PLEASE PAY ATTENTION TO THE CASE STUDY and CHAPTERS ATTACHED
PLEASE FOLLOW THE PROMPTS OF THE WAY THE QUESTIONS WERE ASKED.
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The Assignment
Examine Case Study: A Middle-Aged Caucasian Man With Anxiety. You will be asked to make three decisions concerning the medication to prescribe to this client. Be sure to consider factors that might impact the client’s pharmacokinetic and pharmacodynamic processes.
At each decision point stop to complete the following:
- Decision #1
Which decision did you select?
Why did you select this decision? Support your response with evidence and references to the Learning Resources.
What were you hoping to achieve by making this decision? Support your response with evidence and references to the Learning Resources.
Explain any difference between what you expected to achieve with Decision #1 and the results of the decision. Why were they different?
- Decision #2
Why did you select this decision? Support your response with evidence and references to the Learning Resources.
What were you hoping to achieve by making this decision? Support your response with evidence and references to the Learning Resources.
Explain any difference between what you expected to achieve with Decision #2 and the results of the decision. Why were they different?
- Decision #3
Why did you select this decision? Support your response with evidence and references to the Learning Resources.
What were you hoping to achieve by making this decision? Support your response with evidence and references to the Learning Resources.
Explain any difference between what you expected to achieve with Decision #3 and the results of the decision. Why were they different?
Also include how ethical considerations might impact your treatment plan and communication with clients.
Anxiety disorders and anxiolytics
This chapter will provide a brief overview of anxiety disorders and their treatments. Included here are
descriptions of how the anxiety disorder subtypes overlap with each other and with major depressive
disorder. Clinical descriptions and formal criteria for how to diagnose anxiety disorder subtypes are
mentioned only in passing. The reader should consult standard reference sources for this material.
The discussion here will emphasize how discoveries about the functioning of various brain circuits
and neurotransmitters – especially those centered on the amygdala – impact our understanding of
fear and worry, symptoms that cut across the entire spectrum of anxiety disorders.
The goal of this chapter is to acquaint the reader with ideas about the clinical and biological aspects
of anxiety disorders in order to understand the mechanisms of action of the various treatments for
these disorders discussed along the way. Many of these treatments are extensively discussed in
other chapters. For details of mechanisms of anxiolytic agents used also for the treatment of
depression (i.e., certain antidepressants), the reader is referred to ; for those anxiolyticChapter 7
agents used also for chronic pain (i.e., certain anticonvulsants), the reader is referred to .Chapter 10
The discussion in this chapter is at the conceptual level, and not at the pragmatic level. The reader
should consult standard drug handbooks (such as Stahl’s Essential Psychopharmacology: the
) for details of doses, side effects, drug interactions, and other issues relevant toPrescriber’s Guide
the prescribing of these drugs in clinical practice.
Symptom dimensions in anxiety disorders
When is anxiety an anxiety disorder?
Anxiety is a normal emotion under circumstances of threat and is thought to be part of the
evolutionary “fight or flight” reaction of survival. Whereas it may be normal or even adaptive to be
anxious when a saber-tooth tiger (or its modern-day equivalent) is attacking, there are many
circumstances in which
Figure 9-1. . Although the core symptoms ofOverlap of major depressive disorder and anxiety disorders
anxiety disorders (anxiety and worry) differ from the core symptoms of major depression (loss of interest and
depressed mood), there is considerable overlap among the rest of the symptoms associated with these
disorders (compare the “anxiety disorders” puzzle on the right to the “MDD” puzzle on the left). For example,
fatigue, sleep difficulties, and problems concentrating are common to both types of disorders.
the presence of anxiety is maladaptive and constitutes a psychiatric disorder. The idea of anxiety as
a psychiatric disorder is evolving rapidly, and is characterized by the concept of core symptoms of
excessive fear and worry (symptoms at the center of anxiety disorders in ), compared toFigure 9-1
major depression, which is characterized by core symptoms of depressed mood or loss of interest
(symptoms at the center of major depressive disorder in ).Figure 9-1
Anxiety disorders have considerable symptom overlap with major depression (see those symptoms
surrounding core features shown in ), particularly sleep disturbance, problemsFigure 9-1
concentrating, fatigue, and psychomotor/arousal symptoms. Each anxiety disorder also has a great
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deal of symptom overlap with other anxiety disorders ( through ). Anxiety disorders areFigures 9-2 9-5
also extensively comorbid, not only with major depression, but also with each other, since many
patients qualify over time for a second or even third concomitant anxiety disorder. Finally, anxiety
disorders are frequently comorbid with many other conditions such as substance abuse, attention
deficit hyperactivity disorder, bipolar disorder, pain disorders, sleep disorders, and more.
