose antipsychotics may
be particularly helpful in patients with anxiety or agitation associated with
personality disorders 7 , 8 (see subsequent text). Trazodone is a cost-effective
alternative that needs further study. Prazosin can be useful as a p.r.n. during the
day for patients with post-traumatic stress disorder (PTSD) as well as at night for
sleep. 9 , 10
Insomnia is probably the single symptom for which p.r.n. medication is most
frequently requested. Insomnia may be due to the environment, a side effect of
medication, a complication of a general medical condition (such as restless legs
syndrome [RLS] or obstructive sleep apnea), a consequence of excessive intake
of caffeine or nicotine, a symptom of withdrawal, and so on. Although sleep
hygiene should be addressed, often medication is required. Choices include
antihistamines, benzodiazepines, trazodone, low-dose sedating tricyclic
antidepressants, prazosin, and newer hypnotics.
Psychotropic medicines, both p.r.n. and standing, also play a crucial role in
the treatment of patients with borderline personality disorder (BPD). Often
patients with BPD are admitted to inpatient units when they are emotionally
overwhelmed, regressed, and in poor behavioral control. Heightened emotional
lability, irritability, anger, impulsivity, transient psychosis, and agitation can all
be present. Frequently p.r.n. medicines are used to decrease the intensity of these
symptoms, and, if helpful, may be continued as standing treatment. When the
patient with BPD exhibits dangerous agitation that places the patient or others
directly at risk of harm, then, as is the case in the schizophrenic or manic patient,
intramuscular or oral antipsychotics are likely to be needed. Overall total doses
needed are usually less than those employed in manic or psychotically agitated
patients. Even when immediate dangerousness is not an issue, antipsychotics can
be used to decrease patient hostility and transient psychosis. 11 Although there is
no reason to believe that any one antipsychotic is more effective than any other,
in acute situations many clinicians prefer to use an antipsychotic that can have
immediate and observable effect (e.g., perphenazine, haloperidol, or
risperidone). Quetiapine is also frequently used for p.r.n. treatment of anxiety in
patients with BPD. Disinhibition from benzodiazepines (which as previously
noted is of limited concern when treating violent behavior in general) is of
particular concern in patients with BPD and may lead to further behavioral
dyscontrol; 12 benzodiazepines, therefore, should not be used to treat anxiety in
these patients. Once acuity has decreased and transient psychotic phenomena
have subsided, continuing an antipsychotic as a standing medication may help
reduce impulsivity and aggression, and improve overall functioning. 13 Again,
total doses needed are usually lower than those needed for the ongoing treatment
of a primary psychotic disorder. 14 , 15 Quetiapine and aripiprazole may also be
helpful for ongoing mood and anxiety symptoms in these patients.8 , 16
Serotonergic antidepressants and mood stabilizers may help primarily with
affective lability and anger.11 , 13 One controlled study of 30 patients suggested
that omega-3 fatty acids may reduce depression and aggression in patients with
moderate BPD. 17 On the other extreme with respect to toxicity, clozapine has
been reported in several uncontrolled studies to be helpful in reducing morbidity
in some treatment refractory patients. 18 , 19
PATIENT’S PSYCHOPHARMACOLOGIC
HISTORY
An advantage the inpatient psychiatrist has is extended time to obtain a history
of the psychopharmacologic treatment the patient has received. It is time well
spent. The psychiatrist should have several interviews with the patient over a
few days to ascertain as much detail as possible about what the patient
remembers about his medication history. Information about dose, efficacy, side
effects, duration of treatment, and use of different medication combinations is
necessary to formulate an approach and apply relevant treatment algorithms. The
level of functional recovery with previous treatment interventions is critical to
assess. An understanding of the factors that contribute to compliance or
noncompliance is essential for establishing the ongoing medication treatment
alliance. Repeating treatment trials that have failed in the past is to be avoided if
possible. It is important to obtain a comprehensive list of all prescribed and over-
the-counter medicines used by the patient for general medical ailments to
evaluate for possible drug interactions.
Careful medication reconciliation on admission is required. The physician
must accurately determine what the patient was taking immediately before
admission. For each identified item, there should be clear documentation of the
plan to continue, change, or stop the medication. This practice promotes the
accurate administration of medication.
Because the patient may be an unreliable informant, collateral information
from outpatient clinicians and family members should be actively sought as soon
as possible. They often have critical insights and observations about how
effective different psychopharmacologic interventions have been.
When medical records are available to supplement the data collected from
patients and significant others, history gathering is easier. Fortunately, more and
more health care organizations are switching to electronic information systems
that enable all clinicians to have fast, convenient, and accurate access to
psychiatric and general medical histories at the touch of a keyboard. However,
when the patient is treated in multiple unrelated health care systems, it can still
be extremely difficult to obtain accurate, sequenced historical information in a
timely manner for a short inpatient stay. Error-prone educated guesswork can
often not be avoided especially in the early days of an admission.
PREEXISTING GENERAL MEDICAL
CONDITIONS
There are certain common general medical concerns that influence the selection
of pharmacologic agents. Very early in the decision-making process, many
physicians first glance at the patient’s past medical history to clarify the
“medical milieu” in which they will be prescribing. Rapid access to laboratory
data as well as other testing (e.g., electrocardiogram [ECG]), and review of
general medical history especially in an electronic medical record, when
available, are extremely helpful.
Cardiac
Many psychotropics can affect cardiac conduction, with the potential to delay
conduction enough to lead to fatal arrhythmias. There is an association between
sudden death and the use of antipsychotics 20 and tricyclic antidepressants at high
doses 21 (but not selective serotonin reuptake inhibitors [SSRIs]), although
causality has not been completely established, and there may be multiple
etiologies. The cardiovascular effects of psychotropics should therefore be taken
into account before beginning treatment.
Prolonged QT interval (reported as QTc when corrected for heart rate) is
believed to be associated with torsades de pointes , a potentially fatal ventricular
arrhythmia. The QT interval includes both the QRS interval as well as the ST
segment. Whereas QRS (depolarization phase) lengthening is primarily
associated with the use of tricyclic antidepressants (or low-potency typical
antipsychotics with tricyclic structure) and their effect on sodium channels,
atypical antipsychotics may potentially prolong the ST segment (repolarization
phase) through their effect on potassium channels. 22 Although there is some
question whether QT prolongation is a reliable indicator for the risk of torsades
de pointes , 23 measuring this interval is the simplest way to estimate this risk.
Antipsychotics are not equal in their potential to affect the QT interval.
Thioridazine, mesoridazine, pimozide, and droperidol 24 have shown significant
potential to prolong QT and should generally be avoided. Among the newer
antipsychotics, ziprasidone is considered to have the greatest potential to
lengthen QT.22 Some postmarketing studies such as the Clinical Antipsychotic
Trials of Intervention Effectiveness (CATIE) have not confirmed this. 25 , 26
Premarketing data with aripiprazole indicate little risk. 27 Clozapine may
contribute to QT prolongation primarily in patients with other risk factors. 28 The
other cardiac risks of clozapine, that is risk of developing myocarditis or
cardiomyopathy, are etiologically independent of its effect on cardiac
conduction.
Tricyclic antidepressants, especially at high doses (particularly in the setting
of overdose), have long been known for their potential to interfere with cardiac
conduction and have traditionally been used with caution in patients with cardiac
disease. Lithium may worsen sick sinus syndrome, produce blockade of the
sinoatrial node, and also prolong QT. 29 SSRIs do not appear to significantly
prolong QT, although there has been concern regarding their potential to induce
bradycardia . 30 – 32
Patients at higher cardiac risk should be identified before starting treatment
with antipsychotics, tricyclic antidepressants, and lithium. Caution should be
used in the care of the elderly, those with preexisting cardiac disease or
preexisting QT prolongation, bradycardia, hypokalemia, or hypomagnesemia,
and in those taking concomitant medication with proarrhythmic potential. A
baseline ECG should be obtained in these patients; if the QTc is >440 to 450
msec, the patient should be monitored more carefully, and a QTc >500 msec
should greatly increase concern for arrhythmias. Ziprasidone is contraindicated
if the QTc is >500 msec. Magnesium and potassium abnormalities should be
corrected early on. In high-risk patients, medicines with lower potential for
cardiac toxicity should be used, and an effort should be made to use the lowest
effective dose. Additionally, the clinician should be aware of medication
interactions that may increase the serum level of the selected agent (see section
on Medication Interactions). The clinician should also consider obtaining repeat
ECGs on any patient who is being treated with two or more psychotropics with
high risks of QT prolongation as the doses of these medications are titrated.
Blood Pressure
Many commonly used psychotropics have a-adrenergic blocking effects and can
therefore lower blood pressure. Some of the observed cases of sudden death in
patients taking antipsychotics or tricyclic antidepressants may be primarily due
to severe hypotension rather than to cardiac arrhythmias. Vital signs, commonly
checked on admission and daily thereafter, can identify those with preexisting
hypotension. Patients at risk for orthostatic hypotension include the elderly,
those with cardiac disease, and those taking other medicines that can lower
blood pressure. Medicines whose propensity to lower blood pressure mandates
caution are clozapine, chlorpromazine, risperidone, quetiapine, tricyclic
antidepressants, and trazodone. Clozapine, which carries the highest risk of
causing orthostasis, requires a very gradual and careful titration (i.e., starting at
12.5 mg once or twice a day with increases starting with 25 mg increments
daily). In the patient who has been noncompliant it should not be restarted at
prior doses if treatment has been interrupted for 2 or more days. Chlorpromazine
administered intramuscularly or at sudden high oral doses carries a similar risk.
Although tolerance to this side effect usually develops, care should be exercised
when starting these medicines (or restarting them at previously prescribed high
doses in patients who may have been recently nonadherent to their regimen).
Increased fluid intake should be encouraged as tolerated and orthostatic blood
pressure should be monitored in symptomatic patients until the appropriate dose
is reached.
In regard to the risk of increasing blood pressure, there has been concern
regarding the use of serotonin and norepinephrine reuptake inhibitors (SNRIs) in
patients at risk for hypertension. Venlafaxine used at high doses can increase
blood pressure. 33 , 34 This effect may be less pronounced with duloxetine and
may not be clinically significant. 35 , 36 Patients with stable, effectively treated
hypertension have not been found to show an increase in blood pressure from
venlafaxine. 37
Hepatic
There are two considerations regarding choice of psychiatric drug in a patient
with compromised hepatic function. The first is the issue of hepatotoxicity with
certain medicines, and the second is the use of hepatically metabolized agents in
patients with preexisting liver disease. Baseline liver function tests should be
measured, and if high, should influence care when using certain psychotropics.
Valproate, olanzapine, and quetiapine can cause hepatotoxicity. Although in
the vast majority of cases any elevation in transaminases is mild and transient,
these medicines should be used cautiously. The presence of clinically active liver
disease or cirrhosis would suggest use of other agents (e.g., lithium rather than
valproate for mania). If, during early inpatient treatment, transaminase levels
increase to more than three times the upper end of the normal range,
discontinuing or decreasing the dose of the offending agent should be
considered. Patients with previous exposure to hepatitis B or C virus who are not
acutely ill can still be treated with these medicines, although transaminases
should be carefully monitored. 38 , 39 Given the concern that one would be
exposing these patients with potentially worsening liver disease to yet another
toxic insult, alternative nonhepatotoxic agents (e.g., lithium) should be
considered when appropriate. Valproate may also rarely cause hyperammonemic
encephalopathy without causing transaminase elevation, 40 although this is
controversial. 41
In the case of a patient admitted with preexisting liver disease, medicines
which are primarily hepatically metabolized should be started at lower doses and
increased slowly and agents with shorter half-lives should be used preferentially.
Renal
Measurement of kidney function, that is serum creatinine, is routinely done upon
admission to an inpatient unit. Lithium, topiramate, and gabapentin are cleared
by the kidneys, and any decrease in renal function warrants dose reduction of
these medicines.
A common scenario is the admission to the inpatient unit of a patient whose
lithium has been discontinued as an outpatient, because of concerns regarding
worsening renal function (as can occur in up to 20% of patients on long-term
lithium treatment). 42 Often the patient had been previously well maintained for
many years on lithium. Once lithium is discontinued, however, the patient may
decompensate and require multiple alternative medication trials and multiple
hospitalizations for recurrent manic or depressive episodes. In these patients, the
overall risks of morbidity and mortality may be less with rechallenge with
lithium than if lithium treatment is withheld. After a clear risk and benefit
assessment, and in close consultation with a nephrologist, it may be clinically
appropriate for these patients to resume taking lithium. Close monitoring from
then on, while avoiding further episodes of lithium toxicity, and administration
of lithium once a day at bedtime, may decrease the risk of worsening renal
effects. 43
Metabolic Syndrome
Metabolic syndrome is characterized by dyslipidemia, hyperglycemia, and
weight gain and is a major risk associated with some second-generation
antipsychotics.
Hyperglycemia/Diabetes
The prevalence of diabetes is higher in patients with schizophrenia (in part
because of unhealthy lifestyles) independent of treatment with antipsychotics. 44
Clozapine and olanzapine have clearly been implicated in increased risk of onset
of hyperglycemia and diabetes, and in the exacerbation of preexisting diabetes,
even leading to diabetic ketoacidosis. The propensity of quetiapine to cause
hyperglycemia is numerically greater than that of other second-generation
antipsychotics but less than that of the two agents mentioned earlier.25 The data
regarding risperidone are mixed. 45 One putative mechanism is that some of these
agents rapidly induce insulin resistance, with or without causing weight gain.
Measuring fasting plasma glucose and inquiring about a patient’s personal and
family history of hyperglycemia and/or diabetes can help identify those at risk
for developing diabetes, and determining hemoglobin A1c can provide a measure
of recent glycemic control. In patients at high risk of developing diabetes,
aripiprazole or ziprasidone should be considered. 46 If fasting glucose is elevated,
a glucose tolerance test has excellent predictive value regarding who is going to
develop overt diabetes. 47
Weight Gain
The risk of significant weight gain, particularly in the first few months of
treatment, should be considered when prescribing atypical antipsychotics. A 2-
to 3-kg weight gain early in the course of treatment (i.e., within the first 3
weeks) often predicts the risk of substantial weight gain over the long term. 48
However, different antipsychotics are not equal in their propensity to cause
obesity. Clozapine and olanzapine are generally considered to be more likely to
cause weight gain than quetiapine and risperidone, and in turn aripiprazole and
ziprasidone are the least likely to contribute to weight gain. 49 Measuring
baseline body mass index (BMI) and waist circumference are recommended by
recent guidelines.46 A patient’s admission weight must be measured to establish
a pretreatment baseline.
Hyperlipidemia
Antipsychotics that have the highest propensity to cause weight gain also carry
the highest risk of worsening lipid profile. Risperidone may be more neutral in
this regard, and ziprasidone may actually improve lipid profile.25 Triglycerides
are the lipids most affected by the use of atypical antipsychotics. 50 A fasting
lipid profile can identify those patients already at higher cardiac risk and again
serve as a pretreatment baseline. Pharmacotherapy of hyperlipidemia may be
necessary. Also education on diet and lifestyle changes necessary to manage
these side effects is essential, although compliance with these changes over time
can be more unsatisfactory than compliance with the antipsychotic treatment
itself. 51
Leukopenia, Thrombocytopenia
Although many psychotropics (e.g., antipsychotics) can cause leukopenia,
clozapine and carbamazepine are the primary medicines that need to be avoided
in leukopenic patients. Of the antidepressants, mirtazapine may be associated
with leukopenia, although causality has not been established and this has been
rarely observed in clinical practice. 52 Gabapentin can also infrequently have a
mild leukopenic effect.27 Lithium, on the other hand, has been suggested for
treatment of leukopenia and may be beneficial in this regard; 53 the mechanisms
for increased white blood count may include demarginalization of neutrophils as
well as possible release of colony-stimulating factors. 54 – 56
The use of mood stabilizers such as carbamazepine, oxcarbazepine, 57 and
valproate 58 , 59 is problematic in patients with preexisting thrombocytopenia
because of their potential for lowering platelet count. Even when platelet count
is normal, valproate may cause platelet dysfunction and prolong bleeding time. 60
, 61 Therefore, patients taking valproate should be assessed for bleeding risk
before any invasive surgical procedures.
Hyponatremia
The syndrome of inappropriate antidiuretic hormone secretion (SIADH),
resulting in hyponatremia, has been documented in patients, especially the
elderly, who have been taking antidepressants. In addition to SSRIs, mirtazapine,
duloxetine, and bupropion have all been implicated. 62 – 64 Among mood
stabilizers, carbamazepine and oxcarbazepine can both cause hyponatremia, 65
although the mechanism is not secondary to SIADH and is not well understood.
66
Neurologic Disease
Seizures
Patients with seizure disorders provide challenges in the choice of medication.
Antidepressants and antipsychotics are thought to lower seizure threshold and
this effect is generally dose dependent. 67 The most likely to do so are clozapine,
chlorpromazine, olanzapine, quetiapine, tricyclic antidepressants, and bupropion
(contraindicated in patients with seizure disorders). The risk with monoamine
oxidase inhibitors (MAOIs) and SSRIs and other new antidepressants are
considered to be low. 68 This is controversial, however. Depression itself appears
to increase seizure risk and a review of FDA clinical trial data for
antidepressants has shown a possible anticonvulsant effect of newer
antidepressants at therapeutic doses 69 (although in overdoses antidepressants are
still considered to increase seizure risk). Among antipsychotics, haloperidol and
risperidone are less likely to affect seizure threshold. 70 All psychotropics should
be used cautiously in patients with seizure disorders or when patients are
seizure-prone (e.g., during alcohol or benzodiazepine withdrawal).
Stroke
Antipsychotics increase the incidence of stroke in patients with dementia. 71 – 73
First- and second-generation antipsychotics likely pose equal risk. 74 Possible
etiologies for stroke may be related to cardiovascular effects or changes
secondary to excessive sedation. In patients with dementia and significant
behavioral dyscontrol or assaultiveness, SSRIs, 75 trazodone, or mood stabilizers
should be considered. 76 However given their more rapid onset of action,
antipsychotics should not be withheld if there is imminent risk of harm
secondary to behavioral dyscontrol. The clinician should be aware that the use of
both typical and atypical antipsychotics may be associated with an increased risk
of death in patients with dementia.71
Extrapyramidal Symptoms
Patients with a prior history of dystonic reactions or substance abuse, and young,
male patients are at higher risk for developing acute dystonias. Dystonias are
primarily caused by typical antipsychotics but can occur with any antipsychotic
with higher D2 receptor occupancy (e.g., risperidone). Olanzapine, especially in
high doses, can also cause EPS, although at lower rates than typical
antipsychotics, possibly because of its own anticholinergic effects.45 Quetiapine
and clozapine are least likely to cause dystonias and parkinsonism.
Clozapine should also be considered in a patient presenting with tardive
dyskinesia (TD), although all antipsychotics may mask, and therefore appear to
improve, symptoms with treatment. Clinicians should attempt to avoid using
typical antipsychotics in patients with preexisting abnormal movements. If
abnormal movements again develop during treatment, clinicians should be aware
that withdrawing the offending agent (especially if done too rapidly) could
unmask and thereby worsen symptoms of TD. Patients at higher risk for TD are
the elderly, women, those with prolonged treatment or past treatment with high
doses of neuroleptics, those who developed significant parkinsonian side effects
initially, and those with a history of affective disorders.
In contrast to other EPS, akathisia rates are generally similar among atypical
antipsychotics, although there are lower overall rates with atypicals when
compared with typical antipsychotics (10% to 20% vs. 20% to 50%,
respectively).45 Identifying akathisia as the cause of agitation, restlessness, or
even worsening psychosis or suicidality is crucial because treatment would
include decreasing rather than increasing antipsychotic dose.
Restless Legs Syndrome
RLS has been reported with the use of antidepressants such as SSRIs, 77
venlafaxine, 78 and mirtazapine 79 (as well as with several antipsychotics).
Preliminary case reports suggest that bupropion, through modulation of
dopaminergic effect, may be a better alternative antidepressant in patients with
either preexisting or antidepressant-induced RLS. 80
Women of Childbearing Age
Careful attention should be given to the choice of medication in young women.
The general areas of concern are (a) the possibility of unplanned pregnancy
while taking psychotropics and subsequent potential harm to the fetus and (b) the
hormonal effects of medications on nonpregnant women.
Valproate may play a role in the development of polycystic ovary syndrome in
women of reproductive age, 81 thereby affecting fertility (although there is a lack
of clarity regarding rates given a higher-than-baseline occurrence of polycystic
ovaries in bipolar patients not taking valproate). 82 In general, the use of mood
stabilizers in young women can be very problematic given the possibility of
interfering with fertility (e.g., valproate), interacting to decrease effectiveness of
oral contraceptives (e.g., carbamazepine), and then increasing the chances of
congenital malformations (e.g., valproate, carbamazepine, and to a lesser extent
lithium) should pregnancy ensue. Considering alternatives to treatment with
mood stabilizers and providing patient education are particularly important when
treating women of childbearing age.
Another endocrine risk in women is the propensity of many antipsychotics to
increase prolactin. Of the newer antipsychotics risperidone is the most
problematic. Olanzapine, which is generally unlikely to increase prolactin, may
do so at higher than usual doses (e.g., 30 mg per day). 83
MEDICATION INTERACTIONS
The potential for interactions among psychotropics, or interactions between
psychotropics and other classes of medication, often influences the inpatient
clinician’s choice of therapeutic agent. Although occasionally the likelihood of
interactions clearly precludes the use of certain agents, more commonly the
concern about interactions necessitates caution when introducing a new
medicine. A complete list of interactions is beyond the scope of this chapter. The
inpatient psychiatrist is well advised to consult the several available databases
(web-based [e.g., www.genemedrx.com ], 84 print, 85 etc.) when using multiple
medicines. Nevertheless, there are commonly encountered types of interactions,
both pharmacokinetic and pharmacodynamic, that should be kept in mind when
choosing treatment for the hospitalized psychiatric patient. Patients at
particularly high risk for dangerous medication interactions include those with
impaired drug metabolism (including the elderly and those with organ
insufficiencies) and those with chronic conditions (e.g., chronic psychiatric
conditions, human immunodeficiency virus [HIV], cardiac patients) who require
long-term complex pharmacotherapy.
Antidepressants
SSRIs are well known for their ability to interact with other medicines by
affecting the hepatic cytochrome P-450 system. A primary concern is the
potential for an SSRI to inhibit the enzymatic activity of specific P-450
isoenzymes, thereby increasing the serum levels of other hepatically metabolized
medications (i.e., substrates), such as tricyclic antidepressants, antipsychotics,
and warfarin. 86 Potentially harmful dose-dependent side effects (e.g., effects on
cardiac conduction secondary to increased plasma concentrations of tricyclic
antidepressants and antipsychotics, or increased bleeding secondary to increased
warfarin levels) could develop. Not all SSRIs are equal in their potential for
dangerous interactions. Fluoxetine, paroxetine, and fluvoxamine are more likely
to inhibit hepatic enzymes; fluoxetine’s inhibition of CYP2C9 and CYP2D6,
paroxetine’s inhibition of CYP2D6, and fluvoxamine’s inhibition of CYP1A2,
CYP2C9, CYP2C19, and CYP3A4 are of particular concern. Additionally, these
three SSRIs exhibit nonlinear dose-concentration kinetics and small changes in
http://www.genemedrx.com
dose may result in greater than expected enzyme inhibition and serum
concentrations of substrates. These SSRIs should be used with caution when
combined with other medication. 87
Among SSRIs, citalopram and escitalopram have the least potential to affect
serum levels of other medicines through enzymatic inhibition and should be
selected preferentially in patients taking multiple medicines (however,
citalopram can markedly increase clozapine levels through a mechanism that has
not yet been elucidated). 88 , 89 Sertraline also generally causes less enzymatic
inhibition than fluoxetine, paroxetine, and fluvoxamine. Other non-SSRI
antidepressants that also should be favorably considered in the setting of
medication combinations are venlafaxine and mirtazapine, both of which have a
very low risk of medication interactions. However, although citalopram,
venlafaxine, and mirtazapine are not likely to clinically affect the activity of
hepatic enzymes, they themselves are substrates of these enzymes and their
plasma concentrations can increase if used in combination with other enzyme-
inhibiting SSRIs, thereby increasing the chances of unexpected or unwanted
serotonergic effects.
Other antidepressants can also inhibit cytochrome P-450 enzymes. Duloxetine
and bupropion can both moderately inhibit CYP2D6. Nefazodone is a potent
CYP3A4 inhibitor and this can affect the metabolism of many common
substrates such as macrolide antibiotics, statins, calcium channel blockers, and
many HIV protease inhibitors, as well as many antipsychotics including
ziprasidone (see subsequent text).87 , 90
The concomitant use of MAOIs and serotonergic antidepressants is
contraindicated because of the potential to cause serotonin syndrome. A washout
period of 2 weeks (5 weeks after discontinuation of fluoxetine) should be
allowed before starting an MAOI. Two weeks should be allowed before
switching from MAOIs to other antidepressants. 91 SSRIs also should not be
used with linezolid, an antibiotic used for the treatment of infections caused by
gram-positive bacteria, because of this drug’s weak MAOI properties. 92
Antipsychotics
Although newer antipsychotics do have weak cytochrome enzyme-inhibiting
activity (and first- generation antipsychotics, such as phenothiazines, are
stronger enzyme inhibitors), they are themselves substrates of P-450 enzymes
and as such can be affected by enzyme-inducing and enzyme-inhibiting agents.
As noted earlier, certain SSRIs, as well as other medicines (such as valproate
and the frequently used antibiotic ciprofloxacin), can inhibit the metabolism of
many old and new antipsychotics, thereby increasing their plasma
concentrations. Specifically, clozapine and olanzapine are substrates for
CYP1A2; haloperidol, risperidone, clozapine, and olanzapine are substrates for
CYP2D6; and haloperidol, clozapine, risperidone, quetiapine, and ziprasidone
are substrates for CYP3A4.90 When metabolism of these antipsychotics is
inhibited, there is a higher potential for side effects such as EPS or cardiac
toxicity.
Using two or more antipsychotics or combining antipsychotics with other
medicines that prolong the QT interval could be problematic and would require
close monitoring. The addition of ziprasidone, which some studies find to have a
higher propensity to cause QT prolongation, to other QT-prolonging drugs such
as pentamidine, or class Ia (e.g., procainamide, quinidine) or class III (e.g.,
amiodarone) antiarrhythmics, should be avoided.24
Clozapine should not be combined with other medicines, such as
carbamazepine, which can cause leukopenia. The combination of clozapine and
benzodiazepines may rarely cause fatal respiratory suppression and therefore
should generally be used cautiously. 93
Clozapine and olanzapine are metabolized by CYP1A2, and cigarette smoking
can decrease their levels through induction of this isoenzyme. Consequently, a
newly admitted inpatient who is restricted from smoking may experience an
increased plasma clozapine concentration and therefore should be monitored for
increased risk of adverse effects.90 Enzyme induction by cigarette smoke is
primarily a function of polycyclic aromatic hydrocarbons found in tobacco
smoke rather than of nicotine—the use of nicotine replacement therapy would
not therefore cause similar induction. 94 Although paroxetine and fluoxetine can
increase clozapine levels through enzyme inhibition, the use of fluvoxamine is of
particular concern. Fluvoxamine can increase clozapine concentrations 5- to 10-
fold through CYP1A2 inhibition87 , 90 and this combination should usually be
avoided or used very cautiously. Interestingly, however, the addition of
fluvoxamine has been used as a strategy to boost low clozapine levels and
possibly minimize adverse effects of the metabolite norclozapine, including
weight gain. 95
Mood Stabilizers
Carbamazepine is an inducer of many hepatic enzymes (CYP1A2, CYP2C9,
CYP2C19, CYP3A4) and as such can lower the concentration of other medicines
including many tricyclic antidepressants, antipsychotics, benzodiazepines, and
other mood stabilizers, including lamotrigine, as well as nonpsychotropic
medications such as warfarin.90 In the manic patient who requires rapid
behavioral control, and who may be receiving carbamazepine in addition to an
antipsychotic and/or a benzodiazepine, the clinician should be aware that these
adjunctive or other medicines may not be providing full clinical effect because
of decreased plasma levels. This effect seriously limits the utility of
carbamazepine in these situations. (In this regard the clinician should also be
aware that in addition to carbamazepine, the antiepileptic drugs phenobarbital,
phenytoin, and primidone also have similarly strong enzyme-inducing
properties.) 96
Along with carbamazepine, oxcarbazepine, high-dose topiramate, 97 and
possibly lamotrigine may also stimulate the metabolism of oral contraceptives,
and if used would require patients to undertake additional precautions to avoid
pregnancy and/or a change to a stronger contraceptive dose. 98 In women relying
on oral contraceptives, alternative treatments should be considered. Valproate
and gabapentin are less likely to affect oral contraceptive levels.96
Valproate can inhibit the glucuronidation of lamotrigine, and this combination
requires very slow titration of lamotrigine to decrease the risk of dangerous
rash.96 , 99 Sertraline, possibly also through inhibition of glucuronidation, may
also significantly increase lamotrigine levels. 100 Valproate can also increase the
plasma levels of substrates of CYP2C9 and CYP2C19 such as phenobarbital,
phenytoin, many tricyclic antidepressants, and warfarin. Valproate is also highly
protein bound and competition in protein binding with warfarin can cause a
significant increase in the free fraction of warfarin and the prothrombin time.27 ,
101
Lithium and gabapentin are renally excreted and are not likely to interact with
other mood stabilizers. 102 Lithium levels, however, can increase with
concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), thiazide
diuretics, angiotensin-converting enzyme (ACE) inhibitors, metronidazole, and
tetracyclines. 103
SPEED OF RESPONSE
In the acute inpatient setting, speed of pharmacotherapy response is critical.
Unfortunately, there has been little study focused on speed as the primary
outcome measure. Clinicians have been forced to rely on their clinical
experience or that of trusted colleagues and form their own opinion. The present
authors will survey the applicable or possibly applicable literature on strategies
for maximizing speed of response to treatment of schizophrenia, mania, and
depression.
Antipsychotics in Schizophrenia and Schizoaffective Disorder
Osser and Sigadel in 20013 published a comprehensive review of antipsychotic
response speed in schizophrenia. This review concluded that risperidone may
work faster than other antipsychotics, and that olanzapine worked fastest when
started at relatively higher doses (e.g.,15 mg daily) compared with lower doses
(e.g., 5 or 10 mg daily). Risperidone was the only second-generation
antipsychotic that appeared to work faster than the control first-generation
antipsychotic. However, that difference was not statistically significant, and it
was of questionable clinical significance because the data on which it was based
were not primary outcome data in the studies from which it was derived.
Notably, quetiapine and ziprasidone numerically trailed the control first-
generation antipsychotic in the first week or two of treatment. However, the
authors of these studies did not note this in their discussions, although the
implications for antipsychotic therapy in the acute inpatient setting might be
important. This could be because the studies were not designed to focus on the
outcome at 1 or 2 weeks.
Recent studies have suggested that rapid, as opposed to conventional, dosing
of quetiapine speeds response in acute schizophrenia during the first week of
treatment. 104 The starting dose of rapid treatment was 200 mg on the first day,
followed by 400 mg on the second day, 600 mg on the third day, and 800 mg on
day 4. However, the conventional dosing was to begin with 50 mg on day 1, 100
mg on day 2, 200 on day 3, 300 on day 4, and 400 mg on day 5. This is slower
than most clinicians would go, but the side effects of dizziness, restlessness, and
excess sedation on the faster titration were significant.
The possibility of early onset of therapeutic response to risperidone versus
conventional antipsychotics was confirmed in a more recent review. 105 In this
post hoc analysis of four studies involving 757 patients, a significantly greater
proportion of patients at weeks 1 or 2 achieved a 20% reduction in Positive and
Negative Syndrome Scale (PANSS) total scores with risperidone, compared with
perphenazine (mean dose 28 mg daily) or haloperidol 10 to 20 mg daily. This
may be clinically important because a meta-analysis has shown that failure to
achieve a 25% reduction of symptoms on an antipsychotic in the first 2 weeks
predicts poor outcome at 4 weeks (positive predictive value of 63%). 106
The large National Institute of Mental Health (NIMH)-sponsored CATIE
study could have been an opportunity to collect prospective data on early
response, but the investigators did not design the study to shed light on this. The
first evaluation point was 1 month after starting randomized antipsychotic
therapy.
The short-term comparative effectiveness of antipsychotics was tested in
another recent randomized trial that was not supported by pharmaceutical
companies. 107 Three hundred and twenty seven acute schizophrenia and
schizoaffective patients who were newly admitted to a public sector hospital
were randomized in a 3-week open-label study to haloperidol (mean maximum
dose 16 mg), aripiprazole (22 mg), olanzapine (19 mg), quetiapine (650 mg),
risperidone (5.2 mg), or ziprasidone (150 mg). Effectiveness was defined,
controversially, as whether the patient was well enough for discharge. By this
criterion, haloperidol (89%), olanzapine (92%), and risperidone (88%) were
significantly more effective than aripiprazole (64%), quetiapine (63%), and
ziprasidone (64%) over the 3-week period of the study
Secondary outcome measures involving various rating scales did not show
significant differences. This “pragmatic” outcome measure of dischargeability
could have been subject to a variety of biases, but the study is interesting in that
it supports the suggestion that not all antipsychotics are equal in rapidity of
response and finds olanzapine, the conventional antipsychotic, and (again)
risperidone to work faster.
When antipsychotics do work, they work fairly quickly. Leucht et al. pooled
data from seven randomized trials of one antipsychotic (amisulpride, not
available in the United States) and found that more reduction of positive and
total symptoms occurred in the first 2 weeks than in the second 2 weeks (p
<0.0001). 108 By the end of 4 weeks, 68% of the improvement that will be found
at 1 year was already achieved.
Speed of Response in Mania
Rapid response is highly desirable in the management of the acutely manic
patient, especially when there is extreme hyperactivity or serious medical illness
that may be exacerbated by the manic state. For this reason, many clinicians
combine mood stabilizers and antipsychotics early, for example, in the first week
of admission. Some evidence supports this, but the relevant studies did not
compare untreated patients assigned to either cotherapy or monotherapy. Rather,
the patients studied had already been treated with mood stabilizers and had failed
on them (or received inadequate doses) after which they had an antipsychotic or
placebo added. 109 Often, newly admitted patients will have been tried on
monotherapy with a mood stabilizer or antipsychotic in the community before
needing admission; therefore, it is certainly reasonable for them to get early
combination treatment once hospitalized.
Regarding the choice of which antipsychotic to add, typical or atypical,
naturalistic data seem to favor the atypicals at least with respect to
extrapyramidal side effects, 110 but head-to-head comparisons (e.g., olanzapine
vs. haloperidol) have found no efficacy differences in mania. 111
If monotherapy is to be initiated in a first-onset or untreated, newly admitted
patient, it is difficult to discern what choice would work most rapidly. There is
no clear evidence to favor a mood stabilizer or an antipsychotic as monotherapy.
However, oral-loaded divalproex seems to work faster than standard-titration
methods. 112 With rapid oral loading, the patient is given (in one method) 30
mg/kg/day on days 1 and 2, followed by 20 mg/kg/day on subsequent days. In a
pooled analysis of three studies involving 348 patients, this approach worked
faster than lithium (300 mg three times daily for 2 days followed by titration to
levels 0.4 to 1.5 mEq per L), and it worked equally rapidly to olanzapine 10 mg
for 2 days followed by increase to a maximum of 20 mg daily.112
All five atypical antipsychotics have been approved by the FDA for the
treatment of acute mania based on placebo-controlled studies. However, it must
be kept in mind that the ethical requirements of placebo-controlled studies
mandated that the sicker patients were not included. 113 Therefore, the
effectiveness of monotherapy with atypicals in real-world patients is unclear.
Although there have been claims that the evidence suggests some atypicals
work faster than others in mania, this seems to be an artifact of design variations
in the registration trials. 114 Risperidone and ziprasidone patients were first rated
at 1 and 2 days, aripiprazole at 4 days, and olanzapine at 7 days in these trials.
Doses used were risperidone 1 mg every 6 to 8 hours, with maximum 6 to 10 mg
daily; aripiprazole 30 mg daily (although a recent study used 15 mg and it
worked well 115 ); ziprasidone 40 mg twice daily with food, increased to 60 to 80
mg twice daily on the second day; olanzapine 15 mg daily to start and then
adjusted to 5 to 20 mg daily. As is the case in schizophrenia treatment,
quetiapine may work most rapidly in mania with an oral-loading schedule of 200
mg on day 1 with daily increases of 200 mg until 800 mg is reached by day 4,
given in two divided doses. 116
Patients who have new-onset bipolar mania who do not need urgent
behavioral control are best treated with monotherapy with lithium. Although
slower in treating the acute episode, no other treatment has performed as well in
preventing recurrences of mania and depression and in reducing risk of suicidal
behavior. 117 Observational data indicate that monotherapy with lithium, if
initiated, is more likely to be sustained as a monotherapy, compared with
anticonvulsants and antipsychotics which lead more often to polytherapy. 118
Speed of Response in Depression
There has been a long-standing interest in finding ways to increase the response
rate to antidepressants because of the clinical impression that they require many
weeks to work. However, is this impression based on fact? According to a meta-
analysis of 47 double-blind, placebo-controlled trials that evaluated the
progression of improvement weekly or biweekly, >60% of the improvement that
was going to occur on medication occurred in the first 2 weeks. 119 Also, the
biggest differences between drug and placebo were seen during this initial
period, suggesting that this initial improvement was a true antidepressant effect.
This analysis also failed to support another long-standing impression, that rapid
early response is a predictor of placebo response.
Are there any differences in the speed of response of different individual
antidepressants? In a recent meta-analysis of all antidepressant controlled trials
by the U.S. Agency for Healthcare Research and Quality, 120 one antidepressant
had sufficient evidence to deserve mention as possibly having a faster onset of
action. Mirtazapine, in seven studies, all sponsored by the manufacturer,
consistently had faster effect in comparison with four different SSRIs. The effect
size was moderate; the number needed to treat to yield one additional responder
after 1 to 2 weeks of treatment was 7. Also, one antidepressant seemed to work
consistently slower than at least four other antidepressants—fluoxetine. This is
presumed to be due to the long half-life of fluoxetine and its metabolite
norfluoxetine, which results in a long period (which can be months) until
development of steady-state levels when the patient is started on the lowest
effective dose of 20 mg daily. 121
Augmentation strategies to speed response have been the subject of interest
for decades. Prospects that have had periods of popularity include combining
SSRIs and tricyclic antidepressants and adding pindolol to SSRIs (which seems
to speed response in Europe but not in the United States). 122 More recently,
studies in which atypical antipsychotics are added to SSRIs have been financed
by the atypical antipsychotic drug companies. 123 This costly approach can
augment a partial response to an SSRI, but there have been no studies evaluating
whether initial cotherapy would speed response.
There is a possibility that antidepressants will be developed that have a much
more rapid onset, even within hours, based on recent studies with intravenous
infusions of the N -methyl-D-aspartate receptor agonist ketamine. 124 More
research is needed to find a way of sustaining the benefits and dealing with
toxicity, but the findings are of great interest.
Suicidal depressed patients present a particular challenge. There is an urgent
need to see rapid improvement in suicidal thinking. With effective treatment,
most patients will become less suicidal, but for a few, suicidal ideation and
activity may increase, or occur de novo , in the early weeks of treatment. This
has been observed since the beginning of the antidepressant era. It was thought
to be due to a progression of response to antidepressants. Patients might initially
show improvement in psychomotor retardation, with a lag in improvement in
mood, leading to increased risk of suicidal actions. Possibly, this might be the
mechanism with antidepressants like tricyclics with their primarily
noradrenergically mediated pharmacodynamics. Other causes of increased
suicidality have been proposed with the SSRIs and other second-generation
antidepressants, including an activation or akathisia-like effect associated with
dysphoria. All antidepressants could cause the emergence of a mixed state in a
latent bipolar patient. The FDA has recently, though controversially, determined
that the risk for antidepressant-emergent suicidality is higher in children,
adolescents, and young adults, and required package insert alerts to watch for
this adverse effect. 125 In any case, it is reasonable to monitor all patients closely
when they are started on antidepressants.
MATCHING SIDE EFFECT PROFILES TO
PRESENTING SYMPTOMS
A simple, yet common, consideration when choosing among treatment options
concerns the issue of attempting to match the immediate effects (or side effects)
of medication to patients’ presenting symptoms. For example, while waiting for
the effect of an antidepressant on the primary depressive disorder, the patient
may have prominent neurovegetative symptoms that cause much distress.
Choosing an antidepressant that could ameliorate, or at least not worsen, these
symptoms may decrease the need to use multiple drugs and increase the
likelihood of continued treatment adherence.
Sleep Changes
Sleep Changes
When choosing an antidepressant, mirtazapine or nefazodone given at bedtime
may be more helpful than other serotonergic antidepressants for a patient with
insomnia. On the other hand, patients prescribed paroxetine may subjectively
feel more tired but are just as likely to have continued insomnia. 126 Bupropion or
fluoxetine given during the day may be better suited for a depressed patient with
somnolence. Among antipsychotics, quetiapine and olanzapine would probably
help more with sleep, whereas aripiprazole or ziprasidone might be better suited
for the already somnolent or anergic psychotic patient.
Appetite Changes
If the depressed patient is cachectic, mirtazapine can increase appetite and oral
intake earlier than the time required for the antidepressant effect to occur. In
contrast, bupropion, nefazodone, or venlafaxine would be good choices for an
overweight patient. In a bipolar patient, lithium and valproate can be helpful if
weight loss is a presenting symptom. Among antipsychotics, olanzapine and
quetiapine could be chosen if weight gain would actually be desirable. However,
the risks would include increased triglycerides, hyperglycemia, and insulin
resistance. For the already overweight psychotic patient, aripiprazole or
ziprasidone may be more appropriate.
POLYPHARMACY
Polypharmacy—or more appropriately “polytherapy”—may be defined as the
concomitant use of two or more agents within the same class (e.g., two
antipsychotics). The addition of medication from other classes, possibly for
amelioration of side effects or improved control of symptoms (e.g., an
antipsychotic plus a mood stabilizer for acute mania), is not always considered
to be polytherapy. However, these combinations may still constitute “relative”
polytherapy if the use of an available alternative single agent would have worked
equally well.
Most practice guidelines and evidence-based algorithms recommend the use
of sequential trials of monotherapy for treatment of acute episodes of psychiatric
illness and may suggest polytherapy only as a last resort. There continues to be a
dearth of controlled trials studying the use of polytherapy in hospitalized
patients. Still, if one considers the use of combination psychotropics across
different classes of medication, then clearly the use of polytherapy is the norm
rather than the exception in the hospitalized patient. 127 However, the
concomitant use of multiple drugs within the same class (e.g., two or more
antipsychotics) is also highly prevalent—40% to 50% for antipsychotics in
schizophrenic and schizoaffective patients 128 , 129 —and this use has increased
over time. 130 Probable reasons for both types of increase likely include the
availability of a greater number of pharmacotherapeutic agents and the presumed
increase in safety of many of the newer available agents. Furthermore,
psychiatric units provide treatment for patients with (a) severe mental illness, (b)
histories of multiple past hospitalizations and medication trials, (c) treatment
resistance, and/or (d) dangerous behavioral problems, indicating the likelihood
of an even greater perceived need for polytherapy for symptom control. The
pressure from managed care for more rapid control of symptoms during briefer
inpatient stays has also contributed to the use of polytherapy in this population.
Understandably, in the absence of evidence, factors such as personal preference,
historical patterns of practice, and pressures from milieu and nursing staff to
treat patients more aggressively 131 have further contributed to the continued
prevalence of polytherapy in inpatient clinical practice.
Although it is frequently unclear if there is any added benefit from the use of
multiple medicines, the downsides and risks of polytherapy are clear. These
include the risks of increased (a) medication-related adverse effects, 132 (b)
dangerous drug-drug interactions, (c) medication errors, (d) mortality rates, 133
(e) medication nonadherence after discharge, and (f) cost. 134 Inpatient
polytherapy has also been associated with longer hospital stays, although this
may be because the most ill patients may be the most likely to be treated with
multiple medicines.132 It is reasonable then that generally polytherapy should be
avoided when possible. To this end the use of treatment algorithms, periodic
reviews of inpatient practice, and raising awareness regarding the risks of
polytherapy can decrease its use in the inpatient setting. 135 However, there are
certain circumstances in which, after a clear review of risks and benefits,
polytherapy may be appropriate in hospitalized patients.
Cross-Titration
Clinicians commonly use cross-titration when adding a new medicine while
discontinuing a previously ineffective one. The first agent is not discontinued
abruptly in an effort to decrease the risks of withdrawal or discontinuation-
related phenomena or worsening due to loss of an occult partial response. In the
case of antipsychotics, for example, a 3-week taper can significantly reduce
crossover exacerbations. 136 Frequently, however, as the patient improves with
the addition of the second drug, the clinician is tempted to believe that the
combination therapy (rather than the second drug alone) is responsible for this
improvement and hence both medicines are continued. However, if one assumes
that the response to the first drug was unsatisfactory despite an appropriate trial
(i.e., dosing was appropriate and duration of treatment was adequate), it is not
likely that it would have new-found effectiveness at a subsequently lower dose.
In most cases it is recommended that the cross-titration continue until a clear
switch is made to the second drug. 137 Completing the cross-titration switch need
not occur in the hospital and may continue on an outpatient basis after the patient
is well enough to be discharged. In these circumstances, clear communication
with outpatient providers is necessary to convey the inpatient team’s treatment
plan in order to decrease the chance of continued polytherapy.
The Agitated Manic and/or Psychotic Patient
In manic patients, mood stabilizers may not be immediately effective in the
treatment of mania and a 1- to 2-week time period or longer may be needed to
achieve significant therapeutic effect. Preliminary studies comparing olanzapine,
risperidone, or quetiapine in combination with lithium or valproate versus the
use of either mood stabilizer alone suggest that the combination treatments may
be more effective—although the addition of an antipsychotic increased the rate
of adverse effects. 138 – 142 It is not clear, however, whether polytherapy results in
earlier response. Also, as noted earlier, in these studies patients had a second
agent added because they were not satisfactorily responding to monotherapy; the
studies did not evaluate whether it is more desirable to commence treatment with
the two agents simultaneously.
In schizophrenic patients there can be variable response time with the use of
different antipsychotics.3 In both the agitated manic patient and the agitated
psychotic patient, there can be a real need early on for adjunctive medications
such as benzodiazepines. Clinical experience suggests that adjunctive first-
generation antipsychotics may acutely decrease the risk of harm secondary to
behavioral dyscontrol. They may also be needed for severe insomnia. The
rationale for adding typical antipsychotics should not be to hasten overall
recovery—a prospect for which there is no good evidence—but in the hope of
decreasing dangerous behavior in the short term. Clinicians should take into
account the risks of medication interactions and the increase in risk of
antipsychotic-related adverse effects and carefully balance these against the
potential benefits when considering adding neuroleptics. Once the patient’s
behavior improves and remains stable, adjunctive drugs such as benzodiazepines
and typical antipsychotics can be withdrawn. If the patient has required high
doses of these agents, it is recommended that they be tapered and not abruptly
discontinued, and again, clear communication with the outpatient psychiatrist is
essential to ensure that the taper continues following discharge.
In the nonagitated psychotic patient there is less justification for adjunctive
polytherapy. If there is no response to the first antipsychotic drug within the first
week, increasing to more optimal dosing or switching to a new antipsychotic (to
clozapine if appropriate) should be considered.3 The temptation to use
polytherapy within the first week (or to change to another antipsychotic
prematurely) occurs if there is little response in terms of targeted psychotic
symptoms. With partial response, deciding on the next step is complicated by the
possibilities that (a) the patient may respond better given enough time and that
(b) the observed improvement may be due to placebo effect or to other
therapeutic effects of hospitalization.3 The clinician should ensure that optimum
dosing is being used and despite the uncertainty the best course of action may be
to allow for gradual response. If after 2 to 3 weeks of optimal dosing—by which
time most of the improvement that one is likely to see will have occurred 143 —
there is still insufficient response, the antipsychotic agent should be changed.
(This would constitute a briefer trial and more rapid switch than recommended
by algorithms based on outpatient treatment. 144 ) Again if appropriate the change
should be to clozapine. A lengthy taper of the first agent is usually not needed
under these circumstances.
The Depressed Patient
In depressed patients, unless multiple monotherapies have failed, the use of
combination antidepressant therapy is usually not needed and a relatively rapid
taper can precede the use of a new antidepressant. The concomitant use of two
SSRIs should be avoided due to the risk of serotonergic side effects. If a
combination of antidepressants is considered, then agents with different
mechanisms of action should be used, 145 although dose increase to the optimal
or maximal dose of the first agent should be tried before adding a second
antidepressant. In addition, clinicians should not underestimate the effectiveness
of psychotherapy when combined with antidepressant therapy and its ability to
reduce the need for antidepressant polytherapy. 146 – 148
Adding an antidepressant to an acutely psychotic schizophrenic patient’s
antipsychotic regimen is generally not helpful and may cause symptom
exacerbations or drug interactions. Mood symptoms generally improve as the
patient responds to the prescribed antipsychotic. 149
In the patient with bipolar depression, lithium 150 or quetiapine 151 and possibly
lamotrigine 152 may be used as monotherapies, although there are three
unpublished negative or failed studies with lamotrigine monotherapy.103
However, if these agents cannot be used, then antidepressants may need to be
considered, despite disappointing data on the efficacy of antidepressants over the
long term. 153 In these cases, it may be prudent to treat the patient with another
mood stabilizer (and to reach therapeutic serum levels if applicable) before
carefully introducing an antidepressant, thereby reducing the risk of inducing
mania.
TREATMENT RESISTANCE
Patients who are admitted to acute psychiatric units have frequently had a
number of medication trials with unsatisfactory results, leading to their need for
admission. Therefore, treatment resistance is a typical challenge encountered in
this setting. There are also more severe levels of treatment resistance. Exhaustive
trials may have already occurred in recidivistic patients, and it will be difficult to
determine what to do next. Or the patient may have had more than one
significant trial during the present admission, without success, and the length of
stay to that point may require that the patient be transferred to a tertiary-care
facility.
Although detailed algorithms for the approach to treatment-resistant problems
would require going beyond the scope of this chapter, a list of sometimes
overlooked or avoided options that are especially worthy of consideration will be
offered. As a general principle, making one medication change at a time, and
giving it adequate time to be dosed properly, produces better and faster results
than “treatment as usual” that lacks this organized and consistent approach. 154
Schizophrenia and Schizoaffective Disorder
In the treatment of schizophrenia and schizoaffective disorder, one must first
rule out the perhaps most frequent cause of poor response—noncompliance (e.g.,
cheeking, self-induced vomiting, purging). The most evidence-supported
pharmacotherapy option after there have been a minimum of two adequate
monotherapy trials of antipsychotics is clozapine. 155 , 156 The two trials should
include one first-generation antipsychotic and either risperidone or olanzapine.
The resistance to using clozapine comes from fear of side effects and concern
about the amount of time it takes to start a reasonable trial. Also, a very common
conceptual obstacle on the part of the physician is the assumption that a
previously noncompliant patient would not be willing or able to adhere to the
monitoring regime (i.e., blood draws) that would be needed with clozapine
treatment. This concern is usually misplaced, however, given that if the patient
responds well to clozapine, outpatient compliance could be much better than
expected. The physician has to be prepared to make an appropriately positive
and convincing description of the potential benefits versus the risks of this
option during the consent process. This is the true “art” of medicine—the ability
to persuade the patient (and the managed care reviewer) to agree to an effective,
highly evidence-based, but arduous treatment course. The improvisational
throwing together of unproven combinations of multiple classes of disparate
psychotropic agents is closer to alchemy than to art. (Clozapine is also an
important option for treatment-resistant cases of bipolar disorder and BPD.)18 , 19
If clozapine cannot be used, many patients have never had an adequate trial of
a reasonably well-tolerated first-generation antipsychotic such as perphenazine,
and may benefit substantially even if the more esteemed second-generation
drugs have been ineffective. Fully a quarter of well-defined treatment-resistant
patients with schizophrenia had a substantial response (>30% improvement in
PANSS score) with perphenazine in a controlled study at a dose of
approximately 40 mg daily. 157
Surprisingly, aripiprazole at a dose of 30 mg did equally well in this trial,
although there were somewhat more dropouts due to side effects.
Finally, in thinking about treatment resistance in the pharmacotherapy of
schizophrenia, it is useful to recall the original observations of Dr. Heinz
Lehmann from the 1950s regarding the phases of response to chlorpromazine. 158
He observed three phases, as follows:
1. Medicated cooperation. The patient is no longer assaultive or
uncooperative but does not interact socially and still has persistent
delusions, hallucinations, or formal thought disorder. This phase is
usually achieved within the first week of treatment.
2. Socialization. The patient is able to interact reasonably well but still
has persistent psychotic symptoms on questioning. It may take 4 to 6
weeks to achieve this phase.
3. Elimination of thought disorder. The patient is in substantial
remission, with refinement of social and occupational capacities. It
may take several months to reach this phase, if it occurs at all.
If the patient’s improvement seems to have plateaued at level (1) or (2),
further medication trials including clozapine are indicated. One may then have
the opportunity to observe the patient progressing further on this continuum of
response.
Mania
In the treatment of mania, lithium may be the most overlooked option in the
United States currently. 159 Marketing influences may have led American
physicians to routinely overlook the significant benefits of lithium over the long
term, particularly for suicidal patients and others with resistant depression, and
underestimate the risks of alternative agents (e.g., the greater weight gain and
teratogenicity associated with valproate).
Depression
Inpatients with psychotic depression are often not given the most evidence-
supported pharmacotherapy, 160 which is to use full doses of antipsychotics and
antidepressants in combination.
In the approach to pharmacotherapy-resistant nonpsychotic depression, it is
important to delineate and intervene to ameliorate stress-related and personality
style-mediated contributions to the depressed state. 161 Beyond that, Sequenced
Treatment Alternatives to Relieve Depression (STAR*D) has suggested that
thyroid hormone augmentation of an SSRI, and the quadruple-action
combination of venlafaxine and mirtazapine may deserve more consideration
than previously thought. 162 , 163 ECT, with its high remission rates, 164 deserves
consideration as an alternative to either of these options. 165 Unfortunately, the
likelihood of use of ECT is strongly dependent on its availability in the hospital
to which the patient is admitted.
PHARMACOGENETICS
Pharmacogenetics, the study of genetically determined drug response, can guide
treatment selection by helping to predict how an individual patient would
respond to specific agents. A brief discussion of promising developments can
shed light on the ways in which better understanding of genetically determined
factors can affect clinical treatment. Pharmacogenetic understanding holds
significant potential to decrease morbidity by decreasing the risk of adverse drug
effects and decreasing overall treatment time—time that would otherwise be
spent trying ineffective treatments. At a minimum, it is important to obtain the
family history of drug response in patients admitted to the psychiatric unit. It
may also be of value to think about how psychopharmacologic choices may be
influenced by ethnic and population-based considerations. 166
A primary area has been the improved understanding of genetic
polymorphisms in CYP450 enzymes, especially the CYP2D6 and CYP2C19
variants, and their impact on the pharmacokinetics of drug response and
tolerance. 167 Laboratory testing for 19 genes is now available 168 but not yet part
of mainstream clinical practice, in part because it is not covered by any
insurance programs. Individual genotypes can be identified based on the
function of the enzymatic phenotype (e.g., poor, intermediate, extensive, or
ultrarapid metabolizers). For example, “ultrarapid” metabolizers may carry three
or more active CYP2D6 alleles, whereas “poor metabolizers” may lack
enzymatic activity. Poor metabolizers may therefore be at higher risk of adverse
effects if treated with medicines that are substrates of this isoenzyme, whereas
ultrarapid metabolizers may not show clinical response. Ultrarapid metabolism,
for example, may be one reason for treatment refractoriness to antipsychotics,
many of which are metabolized by CYP2D6. What is additionally important is
that relevant genotypes are represented differently in different populations. For
example, approximately 30% of patients from North Africa and the Middle East
may be ultrarapid metabolizers of CYP2D6 substrates;167 up to 50% of Asians
may have a partially deficient form of the CYP2D6 allele. 169
Pharmacodynamic implications of genetically determined response could also
have direct influence on choice of treatment. A major area of study is that of the
genetic variants of the serotonin transporter gene (SLC6A4 ). The “short” form
of the serotonin transporter gene promoter has a polymorphism that has been
associated with decreased response to SSRIs, whereas the presence of the long
allele is associated with positive drug response. 170 Also interestingly the short
allele variant may be associated with increased risk of antidepressant-induced
mania. 171 This correlation of long versus short forms of the alleles with
treatment response, however, may apply only to SSRIs and not to
antidepressants with other mechanisms of action (e.g., mirtazapine). 172
For antipsychotics, polymorphisms in receptor genes have been associated
with both effectiveness and with the risk of adverse effects. Examples
particularly relevant to inpatient psychiatry are studies showing the possibility of
an association between variations in D2-receptor genes and the speed of
response to antipsychotics 173 and effects of variations in D3-receptor genes on
the development of TD.170 There also could be important economic ramifications
—the potential to predict those who can benefit from more affordable first-
generation antipsychotics without being genetically predisposed to TD would
significantly influence treatment decisions. 174
In regard to mood stabilizers, the study of lithium responders and genetic
inheritance of bipolar disorder may eventually guide treatment. Positive response
to lithium may be associated with bipolar disorder that is more genetically based.
175 A known clear family history of bipolar disorder therefore may argue for the
selection of lithium for these patients.
MANAGED CARE AND FINANCIAL
CONSIDERATIONS
Although physicians would like to feel that they have the autonomy, right, and
responsibility to prescribe whatever they think is best, the reality is that health
care resources are limited and it is impossible to avoid oversight by managed
care. Questions will be raised about the high costs of certain medicines. At the
same time, the primary interest of managed care review teams is to keep the
length of stay as short as possible and their criteria mainly focus on safety issues
and ensuring that “active treatment” is occurring. Often this means to them that
there have to be frequent medication changes. They see this as concrete evidence
of active interventions, whereas the other no less important and effective
inpatient interventions such as intensive individual or group psychotherapy are
less appreciated in justifying ongoing inpatient stay. There is often scant
acknowledgment that most psychotropic medicines have latency periods before
their onset of action and often it is the therapeutic milieu that is responsible for
the rapid initial improvement in the patient’s distress.
Nevertheless, difficult as it is, psychiatrists should avoid the temptation,
fanned by the impatience of managed care reviewers, to increase doses too
rapidly or to add additional medicines before current ones have had a reasonable
chance to take effect. Evidence-supported approaches should influence treatment
decisions and not the usually unseen managed care criteria for allowing
additional days of inpatient care that usually have little scientific basis.
Drug formularies inform physicians of the availability of more economical
choices when selecting medication. The hope and expectation is that these lists
are guided not only by economic concerns but also by the realities of clinical
practice. Requests by physicians for exceptions based on these realities should
follow from thoughtful, cost-effective, stepwise sequences of choices that can be
justified to the cost managers in terms that they will understand.
With a significant proportion of the population in the United States lacking
health benefits, the psychiatrist may have to opt for alternative medication to
accommodate a patient’s ability to pay for it.
Sometimes, this may expose the patient to the risk of more side effects
compared with a newer drug. For example, the atypical antipsychotics have
fewer motor side effects but they are not currently available in a generic
formulation and therefore none may be affordable without health benefits. Even
if the health plan allows the use of newer medicines, they may still be
unaffordable because of the high copayments or limited allowable yearly
coverage. Psychiatrists in many parts of the world confront this problem
routinely. As the costs of health care continue to escalate and fewer financial
resources are available for patient care, physicians can expect to be required to
factor economics more and more into their clinical decisions.
IMPROVING OUTCOME AFTER DISCHARGE
Up to 50% of discharged psychiatric inpatients may be readmitted within 1 year
of discharge. 176 Many factors can help prevent readmission but the two most
important ones are compliance with treatment appointments and medication.
Studies have shown that up to half of discharged patients with schizophrenia or
related disorders miss their first follow-up appointment after their hospital
release. 177 Boyer et al. 178 reported that aftercare appointment compliance can be
enhanced by three clinical “bridging strategies.” These are (a) communication
between inpatient and outpatient providers about discharge plans, (b) starting
outpatient programs before discharge, and (c) family involvement during the
hospitalization.
Disease-management programs promoted by managed care companies for
medical diagnoses are beginning to be developed for psychiatric illnesses.
Kopelowicz et al. 179 demonstrated that patients and their families who received
skills training had better outcomes in the first 9 months in regard to relapse,
functioning, and rehospitalization. Psychoeducation of patients, especially when
their families are involved, has produced reduction of relapse and readmission
rates of up to 50%. Inpatient teams should therefore take advantage of the ability
to involve family members in meetings during the hospital stay.
Finally, compliance is negatively associated with the complexity of a
medication regimen. The inpatient psychiatrist has the opportunity to examine
closely whether polytherapy regimens that require multiple daily doses of
various therapeutic agents are really necessary. Simplification of a patient’s
pharmacotherapeutic regimen can significantly contribute to continued
improvement and stability after discharge from the inpatient setting.
SUMMARY
The pharmacologic approach to the psychiatric inpatient is influenced by
multiple considerations. Treatment needs to be provided for the most severely
psychiatrically ill patients within a short period of time and it needs to be safe
and effective and also to increase the likelihood that patients remain well after
discharge.
1. The provision of safe treatment means that any dangerous or assaultive
behavior has to be treated urgently, often before a definitive diagnosis
is reached. Typical antipsychotics and benzodiazepines remain the
mainstay for rapid parenteral treatment.
2. In decreasing patient distress, p.r.n. medication does play a role in
decreasing patient distress, although the request for such medication
by patients and staff may suggest a need to consider psychological
methods of managing this distress.
3. Efforts should be made to clarify patients’ past pharmacotherapeutic
treatments. Collateral information is often necessary. Data regarding
past medication trials, both successful and otherwise, as well as
information regarding reasons for past medication nonadherence, can
be invaluable.
4. In all patients, but particularly in those with concomitant medical
illness, the choice of agent should be guided by an effort to decrease
overall medical risk and to avoid worsening the patient’s medical
comorbidities. The effect of psychiatric medication on all major
systems, including cardiovascular, neurologic, hematologic, hepatic,
renal, metabolic, and reproductive should be considered, and adequate
steps should be taken to identify high-risk patients and monitor them
when appropriate.
5. Antipsychotics, antidepressants, and mood stabilizers carry the risk of
dangerous medication interactions. In the patient being treated with
multiple medicines, psychiatric or otherwise, an effort should be made
to decrease the risk of these interactions.
6. Although some agents may bring about response quicker than others
(e.g., risperidone for psychosis, mirtazapine for depression), dose and
speed of titration also likely affect speed of response for antipsychotics
(e.g., olanzapine and quetiapine) and for mood stabilizers (e.g.,
valproate).
7. Psychiatric medicines should be used that would preferentially
improve, rather than worsen, patients’ associated neurovegetative
symptoms, such as sleep and appetite changes, by matching side effect
profiles to these symptoms .
8. Polytherapy should be minimized when there is a lack of evidence for
its effectiveness and risk of increased overall side effects. However, in
certain contexts (e.g., during cross titrations, or while treating agitated
manic or psychotic patients) polytherapy may be temporarily
necessary.
9. Treatment resistance constitutes a significant problem in the inpatient
population. Clozapine use should not be avoided when there is clear
treatment resistance to multiple other antipsychotics. In patients with
bipolar disorder, lithium should not be overlooked. In refractory
depressed patients, ECT and evidence-supported antidepressant
combinations (e.g., venlafaxine and mirtazapine) should be
considered.
10. Pharmacogenetic factors may explain lack of response to, or lack of
tolerability of, certain medications in specific patients. Laboratory
testing for genetic polymorphisms will increasingly aid in the
identification of patients who would be likely to respond to certain
therapies earlier during inpatient treatment.
11. Efforts should be made to resist managed care reviewers who push for
aggressive psychopharmacologic interventions when psychotherapy is
more appropriately indicated. On the other hand, outpatient insurance
formularies, and patients’ lack of ability to afford expensive prescribed
medications after discharge cannot be ignored when deciding the
inpatient choice of treatment.
12. The inpatient psychiatrist should keep in mind that for any
pharmacotherapeutic regimen to be successful it should be tied to
psychosocial interventions. Individual and group psychotherapy,
family involvement in patient treatment, communication with
outpatient systems of care, and strategies to increase likelihood of
treatment adherence are all critical for a successful outcome.
Comprehensive treatment of the whole patient is necessary for the
ongoing provision of safe and effective treatment.
REFERENCES
1. Agency for Health Care Research and Quality. Care of adults with mental health and substance abuse
disorder in U.S. community hospitals: Health and Human Services Agency for Health Care Research
and Quality , 2004.
2. Woodward SA, Zeiss RA, Wheeler R, et al. Smoking Cessation and Decreased Behavioral Restraints in
Inpatient Psychiatry. American Psychiatric Association Annual Meeting , New Research Poster NR
579. San Diego, 2007.
3. Osser DN, Sigadel R. Short-term inpatient pharmacotherapy of schizophrenia. Harv Rev Psychiatry .
2001;9(3):89-104.
4. Brook S, Walden J, Benattia I, et al. Ziprasidone and haloperidol in the treatment of acute exacerbation
of schizophrenia and schizoaffective disorder: Comparison of intramuscular and oral formulations in a
6-week, randomized, blinded- assessment study. Psychopharmacology (Berl) . 2005;178(4):514-523.
5. Breier A, Meehan K, Birkett M, et al. A double-blind, placebo-controlled dose-response comparison of
intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen
Psychiatry . 2002;59(5):441-448.
6. Tran-Johnson TK, Sack DA, Marcus RN, et al. Efficacy and safety of intramuscular aripiprazole in
patients with acute agitation: A randomized, double-blind, placebo-controlled trial. J Clin Psychiatry .
2007;68(1):111-119.
8. Villeneuve E, Lemelin S. Open-label study of atypical neuroleptic quetiapine for treatment of
borderline personality disorder: Impulsivity as main target. J Clin Psychiatry . 2005;66(10):1298-1303.
9. Taylor FB, Lowe K, Thompson C, et al. Daytime prazosin reduces psychological distress to trauma
specific cues in civilian trauma posttraumatic stress disorder. Biol Psychiatry . 2006;59(7):577-581.
10. Raskind MA, Peskind ER, Hoff DJ, et al. A parallel group placebo controlled study of prazosin for
trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol
Psychiatry . 2007;61(8):928-934.
11. Binks CA, Fenton M, McCarthy L, Lee T, et al. Pharmacological interventions for people with
borderline personality disorder. Cochrane Database Syst Rev . 2006(1):CD005653.
12. Cowdry RW, Gardner DL. Pharmacotherapy of borderline personality disorder. Alprazolam,
carbamazepine, trifluoperazine, and tranylcypromine. Arch Gen Psychiatry . 1988;45(2):111-119.
13. Nose M, Cipriani A, Biancosino B, et al. Efficacy of pharmacotherapy against core traits of
borderline personality disorder: Meta-analysis of randomized controlled trials. Int Clin
Psychopharmacol. 2006;21(6):345-353.
14. Bellino S, Paradiso E, Bogetto F. Efficacy and tolerability of quetiapine in the treatment of borderline
personality disorder: A pilot study. J Clin Psychiatry. 2006;67(7):1042-1046.
15. Soler J, Pascual JC, Campins J, et al. Double-blind, placebo-controlled study of dialectical behavior
therapy plus olanzapine for borderline personality disorder. Am J Psychiatry. 2005 ; 162(6):1221-
1224.
16. Nickel MK, Loew TH, Gil FP. Aripiprazole in treatment of borderline patients, part II: An 18-month
follow-up. Psychopharmacology (Berl). 2007;191(4):1023-1026.
17. Zanarini MC, Frankenburg FR. Omega-3 fatty acid treatment of women with borderline personality
disorder: A double-blind, placebo-controlled pilot study. Am J Psychiatry . 2003;160(1):167-169.
18. Chengappa KN, Ebeling T, Kang JS, et al. Clozapine reduces severe self-mutilation and aggression
in psychotic patients with borderline personality disorder. J Clin Psychiatry. 1999;60(7):477-484.
19. Benedetti F, Sforzini L, Colombo C, et al. Low- dose clozapine in acute and continuation treatment
of severe borderline personality disorder. J Clin Psychiatry. 1998;59(3):103-107.
20. Straus SM, Bleumink GS, Dieleman JP, et al. Antipsychotics and the risk of sudden cardiac death.
Arch Intern Med . 2004;164(12): 1293-1297.
21. Ray WA, Meredith S, Thapa PB, et al. Cyclic antidepressants and the risk of sudden cardiac death.
Clin Pharmacol Ther . 2004;75(3): 234-241.
22. Glassman AH, Bigger JT Jr. Antipsychotic drugs: Prolonged QTc interval, torsade de pointes, and
sudden death. Am J Psychiatry . 2001;158(11): 1774-1782.
23. Shah RR. Drug-induced QT dispersion: Does it predict the risk of torsade de pointes? J
Electrocardiol . 2005;38(1):10-18.
24. Fayek M, Kingsbury SJ, Zada J, et al. Cardiac effects of antipsychotic medications. Psychiatr Serv .
2001;52(5):607-609.
25. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with
chronic schizophrenia. N Engl J Med . 2005; 353(12):1209-1223.
26. Breier A, Berg PH, Thakore JH, et al. Olanzapine versus ziprasidone: Results of a 28-week double-
blind study in patients with schizophrenia. Am J Psychiatry . 2005;162(10):1879-1887.
28. Merrill DB, Dec GW, Goff DC. Adverse cardiac effects associated with clozapine. J Clin
Psychopharmacol . 2005;25(1):32-41.
29. Mamiya K, Sadanaga T, Sekita A, et al. Lithium concentration correlates with QTc in patients with
psychosis. J Electrocardiol . 2005;38(2): 148-151.
30. Brucculeri M, Kaplan J, Lande L. Reversal of citalopram-induced junctional bradycardia with
intravenous sodium bicarbonate. Pharmacotherapy . 2005;25(1):119-122.
31. Isbister GK, Prior FH, Foy A. Citalopram- induced bradycardia and presyncope. Ann Pharmacother .
2001;35(12):1552-1555.
32. Pae CU, Kim JJ, Lee CU, et al. Provoked bradycardia after paroxetine administration. Gen Hosp
Psychiatry . 2003;25(2):142-144 .
33. Mbaya P, Alam F, Ashim S, et al. Cardiovascular effects of high dose venlafaxine XL in patients
with major depressive disorder. Hum Psychopharmacol . 2007;22(3):129-133.
34. Johnson EM, Whyte E, Mulsant BH, et al. Cardiovascular changes associated with venlafaxine in the
treatment of late-life depression. Am J Geriatr Psychiatry . 2006;14(9):796-802.
35. Raskin J, Goldstein DJ, Mallinckrodt CH, et al. Duloxetine in the long-term treatment of major
depressive disorder. J Clin Psychiatry . 2003;64(10):1237-1244.
36. Wohlreich MM, Mallinckrodt CH, Prakash A, et al. Duloxetine for the treatment of major depressive
disorder: Safety and tolerability associated with dose escalation. Depress Anxiety . 2007;24(1):41-52.
37. Feighner JP. Cardiovascular safety in depressed patients: Focus on venlafaxine. J Clin Psychiatry .
1995;56(12):574-579.
38. Felker BL, Sloan KL, Dominitz JA, et al. The safety of valproic acid use for patients with hepatitis C
infection. Am J Psychiatry . 2003;160(1): 174-178.
39. Lott RS, Helmboldt KM, Madaras-Kelly KJ. Retrospective evaluation of the effect of valproate
therapy on transaminase elevations in patients with hepatitis C. Pharmacotherapy . 2001;
21(11):1345-1351.
40. Mallet L, Babin S, Morais JA. Valproic acid- induced hyperammonemia and thrombocytopenia in an
elderly woman. Ann Pharmacother . 2004;38(10):1643-1647.
41. Carr RB, Shrewsbury K. Hyperammonemia due to valproic acid in the psychiatric setting. Am J
Psychiatry. 2007;164(7):1020-1027.
42. Lepkifker E, Sverdlik A, Iancu I, et al. Renal insufficiency in long-term lithium treatment. J Clin
Psychiatry. 2004;65(6):850-856.
43. Gitlin M. Lithium and the kidney: An updated review. Drug Saf. 1999;20(3):231-243.
44. Dixon L, Weiden P, Delahanty J, et al. Prevalence and correlates of diabetes in national
schizophrenia samples. Schizophr Bull . 2000;26(4): 903-912.
45. Shirzadi AA, Ghaemi SN. Side effects of atypical antipsychotics: Extrapyramidal symptoms and the
metabolic syndrome. Harv Rev Psychiatry . 2006;14(3):152-164.
46. Clark NG. Consensus development conference on antipsychotic drugs and obesity and diabetes.
Diabetes Care . 2004;27(2):596-601.
47. van Winkel R, De Hert M, Van Eyck D, et al. Screening for diabetes and other metabolic
abnormalities in patients with schizophrenia and schizoaffective disorder: Evaluation of incidence
and screening methods. J Clin Psychiatry . 2006;67(10):1493-1500.
48. Lipkovich I, Citrome L, Perlis R, et al. Early predictors of substantial weight gain in bipolar patients
treated with olanzapine. J Clin Psychopharmacol . 2006;26(3):316-320.
49. Gentile S. Long-term treatment with atypical antipsychotics and the risk of weight gain: A literature
analysis. Drug Saf . 2006;29(4): 303-319.
51. Piette JD, Heisler M, Ganoczy D, et al. Differential medication adherence among patients with
schizophrenia and comorbid diabetes and hypertension. Psychiatr Serv . 2007;58(2): 207-212.
52. Anghelescu I, Klawe C, Dahmen N. Venlafaxine in a patient with idiopathic leukopenia and
mirtazapine-induced severe neutropenia. J Clin Psychiatry . 2002;63(9):838.
53. Sedky K, Lippmann S. Psychotropic medications and leukopenia. Curr Drug Targets .
2006;7(9):1191-1194.
54. Hager ED, Dziambor H, Hohmann D, et al. Effects of lithium on thrombopoiesis in patients with low
platelet cell counts following chemotherapy or radiotherapy. Biol Trace Elem Res . 2001;83(2):139-
148.
55. Hager ED, Dziambor H, Winkler P, et al. Effects of lithium carbonate on hematopoietic cells in
patients with persistent neutropenia following chemotherapy or radiotherapy. J Trace Elem Med Biol
. 2002;16(2):91-97.
56. Gallicchio VS, Messino MJ, Hulette BC, et al. Lithium and hematopoiesis: Effective experimental
use of lithium as an agent to improve bone marrow transplantation. J Med . 1992;23(3-4):195-216.
57. Mahmud J, Mathews M, Verma S, et al. Oxcarbazepine-induced thrombocytopenia. Psychosomatics .
2006;47(1):73-74 .
58. Conley EL, Coley KC, Pollock BG, et al. Prevalence and risk of thrombocytopenia with valproic
acid: Experience at a psychiatric teaching hospital. Pharmacotherapy . 2001;21(11):1325-1330.
59. Trannel TJ, Ahmed I, Goebert D. Occurrence of thrombocytopenia in psychiatric patients taking
valproate. Am J Psychiatry . 2001;158(1):128-130.
60. Gerstner T, Teich M, Bell N, et al. Valproate-associated coagulopathies are frequent and variable in
children. Epilepsia . 2006;47(7):1136-1143.
61. De Berardis D, Campanella D, Matera V, et al. Thrombocytopenia during valproic acid treatment in
young patients with new-onset bipolar disorder. J Clin Psychopharmacol . 2003;23(5):451-458.
62. Kruger S, Lindstaedt M. Duloxetine and hyponatremia: A report of 5 cases. J Clin Psychopharmacol
. 2007;27(1):101-104.
63. Ladino M, Guardiola VD, Paniagua M. Mirtazapine-induced hyponatremia in an elderly hospice
patient. J Palliat Med . 2006;9(2):258-260.
64. Bagley SC, Yaeger D. Hyponatremia associated with bupropion, a case verified by rechallenge. J
Clin Psychopharmacol . 2005;25(1):98-99.
65. Dong X, Leppik IE, White J, et al. Hyponatremia from oxcarbazepine and carbamazepine. Neurology
. 2005;65(12):1976-1978.
66. Sachdeo RC, Wasserstein A, Mesenbrink PJ, et al. Effects of oxcarbazepine on sodium concentration
and water handling. Ann Neurol . 2002;51(5):613-620.
67. Alldredge BK. Seizure risk associated with psychotropic drugs: Clinical and pharmacokinetic
considerations. Neurology . 1999;53(5 Suppl 2):S68-S75.
68. Montgomery SA. Antidepressants and seizures: Emphasis on newer agents and clinical implications.
Int J Clin Pract . 2005;59(12):1435-1440.
69. Alper K, Schwartz KA, Kolts RL, et al. Seizure incidence in psychopharmacological clinical trials:
An analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol
Psychiatry . 2007;62(4):345-354.
70. Pisani F, Oteri G, Costa C, et al. Effects of psychotropic drugs on seizure threshold. Drug Saf .
2002;25(2):91-110.
71. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for
dementia: Meta-analysis of randomized placebo-controlled trials. JAMA . 2005;294(15):1934-1943.
72. Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for
dementia: Meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry .
2006;14(3):191-210.
73. Herrmann N, Lanctot KL. Do atypical antipsychotics cause stroke? CNS drugs . 2005;19(2): 91-103.
74. Gill SS, Rochon PA, Herrmann N, et al. Atypical antipsychotic drugs and risk of ischaemic stroke:
Population based retrospective cohort study. Br Med J . 2005;330(7489):445.
75. Pollock BG, Mulsant BH, Rosen J, et al. Comparison of citalopram, perphenazine, and placebo for
the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. Am J
Psychiatry . 2002;159(3):460-465.
76. Salzman C. Treatment of the agitation of late-life psychosis and Alzheimer’s disease. Eur Psychiatry
. 2001;16(Suppl 1):25s-28s.
77. Yang C, White DP, Winkelman JW. Antidepressants and periodic leg movements of sleep. Biol
Psychiatry . 2005;58(6):510-514.
78. Salin-Pascual RJ, Galicia-Polo L, Drucker-Colin R. Sleep changes after 4 consecutive days of
venlafaxine administration in normal volunteers. J Clin Psychiatry . 1997;58(8):348-350.
79. Agargun MY, Kara H, Ozbek H, et al. Restless legs syndrome induced by mirtazapine. J Clin
Psychiatry . 2002;63(12):1179.
80. Kim SW, Shin IS, Kim JM, et al. Bupropion may improve restless legs syndrome: A report of three
cases. Clin Neuropharmacol . 2005;28(6): 298-301.
81. Bilo L, Meo R. Epilepsy and polycystic ovary syndrome: Where is the link? Neurol Sci . 2006;
27(4):221-230.
82. Klipstein KG, Goldberg JF. Screening for bipolar disorder in women with polycystic ovary
syndrome: A pilot study. J Affect Disord . 2006;91(2-3):205-209 .
83. Wilson DR. High dose olanzapine and prolactin levels. Presented at the 51st American Psychiatric
Association Institute on Psychiatric Services . New Orleans, 1999. www.genemedrx.com .
84. Ciraulo DA, ed. Drug interactions in psychiatry , 3rd ed. Philadelphia: Lippincott Williams &
Wilkins; 2006.
85. Sayal KS, Duncan-McConnell DA, McConnell HW, et al. Psychotropic interactions with warfarin.
Acta Psychiatr Scand . 2000;102(4): 250-255.
86. Ereshefsky L, Jhee S, Grothe D. Antidepressant drug-drug interaction profile update. Drugs R D .
2005;6(6):323-336.
87. Borba CP, Henderson DC. Citalopram and clozapine: Potential drug interaction. J Clin Psychiatry .
2000;61(4):301-302.
88. Novartis. Product Information: Drug Warning and New Information, Clozaril(R), clozapine. 2005.
89. Spina E, Scordo MG, D’Arrigo C. Metabolic drug interactions with new psychotropic agents.
Fundam Clin Pharmacol . 2003;17(5): 517-538.
90. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med . 2005;352(11):1112-1120.
91. Huang V, Gortney JS. Risk of serotonin syndrome with concomitant administration of linezolid and
serotonin agonists. Pharmacotherapy . 2006;26(12):1784-1793.
92. Grohmann R, Ruther E, Sassim N, et al. Adverse effects of clozapine. Psychopharmacology (Berl) .
1989;99(Suppl):S101-S104.
93. Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm . 2007;64(18):1917-1921.
94. Lu ML, Lane HY, Lin SK, et al. Adjunctive fluvoxamine inhibits clozapine-related weight gain and
metabolic disturbances. J Clin Psychiatry . 2004;65(6):766-771.
95. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol .
2006;61(3):246-255.
96. Bialer M, Doose DR, Murthy B, et al. Pharmacokinetic interactions of topiramate. Clin
Pharmacokinet . 2004;43(12):763-780.
97. Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs .
99. Kaufman KR, Gerner R. Lamotrigine toxicity secondary to sertraline. Seizure . 1998;7(2): 163-165.
100. Guthrie SK, Stoysich AM, Bader G, et al. Hypothesized interaction between valproic acid and
warfarin. J Clin Psychopharmacol . 1995; 15(2):138-139.
101. Spina E, Perucca E. Clinical significance of pharmacokinetic interactions between antiepileptic and
psychotropic drugs. Epilepsia . 2002;43(Suppl 2):37-44.
102. Janicak PG, Davis JM, Preskorn SH, et al. Principles and practice of psychopharmacotherapy , 4th
ed. Lippincott Williams & Wilkins; 2006.
103. Pae CU, Kim JJ, Lee CU, et al. Rapid versus conventional initiation of quetiapine in the treatment
of schizophrenia: A randomized, parallel-group trial. J Clin Psychiatry . 2007; 68(3):399-405.
104. Glick ID, Shkedy Z, Schreiner A. Differential early onset of therapeutic response with risperidone
versus conventional antipsychotics in patients with chronic schizophrenia. Int Clin
Psychopharmacol . 2006;21(5):261-266.
105. Leucht S, Busch R, Kissling W, et al. Early prediction of antipsychotic nonresponse among
patients with schizophrenia. J Clin Psychiatry . 2007;68(3):352-360.
106. McCue RE, Waheed R, Urcuyo L, et al. Comparative effectiveness of second-generation
antipsychotics and haloperidol in acute schizophrenia. Br J Psychiatry . 2006;189:433-440.
107. Leucht S, Busch R, Hamann J, et al. Early- onset hypothesis of antipsychotic drug action: A
hypothesis tested, confirmed, and extended. Biol Psychiatry . 2005;57(12):1543-1549.
108. Smith LA, Cornelius V, Warnock A, et al. Acute bipolar mania: A systematic review and
metaanalysis of co-therapy versus monotherapy. Acta Psychiatr Scand . 2007;115:12-20.
109. Letmaier M, Schreinzer D, Reinfried L, et al. Typical neuroleptics versus atypical antipsychotics in
the treatment of acute mania in a natural setting. Int J Neuropsychopharmacol . 2006;9(5):529-537.
110. Rendell JM, Gijsman HJ, Keck P, et al. Olanzapine alone or in combination for acute mania.
Cochrane Database Syst Rev . 2003;CD004040 .
111. Hirschfeld RMA, Baker JD, Wozniak P, et al. The safety and early efficacy of oral-loaded
divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of
acute mania associated with bipolar disorder. J Clin Psychiatry . 2003;64(7):841-846.
112. Licht RW, Gouliaev G, Vestergaard P, et al. Generalisability of results from randomized drug
trials: A trial on antimanic treatment. Br J Psychiatry . 1997;170:264-267.
113. Goodwin FK, Jamison KR. Manic-depressive illness: bipolar disorders and recurrent depression ,
2nd ed. New York: Oxford University Press; 2007.
114. Keck PE, Sanchez R, Torbenys A, et al. Aripiprazole monotherapy in the treatment of acute bipolar
I mania: A Randomized Placebo and Lithium Controlled Study. American Psychiatric Association
Annual Meeting , New Research Poster NR 304. San Diego, 2007.
115. Hatim A, Habil H, Jesjeet SG, et al. Safety and efficacy of rapid dose administration of quetiapine
in bipolar mania. Hum Psychopharmacol . 2006;21(5):313-318.
116. Baldessarini RJ, Tondo L, Hennen J, et al. Is lithium still worth using? An update of selected recent
research. Harv Rev Psychiatry . 2002;10(2):59-75.
117. Baldessarini RJ, Leahy L, Arcona S, et al. Patterns of psychotropic drug prescription for U.S.
patients with diagnoses of bipolar disorders. Psychiatr Serv . 2007;58(1):85-91.
118. Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. J
Clin Psychiatry . 2005;66(2):148-158.
119. Gartlehner G, Hansen RA, Thieda P, et al. Comparative effectiveness of second-generation
antidepressants in the pharmacologic treatment of adult depression: comparative effectiveness
review No. 7 . Rockville: Agency for Healthcare Research and Quality; 2007.
120. Janicak PG, Davis JM, Preskorn SH. Principles and practice of psychopharmacotherapy , 4th ed.
New York: Lippincott Williams & Wilkins; 2006:228.
121. Ballesteros J, Callado LF. Review: Combining pindolol with an SSRI improves early outcomes in
people with depression. J Affect Disord . 2004;79:137-147.
122. Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive
therapy in major depressive disorder:
124. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate
antagonist in treatment-resistant major depression. Arch Gen Psychiatry . 2006;63(8):856-964.
125. Leon AC. The revised warning for antidepressants and suicidality: Unveiling the black box of
statistical analyses. Am J Psychiatry . 2007;164(12):1786-1788.
126. Preskorn S. Outpatient management of depression , 2nd ed. Caldo: Professional Communications,
Inc; 1999.
127. Rittmannsberger H, Meise U, Schauflinger K, et al. Polypharmacy in psychiatric treatment.
Patterns of psychotropic drug use in Austrian psychiatric clinics. Eur Psychiatry . 1999;14(1):33-
40.
128. Jaffe AB, Levine J. Antipsychotic medication coprescribing in a large state hospital system.
Pharmacoepidemiol Drug Saf . 2003;12(1):41-48.
129. Procyshyn RM, Thompson B. Patterns of antipsychotic utilization in a tertiary care psychiatric
institution. Pharmacopsychiatry . 2004;37(1):12-17.
130. Botts S, Hines H, Littrell R. Antipsychotic polypharmacy in the ambulatory care setting, 1993-
2000. Psychiatr Serv . 2003;54(8):1086.
131. Ito H, Koyama A, Higuchi T. Polypharmacy and excessive dosing: Psychiatrists’ perceptions of
antipsychotic drug prescription. Br J Psychiatry . 2005;187:243-247.
132. Centorrino F, Goren JL, Hennen J, et al. Multiple versus single antipsychotic agents for
hospitalized psychiatric patients: Case-control study of risks versus benefits. Am J Psychiatry .
2004;161(4):700-706 .
133. Waddington JL, Youssef HA, Kinsella A. Mortality in schizophrenia. Antipsychotic polypharmacy
and absence of adjunctive anticholinergics over the course of a 10-year prospective study. Br J
Psychiatry . 1998;173:325-329.
134. Stahl SM, Grady MM. High-cost use of second-generation antipsychotics under California’s
Medicaid program. Psychiatr Serv . 2006;57(1):127-129.
135. Patrick V, Schleifer SJ, Nurenberg JR, et al. Best practices: An initiative to curtail the use of
antipsychotic polypharmacy in a state psychiatric hospital. Psychiatr Serv . 2006;57(1):21-23.
136. Viguera AC, Baldessarini RJ, Hegarty JD, et al. Clinical risk following abrupt and gradual
withdrawal of maintenance neuroleptic treatment. Arch Gen Psychiatry . 1997;54(1):49-55.
137. Stahl SM. Antipsychotic polypharmacy: Evidence based or eminence based?. Acta Psychiatr Scand
. 2002;106(5):321-322.
138. Tohen M, Chengappa KN, Suppes T, et al. Efficacy of olanzapine in combination with valproate or
lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium
monotherapy. Arch Gen Psychiatry . 2002;59(1):62-69.
139. Sachs GS, Grossman F, Ghaemi SN, et al. Combination of a mood stabilizer with risperidone or
haloperidol for treatment of acute mania:
140. A double-blind, placebo-controlled comparison of efficacy and safety. Am J Psychiatry .
2002;159(7):1146-1154.
141. Yatham LN, Grossman F, Augustyns I, et al. Mood stabilisers plus risperidone or placebo in the
treatment of acute mania. International, double-blind, randomised controlled trial. Br J Psychiatry .
2003;182:141-147.
142. Sachs G, Chengappa KN, Suppes T, et al. Quetiapine with lithium or divalproex for the treatment
of bipolar mania: A randomized, double-blind, placebo-controlled study. Bipolar Disord .
2004;6(3):213-223.
143. Yatham LN, Paulsson B, Mullen J, et al. Quetiapine versus placebo in combination with lithium or
divalproex for the treatment of bipolar mania. J Clin Psychopharmacol . 2004;24(6):599-606.
144. Leucht S, Busch R, Hamann J, et al. Early- onset hypothesis of antipsychotic drug action: A
hypothesis tested, confirmed and extended. Biol Psychiatry . 2005;57(12):1543-1549.
145. Miller AL, Chiles JA, Chiles JK, et al. The Texas Medication Algorithm Project (TMAP)
schizophrenia algorithms. J Clin Psychiatry . 1999;60(10):649-657.
146. Dodd S, Horgan D, Malhi GS, et al. To combine or not to combine? A literature review of
antidepressant combination therapy. J Affect Disord . 2005;89(1-3):1-11.
147. Simon J, Pilling S, Burbeck R, et al. Treatment options in moderate and severe depression:
Decision analysis supporting a clinical guideline. Br J Psychiatry . 2006;189:494-501.
148. Keller MB, McCullough JP, Klein DN, et al. A comparison of nefazodone, the cognitive
behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic
depression. N Engl J Med . 2000;342(20):1462-1470.
149. Schramm E, van Calker D, Dykierek P, et al. An intensive treatment program of interpersonal
psychotherapy plus pharmacotherapy for depressed inpatients: Acute and long-term results. Am J
Psychiatry . 2007;164(5):768-777.
150. Levinson DF, Umapathy C, Musthaq M. Treatment of schizoaffective disorder and schizophrenia
with mood symptoms. Am J Psychiatry . 1999;156(8):1138-1148.
151. Goodnick PJ. Bipolar depression: A review of randomised clinical trials. Expert Opin
Pharmacother . 2007;8(1):13-21.
152. Keating GM, Robinson DM. Quetiapine: A review of its use in the treatment of bipolar depression.
Drugs . 2007;67(7):1077-1095.
153. Goldsmith DR, Wagstaff AJ, Ibbotson T, et al. Lamotrigine: A review of its use in bipolar disorder.
Drugs . 2003;63(19):2029-2050 .
154. Leverich G, Altshuler L, Suppes T, et al. Risk of switch in mood polarity to hypomania or mania in
patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and
bupropion as adjuncts to mood stabilizers. Am J Psychiatry . 2006;163(2):232-239.
155. Adli M, Bauer M, Rush AJ. Algorithms and collaborative-care systems for depression: Are they
effective and why? A systematic review. Biol Psychiatry . 2006;59:1029-1038.
156. Kane JM, Honigfeld G, Singer J, et al. Clozapine for the treatment-resistant schizophrenic: A
double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789-796.
157. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine,
quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior
atypical antipsychotic treatment. Am J Psychiatry . 2006;163(4):600-610.
158. Kane JM, Meltzer HY, Carson WH, et al. Aripiprazole for treatment-resistant schizophrenia:
Results of a multicenter, randomized, double-blind, comparison study versus perphenazine. J Clin
Psychiatry . 2007;68(2):213-223.
159. Lehmann H. On acute schizophrenia patients. In: Lehmann H, Ban T, eds. The butyrophenones in
psychiatry . Montreal, Canada: Quebec Psychopharmacological Research Association; 1964.
160. Baldessarini RJ, Leahy L, Arcona S, et al. Patterns of psychotropic drug prescription for U.S.
patients with diagnoses of bipolar disorders. Psychiatr Serv . 2007;58(1):85-91.
161. Andreescu C, Mulsant MH, Peasley-Miklus C, et al. Persisting low use of antipsychotics in the
treatment of major depressive disorder with psychotic features. J Clin Psychiatry . 2007;68(2):194-
200.
162. Parker G, Manicavasagar V. Modelling and managing the depressive disorders: a clinical guide .
New York: Cambridge University Press; 2005.
163. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine
following three failed antidepressant medication trials for depression: A STAR*D report. Am J
Psychiatry . 2006;163:1531-1541.
164. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T3 augmentation
following two failed medication treatments for depression: A STAR*D report. Am J Psychiatry .
2006;163(9):1519-1530.
165. Husain MM, Rush AJ, Fink M, et al. Speed of response and remission in major depressive disorder
with acute electroconvulsive therapy (ECT): A Consortium for Research in ECT (CORE) report. J
Clin Psychiatry . 2004;65(4):485-491.
166. McCall WV. What does STAR*D tell us about ECT? JECT . 2007;23(1):1-2.
167. Ruiz PE. Review of psychiatry, Ethnicity and psychopharmacology , Vol. 19. American Psychiatric
Publishing, Inc; 2000.
168. de Leon J, Armstrong SC, Cozza KL. Clinical guidelines for psychiatrists for the use of
pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics . 2006;47(1):75-85.
169. De Leon J. Amplichip CYP450 test: Personalized medicine has arrived in psychiatry. Expert Rev
Mol Diagn . 2006;6(3):277-286.
170. Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation. Current state of
knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin Pharmacokinet . 1995; 29(3):192-
209.
171. Malhotra AK, Murphy GM Jr, Kennedy JL. Pharmacogenetics of psychotropic drug response. Am J
Psychiatry . 2004;161(5):780-796.
172. Mundo E, Walker M, Cate T, et al. The role of serotonin transporter protein gene in antidepressant-
induced mania in bipolar disorder: Preliminary findings. Arch Gen Psychiatry . 2001;58(6):539-
544.
173. Murphy GM Jr, Hollander SB, Rodrigues HE, et al. Effects of the serotonin transporter gene
promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric
major depression. Arch Gen Psychiatry . 2004;61(11):1163-1169.
174. Lencz T, Robinson DG, Xu K, et al. DRD2 promoter region variation as a predictor of sustained
response to antipsychotic medication in first-episode schizophrenia patients. Am J Psychiatry .
2006;163(3):529-531 .
175. Ozdemir V, Aklillu E, Mee S, et al. Pharmacogenetics for off-patent antipsychotics: Reframing the
risk for tardive dyskinesia and access to essential medicines. Expert Opin Pharmacother .
2006;7(2):119-133.
176. Alda M. Pharmacogenetics of lithium response in bipolar disorder. J Psychiatry Neurosci .
1999;24(2): 154- 158.
177. Bridge JA, Barbe RP. Reducing hospital readmission in depression and schizophrenia: Current
evidence. Curr Opin Psychiatry . 2004;17(6):505-511.
178. Klinkenberg WD, Calsyn RJ. Predictors of receipt of aftercare and recidivism among persons with
severe mental illness: A review. Psychiatr Serv . 1996;47(5):487-496.
179. Boyer CA, McAlpine DD, Pottick KJ, et al. Identifying risk factors and key strategies in linkage to
outpatient psychiatric care. Am J Psychiatry . 2000;157(10):1592-1598.
180. Kopelowicz A, Zarate R, Gonzalez SV, et al. Disease management in Latinos with schizophrenia:
A family-assisted, skills training approach. Schizophr Bull . 2003;29(2):211-227.
I
UPDATE
Inpatient Psychopharmacology
n the 11 years since the publication of this book chapter on the use of
psychopharmacology with the psychiatric inpatient, the general and
specific principles and advice seem to have changed very little. It is
surprisingly current. Anyone working on an inpatient unit, it would seem,
could profit from reading this material—there will likely be at least a few
practical or informational points that will be immediately applicable. A few
updates for certain sections of the chapter are provided below.
Selecting Treatment
This long section begins with advice on managing the agitated patient with
oral or parenteral medication directed at symptoms that must be addressed
urgently. A new and fairly large prospective randomized double-blind
controlled trial evaluated four intramuscular (IM) treatments for acute
agitation in an emergency room setting in Brazil. 1 A total of 100
consecutive patients (consent obtained from relatives or friends
accompanying the subjects) were randomized to haloperidol 2.5 mg plus
midazolam 7.5 mg, haloperidol 2.5 mg plus promethazine 25 mg,
olanzapine 10 mg, or ziprasidone 10 mg. The majority of the patients had
schizophrenia, with 36% having a diagnosis of mania. One hour after the
treatment, the best results were with either the haloperidol plus
benzodiazepine or the olanzapine. However, the odds ratio for significant
side effects was 1.6 higher for olanzapine. The other two treatments were
inferior in effectiveness and the odds ratio for side effects was 3.6, that is,
much higher, with the haloperidol plus the sedating antiparkinsonian agent
promethazine. This study further supports the recommendation in the
chapter that haloperidol plus a benzodiazepine (often it is lorazepam in the
United States) is still the best and safest IM treatment for acute agitation in
the urgent or emergency setting.
This section continues with an extended discussion of the oral use of
“prn” (abbreviation for the Latin words “pro re nata,” or “as the thing is
born”) as-needed medication for different urgent problems in the inpatient
setting. The essential point, still valid today, is that while there are times
when one must resort to offering prn’s, there is a downside, which is that
they encourage the patient in the belief that when they are feeling mental
distress there is a pill they can take to immediately feel better. Usually, we
are trying to teach patients to use nonmedication coping strategies for their
dysphoric states, and the use of prn’s can work against those strategies. It
would be better, when the patient comes to the nurse to ask for the prn that
he/she has on order, to sit down with the patient and figure out what is
causing the distress and develop a nonmedication coping strategy for that
precipitant. Many patients may already be heavily committed to self-
medications for immediate symptom relief, ranging from nicotine products,
to cannabis, to alcohol, cocaine, benzodiazepines, and other abusable
substances. Using prn’s in those patients, in particular, can be
counterproductive and foster the very habits that the clinical team is
working to undermine.
This section proceeds to discuss a variety of general medical conditions
that inpatients may have comorbid with their psychiatric problems and how
the management is affected by these comorbidities. Most of it is still very
relevant and useful. The association between the use of antipsychotics and
sudden death (likely in part from arrhythmias) is mentioned and new data
have been added to the evidence base confirming this risk. 2 Sudden death
is particularly a problem when these medications are used for dementia
symptoms in the elderly, as mentioned. 3 A black box warning regarding
this risk has been added to all antipsychotics. Weight gain, metabolic
syndrome, and induction of diabetes are also discussed. New data indicate
that even one 10 mg dose of olanzapine significantly impairs insulin
resistance and elevates inflammatory markers in healthy control volunteers
4.5 hours after administration. 4 The longer term effects of this one dose
were not evaluated but this “requires elucidation” according to the authors.
Quetiapine probably has similar effects, 5 and clozapine almost certainly
does as well. Since the chapter was written, we do have newer second-
generation antipsychotics with relatively fewer metabolic side effects,
including aripiprazole, lurasidone, brexpiprazole, and cariprazine—
although ziprasidone still seems to have the least.
In the treatment of agitation in patients with dementia, the
recommendations in the chapter are supported by more recent studies. 6 , 7
Restless leg syndrome is mentioned as a problem encountered in
inpatients. Quetiapine should be added to the list of medications that often
cause this as a side effect. 8 Since the review by Rittmannsberger and
colleagues of 16 cases from 6 years ago, there have been at least 9 other
reports of varying numbers of cases in the literature.
This section ends with some discussion of issues for women including
women of childbearing age. Without doubt the most undesirable (though
still often used) medication in young women with bipolar disorder is
valproate. 9 It received an “X” rating (for antiepileptic treatment) from the
Food and Drug Administration (FDA)—because of being associated with
an 11% risk of significant congenital abnormalities including spina bifida
and cardiac defects. 10 Another important problem for women, and many
men, is prolactin-mediated side effects of certain antipsychotics such as
risperidone, paliperidone, and most first-generation antipsychotics. It is
now thought that the health consequences are more significant than once
thought and prolactin levels should be routinely measured and medications
changed to prolactin-sparing antipsychotics (like aripiprazole) when
possible. 11
Polypharmacy, Treatment Resistance, Pharmacogenetics,
Managed Care/Financial Considerations
There are discussions of polypharmacy in the management of psychotic,
manic, and depressed patients. Algorithm chapters in this book will be a
more updated source for the most current thinking on sequences of
medications to use for these disorders and when use of more than one
medication within the same class (e.g., anticonvulsants or antipsychotics)
might be justified. Treatment resistance is also addressed much more
comprehensively than it is in this overview chapter and the reader is
referred to the individual diagnoses and their algorithms. The discussion of
pharmacogenetics still seems pertinent—which is surprising given the lapse
of 11 years since this was written.
REFERENCES
1. Mantovani C, Labate CM, Sponholz A Jr, et al. Are low doses of antipsychotics effective in the
management of psychomotor agitation? A randomized, rated-blind trial of 4 intramuscular
interventions. J Clin Psychopharmacol. 2013;33:306-312.
2. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden
cardiac death. N Engl J Med . 2009;360:225-235.
3. Chahine LM, Acar D, Chemali Z. The elderly safety imperative and antipsychotic usage. Harv
Rev Psychiatry . 2010;18:158-172.
4. Hahn MK, Wolever TM, Arenovich T, et al. Acute effects of single-dose olanzapine on
metabolic, endocrine, and inflammatory markers in healthy controls. J Clin Psychopharmacol .
2013;33:740-746.
5. Ngai YF, Sabatini P, Nguyen D, et al. Quetiapine treatment in youth is associated with decreased
insulin secretion. J Clin Psychopharmacol . 2014;34:359-364.
6. Osser DN, Fischer MA. Management of the behavioral and psychological symptoms of
dementia: review of current data and best practices for health care professionals. The National
Resource Center for Academic Detaili ng. Boston, MA: Alosa Foundation, Inc.; December 28,
2013:1-51.
7. Walaszek A. Behavioral and psychological symptoms of dementia . Washington, DC: American
Psychiatric Association Publishing; 2020.
8. Rittmannsberger H, Werl R. Restless legs syndrome induced by quetiapine: report of seven cases
and review of the literature. Int J Neuropsychopharmacol . 2013;16:1427-1431.
9. Balon R, Riba M. Should women of childbearing potential be prescribed valproate? A call to
action. J Clin Psychiatry . 2016;77:525-526.
10. Bromley RL, Weston J, Marson AG. Maternal use of antiepileptic agents during pregnancy
and major congenital malformations in children. JAMA . 2017;318:1700-1701.
11. Osser DN. Prolactin monitoring in first-episode psychotic patients. Schizophr Res .
2017;189:2-3.
* From Principles of Inpatient Psychiatry. Ovsiew F and Munich RI, Eds. Wolters Kluwer
Health/Lippincott Williams & Wilkins. New York, 2009: 43-69.
Guidelines, Algorithms, and Evidence-Based
Psychopharmacology Training for Psychiatric
Residents
David N. Osser, MD, Robert D. Patterson, MD, and James J. Levitt,
MD
Objective: The authors describe a course of instruction for psychiatry residents that attempts to
provide the cognitive and informational tools necessary to make scientifically grounded decision
making a routine part of clinical practice.
Methods: In weekly meetings over two academic years, the course covers the psychopharmacology
of various psychiatric disorders in 32 3-hour modules. The first half of each module is a case
conference, and the second is a literature review of papers related to the case. The case conference
focuses on the extent to which past treatment has been consistent with evidence-supported guidelines
and algorithms, and the discussants make recommendations that take the relevant scientific evidence
into consideration. The second half of each module focuses on two papers: 1) a published guideline,
algorithm, or review article and 2) a research study.
Results: Residents absorb a comprehensive overview of recommended clinical practices and acquire
skills in assessing knowledge that affects decision making. Satisfaction with the course is rated
highly.
Conclusion: The course appears useful by its face validity, but research comparing the attitudes and
practice outcomes of graduates of this course compared with recipients of other training methods is
needed.
There is growing concern about how to enable physicians to use research
findings in the care of their patients. Evidence-based medicine (EBM) is a way
physicians can merge research with patient care ( 1 – 3 ). There seems to be a
large gap between evidence-supported practice and typical practice ( 4 ). To
narrow this gap, many practice guidelines, algorithms, and compilations of
expert interpretation of evidence-based medicine have been issued in recent
years. However, studies have shown that simple dissemination of these
documents is generally not effective in changing practice ( 5 , 6 ). Some systems
designed to change behavior show promise. Examples of such systems include:
computerized reminders, flowcharts posted on walls, and performance feedback
and reviews. The changes in physician prescribing behavior have been modest,
however ( 7 – 9 ). The targeted practices often return to preintervention levels,
unless multifaceted, resource-intensive interventions are sustained ( 10 ).
This article describes a course in psychopharmacology for psychiatry
residents designed to address these concerns and the problem of commercial
influence in medical education. The authors wish to prepare students to be able
to use valid new information and resist influences that are not evidence-based.
Detailing, gifts, and sponsored educational products are highly influential, but,
unfortunately, this influence is often in the direction of irrational prescribing,
especially with respect to cost-effectiveness ( 11 – 13 ). Industry-sponsored
education has been dominating residency and postgraduate training in recent
years and is a concern throughout medicine ( 14 ).
The practice of EBM involves stepping back from a clinical scenario and
asking questions about the scientific evidence that pertains to that situation (1 ).
This is a rigorous approach to clinical decision making that may be unacceptably
time consuming. For the psychopharmacologist, a four-step approach is required.
The first step would be to make a criteria-based Diagnostic and Statistical
Manual of Mental Disorders (DSM)-IV diagnostic impression, identifying
subtypes and comorbidity. This is required because virtually all the evidence in
the literature regarding psychopharmacological treatment involves the treatment
of patients who have been identified by these criteria. Regardless of the validity
of DSM criteria, their utility in the context of EBM is difficult to dispute ( 15 ).
Next, a review of past treatment trials, including their adequacy and outcomes,
must be completed. Then, the clinician must search for, find, read, and analyze,
and apply the research evidence that pertains to the treatment situation (1 ).
Finally, a treatment decision is made after the evidence information is integrated
with the clinician’s knowledge of the total patient, taking into account issues
such as side effect sensitivities, patient preferences, family input, and ethnic and
cultural considerations ( 16 , 17 ).
This process is arduous and requires use of some cognitive disciplines that
may be unfamiliar to the physician. These barriers have limited the usefulness of
EBM in the day-to-day practice of medicine and psychiatry. In an effort to
address this problem, high- quality, evidence-based practice guidelines and
algorithms have been developed by appropriately qualified entities. The
physician can consult these academic products and more quickly determine what
the evidence supports for the clinical scenario at hand. However, these products
will usually not address all situations, and the EBM physician must still be able
to utilize the four-step process to look up particular questions or determine
whether there has been important new evidence since the guideline/algorithm
was published.
However, as noted, physicians often do not consult evidence-based guidelines
and algorithms, much less follow them. They present many reasons for not doing
so ( 18 ). The most common reasons involve lack of awareness that the
guidelines exist or apply ( 19 ), belief that the recommendations will not produce
a good outcome; and lack of experiences with some recommended treatments
and consequent discomfort with trying them. Additionally, some physicians may
not trust the guidelines/algorithms, especially if they have reason to doubt
whether they were rigorously and thoughtfully constructed. Many of these
products come embedded in industry sponsored educational material and contain
obviously biased recommendations. Even the term “evidence-based” is losing
meaning and credibility these days because of its ubiquitous presence in the titles
of promotional offerings. Guidelines and algorithms may also be rejected as
“cookbook medicine,” even though, curiously, physicians are likely to agree
with the specific recommendations in a guideline when they are presented
separately from that guideline (18 ). Finally, some physicians assert that they do
not agree with the concept of EBM in general, pointing out that much of the
evidence of EBM is flawed and incomplete and thus irrelevant ( 20 ).
What is the alternative? Instead of employing EBM-informed reasoning, it is
well-known that physicians often fall back on faulty processes of decision
making ( 21 – 23 ). For example, “reflexive decisions” are impulsive judgments
made without consciously considering any alternative. “Bias-driven clinical
judgments” occur when the physician is overconfident and thinks that he or she
knows exactly what to do based on some bias. The “availability heuristic” is the
tendency to grab the first answer that comes to mind and to stick with it despite
evidence to the contrary.
Use of these faulty approaches is sometimes justified by referring to them as
part of the “art” of medicine. Belief in this art appears to be rooted in the
apprentice/ mentor training model [eminence-based medicine ( 24 )] and the
model of placing special value on recollected clinical experience without
adequately taking into account the unreliability of memories. The problem with
clinical experience is that people tend to overestimate the frequency of
intermittent reinforcers ( 25 ) (e.g., a gratifying positive outcome from a
particular treatment). The validity of clinical experience is also limited by the
small Ns of the previous experience, sample differences (i.e., the patient to be
treated now is not really similar to the recollected previous patients), and
investigator bias (i.e., the physician has an undue faith in the proposed
treatment). At times, the art appears to be little more than treatment of symptoms
without precise diagnosis and with unscientific, improvisational treatment
selection. Dr. Abraham Flexner observed the same phenomena in his study of
American medical practice almost 100 years ago. He urged reforms in medical
education to produce a “scientific physician.” Such a physician:
. . .studies the actual situation with keener attention; he is freer of prejudiced prepossession; he is
more conscious of liability to error. Whatever the patient may have to endure from a baffling disease,
he is not further handicapped by reckless medication. . . ( 26 )
Psychiatrists are committed to the principle that each patient’s treatment
should be uniquely crafted, in recognition of the uniqueness of each person.
However, this principle may be misapplied, causing the psychiatrist to see
treatment decision making as a process without significant evidence-based
guideposts that should be considered. Though some of the resistance to EBM
appears to come from a fear that it attacks the humanistic perspective of
psychiatry, EBM should complement it.
TEACHING THE SCIENCE AND ART OF
PSYCHOPHARMACOLOGY
It has been proposed that the best way to overcome these barriers is to begin
training in EBM as early as possible ( 27 , 28 ). This article describes a new
structure for a course of classroom teaching of clinical psychopharmacology for
residents at the Harvard South Shore Psychiatry Residency Training Program. It
emphasizes the development of skills in practicing EBM. However, it goes
beyond traditional EBM and encourages the use of rigorously constructed
practice guidelines and algorithms as primary resources contributing to clinical
decision making. Evidence-based guidelines and algorithms are also used as a
way of organizing knowledge in psychopharmacology for the trainee (and the
expert). Guidelines and algorithms provide contexts in which to place new
information and compare it with previous knowledge. Using this knowledge of
EBM and the contents of guidelines and algorithms, students make better
decisions, and they develop the ability to identify clinical practice decisions that
seem to deviate from the evidence. The course encourages them to become
active consumers of many kinds of evidence (27 ); become skillful at detecting
the biases in publications, in lectures, and in the practice of other clinicians; and
learn to recognize the shortcomings of eminence-based medicine. Finally, at a
time when medication costs have substantially increased, residents are
encouraged to focus on evidence that pertains to making cost-effective
psychopharmacology decisions ( 29 ).
THE CORE PSYCHOPHARMACOLOGY
CONFERENCE: A TWO-YEAR COURSE
The Core Psychopharmacology Conference (CPC) is a 2-year program for PGY-
II and III psychiatry residents that meets weekly for 1.5 hours. Each year, before
the CPC begins, there is a 10-week introductory didactic lecture series in basic
principles of psychopharmacology, combined with structured reading of a basic
text. Topics covered in the introductory course include diagnosis,
neurobiological factors in mental illness, pharmacology of the medications,
kinetics, neurotransmitter issues, side effect management, and risk management
strategies.
The CPC utilizes clinical case conferences coupled with practice guidelines or
algorithms and research studies relevant to the cases presented, including clinical
studies or papers elucidating the neurobiology of the patient’s primary disorder
or the mechanism of action of the medications used to treat that disorder. The
CPC is organized into modules ( Table 1 ). The first module each year focuses
on basic principles of EBM and how to critically assess a paper ( 30 , 31 ).
Eleven psychiatric disorders are covered in the remaining 15 modules. (See
Appendix 1 for specific topics.) There are a total of 64 papers read and critiqued
by the resident group. Each trainee presents at least two case conferences and
leads four paper discussions over 2 years.
Table 1 | Organization of Modules in Years One and Two
APPENDIX 1: Module Topics
Evidence-based medicine and how to read a paper
Schizophrenia and related psychotic disorders ( 2 )
Bipolar disorder (2 )
Depression (2 )
Anxiety disorders (4 )
Dementia
Eating disorders
Attention deficit disorder
Substance abuse/dependence
Child and adolescent psychopharmacology
Overview of new developments
Syllabus papers are chosen by the faculty and distributed at the beginning of
the course each year. Resident-selected papers are chosen in relationship to a
question raised by the clinical material in the case conference: the resident (with
faculty supervision) researches the question, and a relevant paper is selected for
review in the meeting the following week.
Some comment is necessary about the way syllabus papers are selected. The
first-year syllabus contains practice guidelines, algorithms, or review article
papers, depending upon what is available for each diagnosis. Algorithms are a
subset of practice guidelines that are more specific and give step-by-step
elaboration of issues such as treatment sequencing, dosing, and progress
assessment ( 32 ). The selections in the first year syllabus draw somewhat
heavily on work by the course directors (one-third to one-half are theirs), but the
course directors attempt to be rigorous in critiquing their own work during the
class discussions. Algorithms can be evaluated according to several parameters (
33 ). They should:
1. Contain a critical appraisal of the quality of supporting evidence for
each recommendation, and an indication of different levels of
confidence in the recommendations;
2. Be thoroughly reviewed by other experts;
3. Be free of commercial bias;
4. Consider evidence of safety as well as efficacy in determining the
hierarchy of decisions;
5. Offer multiple options at each step as appropriate;
6. Cover a wide range of clinical scenarios;
7. Make special effort to explain the evidence supporting
recommendations that are different from what other prominent experts
have concluded in their interpretation of the literature; and
8. Be kept up-to-date. It is an advantage ( 34 ) that the algorithms and
decision-support information of the Harvard South Shore Program are
computerized, web-based, and frequently updated so residents can
always access the most recent version.
The clinical research papers in the second-year syllabus are selected for their
illustrative value on matters of contemporary clinical interest and for their
usefulness to the residents in gaining experience in applying the principles of
critical appraisal of papers outlined in the first module. They are not intended to
comprise only the best papers. Rather, they ensure coverage of a range of
problems with sampling demographics, sample size, effect size in comparison
with placebo, type I or II error, and statistical analytic issues. Considerable time
is spent addressing the issue of placebo effect in clinical trials, and, in general,
how placebo effect confounds the interpretation of personal clinical experience
in psychopharmacology practice ( 35 ). Sometimes papers are chosen that
provide evidence challenging common, but questionable, practices. Other papers
are selected because, although not high quality, they may be among the only
studies available that pertain to important decision areas. Residents are also
asked to critique the algorithm and guidelines papers according to the parameters
described earlier (33 ). The neuroscience papers are selected by one of the course
directors (JJL), who has expertise in psychiatric neuroimaging.
It should be noted that this course is not the complete curriculum in
psychopharmacology at this residency program. In addition to patient-based
learning through supervision in various settings, there are other courses that
cover research design, epidemiology, diagnosis, biological psychiatry,
integrative treatment, and a didactic lecture series in psychopharmacology.
Grand rounds also cover topics in psychopharmacology.
Although increasing numbers of medical schools and residency programs are
instituting courses on the principles and practice of EBM, there have been a
limited number of studies of clinical outcomes of patients treated by clinicians
who have adhered to evidence-based psychopharmacology guidelines or
algorithms (10 , 36 , 37 ). The course directors do not encourage trainees to
follow any guidelines and algorithms in a rigid way, but rather to use the
structure of the algorithms for organizing or scaffolding their evidence
knowledge base so that it can be readily accessed and consulted when making a
clinical decision.
Course Evaluation
Course Evaluation
A survey of resident opinion about the first CPC course (1999-2001) was
conducted in 2001. A questionnaire was anonymously completed by all 20 of the
trainees who attended the conference, and the answers were collated. Almost all
respondents indicated that the course was successful in structuring their
psychopharmacological knowledge and increasing their confidence in their
clinical decision making. They also approved of the emphasis placed on EBM,
practice guidelines, and algorithms, and reported that they frequently considered
the algorithms in their clinical decisions. Several graduates commented that
having learned to practice this way, and they cannot understand how others
around them do not.
Concluding Comments
Teaching methods and their impact on professional competence should not be
immune from the standards that EBM educators apply to clinical treatments. In
fact, there have been calls for high quality randomized trials of different methods
of medical teaching ( 38 , 39 ). However, there appears to be no satisfactory
method of measuring the clinical performance and competence of physicians,
despite numerous efforts ( 40 ). Even if there were satisfactory methods, random
assignment of trainees to different training approaches would certainly be
impractical. Observational studies could be done, but these would have to try to
control for the many confounding covariates inherent in the baseline
characteristics of the trainees and for the quality and type of teaching that occurs
in other parts of the residency curriculum. Studies should also address whether
trainees continue over the long term to use the thinking processes taught in this
course or whether they eventually fall back upon the automatic thinking
encouraged by industry-influenced education (39 ). Given the lack of such
studies, the authors can only present this course description for its face validity,
while acknowledging that the present approach should not be assumed to be
efficacious. However, we are presently conducting a study to measure residents’
attitudes toward EBM, guidelines, and algorithms 1 to 3 years after completion
of the course. These results will be compared with the attitudes of graduates of a
different psychiatry residency program in our area ( 41 ).
There is one published comprehensive model curriculum for
psychopharmacology training. The American Society of Clinical
Psychopharmacology (ASCP) has a 700-page volume, first published in 1997,
(with a third edition published in 2004) which provides lecture outlines,
reproductions of slides, and other information useful for organizing training ( 42
). Earlier editions were discussed and reviewed ( 43 – 46 ). One reviewer stated
that it lacked what psychiatric residents need the most: algorithms (43 ). One
must add that residents need not just any algorithms, but rigorously evidence-
based and unbiased algorithms (33 ).
Indeed, the ASCP’s important curriculum does discuss a wide variety of
evidence, but it does not teach how to assess and validate evidence for clinical
application, nor does it structure the evidence into formal algorithms or
guidelines. Even the authors acknowledge that the curriculum does not provide
the critical thinking skills necessary for good clinical practice ( 47 ). The
teaching approach described here complements and should ideally be combined
with presentation of the knowledge base in curricula such as that of the ASCP.
We are pleased to report that a description of this course, a citation of its web
site, and the flowcharts of three algorithms reviewed in the course are included
in the 2004 edition of the ASCP Model Curriculum.
In summary, the Core Psychopharmacology Conference establishes that EBM
and high-quality, up-to-date psychopharmacology practice guidelines and
algorithms should be routinely considered in daily clinical practice. The
approach emphasizes case-centered learning, in which cases are directly
associated with guidelines/algorithms and the evidence that supports them.
Residents have an opportunity to absorb the knowledge that experts have filtered
from the research literature and incorporated into the guidelines and algorithms.
They learn how to use EBM techniques to find, filter, critically evaluate, and
apply evidence and update their knowledge structures, including the knowledge
summarized in the guidelines and algorithms. They also explore the cognitive,
social, economic, and other factors that influence clinicians’ acquisition and
utilization of scientific research findings in their practice.
The authors thank Daniel Ioanitescu, M.D. for many useful discussions and
for organizing the course evaluation.
REFERENCES
1. Guyatt GH, Haynes RB, Jaeschke RZ, et al: Users’ guides to the medical literature XXV Evidence-
based medicine: principles for applying the users’ guides to patient care. J the Am Med Assoc 2000;
284:1290–1296
3. Lenfant C: Clinical research to clinical practice – lost in translation? New England J Med 2003;
349:868–874
4. Jencks SF, Cuerdon T, Burwen DR, et al: Quality of medical care delivered to medicare beneficiaries: a
profile at state and national levels. J the Am Med Assoc 2000; 284:1670–1676
Solberg LI: Guideline implementation: what the literature doesn’t tell us. The Joint Commission J on
5.
Solberg LI: Guideline implementation: what the literature doesn’t tell us. The Joint Commission J on
Quality Improvement 2000; 26:525–537
6. Bero LA, Grilli R, Grimshaw JM, et al: Closing the gap between research and practice: an overview of
systematic reviews of interventions to promote the implemetation of research findings. BMJ 1998;
317:465–468
7. Goethe JW, Schwartz HI, Szarek BL: Physician compliance with practice guidelines. Connecticut Med
1997; 61:553–558
8. Cannon DS, Allen SN: A comparison of the effects of computer and manual reminders on compliance
with a mental health clinical practice guideline. J the Am Med Informatics Assoc 2000; 7:196–203
9. Shea S, DuMouchel W, Bahamonde L: A meta-analysis of 16 randomized controlled trials to evaluate
computer-based clinical reminder systems for preventive care in the ambulatory setting. J the Am Med
Informatics Assoc 1996; 3:399–409
10. Bauer MS: A review of quantitative studies of adherence to mental health clinical practice guidelines.
Harvard Rev of Psychiatry 2002; 10:138–153
11. Wazana A: Physicians and the pharmaceutical industry: is a gift ever just a gift? J the Am Med Assoc
2000; 283:373–380
12. Goldman CR, Cutler DL: Pharmaceutical industry support of psychiatric research and education:
ethical issues and remedies, in Ethics in community mental health care: commonplace concerns.
Edited by Backlar P, Cutler D. New York., Kluwer Academic Press/Plenum Publishers, 2002
13. Dana J, Loewenstein G: A social science perspective on gifts to physicians from industry. J the Am
Med Assoc 2003; 290:252–25 5
14. Relman AS: Separating continuing medical education from pharmaceutical marketing. J the Am Med
Assoc 2001; 285:2009–2012
15. Kendell R, Jablensky A: Distinguishing between the validity and utility of psychiatric diagnoses. Am
J Psychiatry 2003; 160:4–12
17. Sackett DL, Rosenberg WM, Gray JA, et al: Evidence-based medicine: what it is and what it isn’t.
It’s about integrating clinical expertise and the best external evidence. BMJ 1996; 312:71–72
18. Cabana MD, Rand CS, Powe NR, et al: Why don’t physicians follow clinical practice guidelines? A
framework for improvement. J the Am Med Assoc 1999; 282:1458–1465
19. Azocar F, Cuffel BD, Goldman W, et al: Dissemination of guidelines for the treatment of major
depression in a managed behavioral health care network. Psychiatr Services 2001; 52:1014–1016
20. Stahl SM: Does evidence from clinical trials in psychopharmacology apply in clinical practice? J
Clin Psychiatry 2001; 62:6–7
21. Leape LL: Error in medicine. J the Am Med Assoc 1994; 272:1851–1857
22. Elstein AS: Cognitive processes in clinical inference and decision making, in Reasoning, inference,
and judgment in clinical psychology. Edited by Turk DC, Salovey P. New York, The Free Press,
1988
23. Poses RM: One size does not fit all: questions to answer before intervening to change physician
behavior. Joint Commission J on Quality Improvement 1999; 25:486–495
24. Berg AO: Dimensions of evidence. J the Am Board of Family Practice 1998; 11:216–223
Ferster CE, Skinner BF: Schedules of Reinforcement. New York, Appleton-Century-Crofts, 1957
25.
Ferster CE, Skinner BF: Schedules of Reinforcement. New York, Appleton-Century-Crofts, 1957
26. Flexner A: Medical education in the United States and Canada: a report to the Carnegie Foundation
for the Advancement of Teaching. New York, Arno Press, 1910
27. Bilsker D, Goldner EM: Teaching evidence-based practice in mental health. Evidence-Based Ment
Health 1999; 2:68–69
28. Waddell C: So much research evidence, so little dissemination and uptake: mixing the useful with the
pleasing. Evidence- Based Ment Health 2001; 4:3–5
29. Duckworth K, Hanson A: Using a clinical and evidence-based strategy to preserve access to
psychiatric medications. Psychiatr Services 2002; 53:1231–1232
30. Miser WF: Critical appraisal of the literature. J the Am Board of Family Practice 1999; 12:315–333
31. Streiner DL: Sample size and power in psychiatric research. Can J Psychiatry 1990; 35:616–620
32. Hadorn DC, McCormick K, Diokno A: An annotated algorithm approach to clinical guideline
development. J the Am Med Assoc 1992; 267:3311–3314
33. Osser DN, Patterson RD: Algorithms for psychopharmacology, in Manual of psychiatric
therapeutics, third ed. Edited by Shader RI. Boston, Lippincott Williams & Wilkins, 2003
34. Trivedi MH, Kern JK, Baker SM, et al: Computerizing medication algorithms and decision support
systems for major psychiatric disorders. J Psychiatr Practice 2000; 6:237–246
35. Quitkin FM: Placebos, drug effects, and study design: a clinician’s guide. Am J Psychiatry 1999;
156:829–836
36. Adli M, Berghofer A, Linden M, et al: Effectiveness and feasibility of a standardized stepwise drug
treatment regimen algorithm for inpatients with depressive disorders: results of a 2-year observational
algorithm study. J Clin Psychiatry 2002; 63:782–790
37. Suppes T: Texas medication algorithm project, phase 3: clinical results for patients with a history of
mania. J Clin Psychiatry 2003; 64:370–382
38. Epstein RM, Hundert EM: Defining and assessing professional competence. J the Am Med Assoc
2002; 287:226–235
39. Hatala R, Guyatt G: Evaluating the teaching of evidence-based medicine. J the Am Med Assoc 2002;
288:1110–1112
40. Landon BE, Normand ST, Blumenthal D, et al: Physician clinical performance assessment: prospects
and barriers. J the Am Med Assoc 2003; 290:1183–118 9
41. Osser DN, Patterson RD, Akhter A: Impact of a psychopharmacology course that emphasizes
evidence-based medicine, practice guidelines, and algorithms, poster 290 in CINP 2004 Congress,
Paris, 2004. Collegium Internationale Neuro-Psychopharmacologicum
42. American S of Clinical Psychopharmacology: Model Psychopharmacology Curriculum for
Psychiatric Residency Programs, Training Directors, and Teachers of Psychopharmacology. New
York, NY, American Society of Clinical Psychopharmacology, Inc., 1997
43. Rieder RO: Book review of A Model Psychopharmacology Curriculum. Acad Psychiatry 2000;24:2–
3
44. Yank G: Book review of the model psychopharmacology curriculum. J Clin Psychiatry 2000;
61:952–953
Lomax JWI: Model curricula in psychiatric residency: evangelical failures or evocative facilitators?
45.
Lomax JWI: Model curricula in psychiatric residency: evangelical failures or evocative facilitators?
Acad Psychiatry 2001;25:109–111
46. Goldberg DA: Model curricula: the way we teach, the way we learn. Acad Psychiatry 2001;25:98–
101
47. Glick ID, Janowsky DS, Zisook S, et al: How should we teach psychopharmacology to residents?
results of the initial experiences with the ASCP model curriculum. Acad Psychiatry 2001;25:90–97
for acute mania, 62
augmentations, 180
for bipolar depression, 52
for generalized anxiety disorder, 198
for posttraumatic stress disorder, 244
for schizophrenia, algorithm for, 145, 148
Attention-deficit hyperactivity disorder (ADHD), 8
Atypical features (ATF) of depression, 96–97
Blood pressure, 290–291
Borderline personality disorder (BPD), 287–288
BPD (borderline personality disorder), 287–288
BP-DEP algorithm. See Bipolar depression (BP-DEP) algorithm
BPRS (Brief Psychiatric Rating Scale), 123
Bridging strategies, 309
Brief Psychiatric Rating Scale (BPRS), 123
British National Health Service, 236
British National Institute for Health and Clinical Excellence guidelines, 44
Bupropion, 22, 90–91, 293, 296, 302
for generalized anxiety disorder, 192, 193
for obsessive-compulsive disorder, 269
and selective serotonin reuptake inhibitors, 238
for unipolar nonpsychotic depression, 94–95
for unipolar nonpsychotic depression, 94–95
BZs. See Benzodiazepines (BZs)
C
Caffeine, 230
California Medicaid program, 148
CAPS (Clinician-Administered PTSD Scale), 236
Capsulotomy, 276
Carbamazepine (CBZ), 17, 293, 297
for acute mania, 50, 61–62
Cardiac conduction, 289
Cardiac medical conditions, 289–290
Cariprazine, 8, 11
for bipolar depression, 15–16
CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness), 152, 289–290
CBZ. See Carbamazepine (CBZ)
Central noradrenergic dysregluation, 244–245
CGI-I (Clinical Global Impression of Improvement Scale), 212, 236
Chlorpromazine, 290, 293
Citalopram, 296
for obsessive-compulsive disorder, 268
for social anxiety disorder, 216
and treatment-resistant schizophrenia, 155–155
for unipolar nonpsychotic depression, 91
generalized anxiety disorder, 191
for obsessive-compulsive disorder, 269
and partial response, 193–194
sexual side effects, 190
for unipolar nonpsychotic depression, 91–92
Dysphoria, 57, 60, 301
syndrome of, 18
E
EBM. See Evidence-based medicine (EBM)
ECT. See Electroconvulsive therapy (ECT)
Electroconvulsive therapy (ECT), 9–11
adverse effects of, 88
availability and side effects, 122
Consortium for Research in, 88
effectiveness, 60
patient’s appropriateness for, 120
response, 9–10
treatment for mania, 60–61
trial of, 88–89
uncontrolled studies, 120
use of, 10
for generalized anxiety disorder, 198
for obsessive-compulsive disorder, 265
selective serotonin reuptake inhibitors, 237–238, 268
for social anxiety disorder, 216
Fluvoxamine, 273, 296, 297
augmentation of, 274
G
Gabapentin, 297
approval of, 99
generalized anxiety disorder, 192–193
leukopenia with, 293
as a mood stabilizer, 298
placebo-controlled RCT, 218
social anxiety disorder, 218
Harvard South Shore Psychiatry Residency Training Program, 326
Health care marketplace, 283
Health care providers, 284
Hepatotoxicity, 291
Hyperglycemia, 292, 302
Hyperlipidemia, 292–293
Inpatient unit
factors influencing pharmacotherapy on, 284
improving outcome after discharge, 309–310
managed care and financial considerations, 308–309
medication interactions, 295
N
N-acetylcysteine (NAC), 273
National Institute for Clinical Excellence (NICE), 236
National Institute for Health and Care Excellence criteria, 81
Nefazodone, 2, 238, 218, 241, 242, 296, 302
Neuroleptic dysphoria, 57
Neurologic disease
algorithms and guidelines, 246t
aripiprazole, 244
beta-blockers, 245
comorbidity and features in, 229–230f , 257–258
demographics, symptom clusters, and tailoring of treatment approaches, 227
DSM-IV criteria for, 227–230
flowchart for algorithm, 227, 228f
guanfacine, 245
hyperarousal symptoms of, 231
initial insomnia, 258
insomnia, medications for, 234–235
lamotrigine for, 243
levetiracetam, 243
medication treatments for, 226
method of algorithm development, 226–227
mirtazapine, 240–242
monoamine-oxidase inhibitors, 245
nefazodone for, 241–242
nightmares/disturbed arousals, 230–231
olanzapine, 244
options to consider, 259–260
vs. other algorithms and guideline recommendations, 245–247
paroxetine, 226
partial response, 242–245
prazosin, 231, 254–257
psychopharmacological strategies for treating, 225
psychotic symptoms, 239
quetiapine, 244
related psychosis, 239–240
risperidone, 239–240, 243–244
sertraline, 226
sleep, 230–234
for acute mania, 58
for generalized anxiety disorder, 193–194, 197, 198
for posttraumatic stress disorder, 239–240, 243–244
for schizophrenia, 144, 145, 149, 151–152, 156
for social anxiety disorder, 218
therapeutic response to, 299
rTMS (repetitive transcranial magnetic stimulation), 93
S
SAD. See Social anxiety disorder (SAD)
S-adenosylmethionine (SAMe), 94
Schizoaffective disorder, 45, 119, 173–174
antipsychotics in, 298–299
treatment resistance, 305–306
with anticonvulsants, 179
with antipsychotics, 179
aripiprazole, 180
clozapine, 157
with electroconvulsive therapy, 179–180
with electroconvulsive therapy, 179–180
augmentations and alternatives to clozapine, 179–180
care for patients with, 138
CATIE study, 153
clinical therapeutics in, 137
clozapine, 154
comorbidity and other features in, 141–143t , 174–176
drug discontinuation in, 148
first antipsychotic trial, 176–177
flowchart of, 138–139, 140f
adequate trial of, 187–190
alternatives to, 208, 238
and atypical antipsychotics, 124–125
augmentation for, 96
bupropion, 238
dose of, 269
escitalopram, 238
fluoxetine, 237–238, 268
fluvoxamine, 268
and mirtazapine, 238
number needed to treat, 235–236
paroxetine, 236, 239
and partial response, 193–194
and partial response, 193–194
and quetiapine, 238, 240
risks of adverse effects from, 190
sertraline, 237, 239, 268
sexual side effects, 190
and typical antipsychotics, 124
and venlafaxine, 271
W
Weight gain, 292
Women of childbearing age, 294–295
Y
YBOCS (Yale-Brown Obsessive-Compulsive Disorder Rating Scale) total score, 269, 273–274
YMRS (Young Mania Rating Scale), 50
Young Mania Rating Scale (YMRS), 50
Z
Ziprasidone, 290, 292, 300
adjunctive use of, 1 6
Half
Title Page
Title Page
Copyright Page
Contributors
Introduction
Acknowledgments
Contents
1) On the Value of Evidence-Based Psychopharmacology Algorithms
2) The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Update on Bipolar Depression
3) The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Algorithm for Acute Mania
4) The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Update on Unipolar Nonpsychotic Depression
5) The Psychopharmacology Algorithm Project at the Harvard South Shore Program: 2012 Update on Psychotic Depression
6) The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Update on Schizophrenia
7) The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Algorithm for Generalized Anxiety Disorder
8) The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Update on Generalized Social Anxiety Disorder
9) The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Update on Posttraumatic Stress Disorder
10) The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Algorithm for Adults with Obsessive-Compulsive Disorder
11) Pharmacologic Approach to the Psychiatric Inpatient
12) Guidelines, Algorithms, and Evidence-Based Psychopharmacology Training for Psychiatric Residents
Index
What Will You Get?
We provide professional writing services to help you score straight A’s by submitting custom written assignments that mirror your guidelines.
Premium Quality
Get result-oriented writing and never worry about grades anymore. We follow the highest quality standards to make sure that you get perfect assignments.
Experienced Writers
Our writers have experience in dealing with papers of every educational level. You can surely rely on the expertise of our qualified professionals.
On-Time Delivery
Your deadline is our threshold for success and we take it very seriously. We make sure you receive your papers before your predefined time.
24/7 Customer Support
Someone from our customer support team is always here to respond to your questions. So, hit us up if you have got any ambiguity or concern.
Complete Confidentiality
Sit back and relax while we help you out with writing your papers. We have an ultimate policy for keeping your personal and order-related details a secret.
Authentic Sources
We assure you that your document will be thoroughly checked for plagiarism and grammatical errors as we use highly authentic and licit sources.
Moneyback Guarantee
Still reluctant about placing an order? Our 100% Moneyback Guarantee backs you up on rare occasions where you aren’t satisfied with the writing.
Order Tracking
You don’t have to wait for an update for hours; you can track the progress of your order any time you want. We share the status after each step.
From brainstorming your paper's outline to perfecting its grammar, we perform every step carefully to make your paper worthy of A grade.
Preferred Writer
Hire your preferred writer anytime. Simply specify if you want your preferred expert to write your paper and we’ll make that happen.
Grammar Check Report
Get an elaborate and authentic grammar check report with your work to have the grammar goodness sealed in your document.
One Page Summary
You can purchase this feature if you want our writers to sum up your paper in the form of a concise and well-articulated summary.
Plagiarism Report
You don’t have to worry about plagiarism anymore. Get a plagiarism report to certify the uniqueness of your work.
Free Features $66FREE
Most Qualified Writer
$10FREE
Plagiarism Scan Report
$10FREE
Unlimited Revisions
$08FREE
Paper Formatting
$05FREE
Cover Page
$05FREE
Referencing & Bibliography
$10FREE
Dedicated User Area
$08FREE
24/7 Order Tracking
$05FREE
Periodic Email Alerts
$05FREE
Our Services
Join us for the best experience while seeking writing assistance in your college life. A good grade is all you need to boost up your academic excellence and we are all about it.
On-time Delivery
24/7 Order Tracking
Access to Authentic Sources
Academic Writing
We create perfect papers according to the guidelines.
Professional Editing
We seamlessly edit out errors from your papers.
Thorough Proofreading
We thoroughly read your final draft to identify errors.
Thorough Proofreading
We thoroughly read your final draft to identify errors.
Delegate Your Challenging Writing Tasks to Experienced Professionals
Work with ultimate peace of mind because we ensure that your academic work is our responsibility and your grades are a top concern for us!
We Analyze Your Problem and Offer Customized Writing
We understand your guidelines first before delivering any writing service. You can discuss your writing needs and we will have them evaluated by our dedicated team.
Clear elicitation of your requirements.
Customized writing as per your needs.
We Mirror Your Guidelines to Deliver Quality Services
We write your papers in a standardized way. We complete your work in such a way that it turns out to be a perfect description of your guidelines.
Proactive analysis of your writing.
Active communication to understand requirements.
We Handle Your Writing Tasks to Ensure Excellent Grades
We promise you excellent grades and academic excellence that you always longed for. Our writers stay in touch with you via email.
Thorough research and analysis for every order.
Deliverance of reliable writing service to improve your grades.