So, what is an anxiety disorder? These disorders all seem to maintain the core features of some form
of anxiety or fear coupled with some form of worry, but their natural history over time shows them to
morph from one into another, to evolve into full syndrome expression of anxiety disorder symptoms (
) and then to recede into subsyndromal levels of symptoms only to reappear again as theFigure 9-1
original anxiety disorder, a different anxiety disorder ( through ), or major depression (Figures 9-2 9-5
). If anxiety disorders all share core symptoms of fear and worry ( and ) and,Figure 9-1 Figures 9-1 9-6
as we shall see later in this chapter, are all basically treated with the same drugs, including many of
the same drugs that treat major depression, the question now arises, what is the difference between
one anxiety disorder and another? Also, one could ask, what is the difference between major
depression and anxiety disorders? Are all these entities really different disorders, or are they instead
different aspects of the same illness?
Overlapping symptoms of major depression and anxiety disorders
Although the core symptoms of major depression (depressed mood or loss of interest) differ from the
core symptoms of anxiety disorders (fear and worry), there is a great deal of overlap with the other
symptoms considered diagnostic both for a major depressive episode and for several different
anxiety disorders
Figure 9-2. . The symptoms typically associated with GAD are shownGeneralized anxiety disorder (GAD)
here. These include the core symptoms of generalized anxiety and worry as well as increased arousal, fatigue,
difficulty concentrating, sleep problems, irritability, and muscle tension. Many of these symptoms, including the
core symptoms, are present in other anxiety disorders as well.
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Figure 9-3. . The characteristic symptoms of panic disorder are shown here, with corePanic disorder
symptoms of anticipatory anxiety as well as worry about panic attacks. Associated symptoms are the
unexpected panic attacks themselves and phobic avoidance or other behavioral changes associated with
concern over panic attacks.
( ). These overlapping symptoms include problems with sleep, concentration, and fatigueFigure 9-1
as well as psychomotor/arousal symptoms ( ). It is thus easy to see how the gain or loss ofFigure 9-1
just a few additional symptoms can morph a major depressive episode into an anxiety disorder (
) or one anxiety disorder into another ( through ).Figure 9-1 Figures 9-2 9-5
From a therapeutic point of view, it may matter little what the specific diagnosis is across this
spectrum of disorders ( through ). That is, first-line psychopharmacological treatmentsFigures 9-1 9-5
may not be much different for a patient who currently qualifies for a major depressive episode plus
the symptom of anxiety (but not an anxiety disorder) versus a patient who currently qualifies for a
major depressive episode plus a comorbid anxiety disorder with full criteria anxiety symptoms.
Although it can be useful to make specific diagnoses for following patients over time and for
documenting the evolution of symptoms, the emphasis from a psychopharmacological point of view
is increasingly to take a symptom-based therapeutic strategy to patients with any of these disorders
because the brain is not organized according to the DSM, but according to brain
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Figure 9-4. . Symptoms of social anxiety disorder, shown here, include the coreSocial anxiety disorder
symptoms anxiety or fear over social performance plus worry about social exposure. Associated symptoms are
panic attacks that are predictable and expected in certain social situations as well as phobic avoidance of those
situations.
Figure 9-5. . The characteristic symptoms of PTSD are shown here.Posttraumatic stress disorder (PTSD)
These include the core symptoms of anxiety while the traumatic event is being re-experienced as well as worry
about having the other symptoms of PTSD, such as increased arousal and startle responses, sleep difficulties
including nightmares, and avoidance behaviors.
circuits with topographical localization of function. That is, specific treatments can be tailored to the
individual patient by deconstructing whatever disorder the patient has into a list of the specific
symptoms a given patient is experiencing (see through ), and then matching theseFigures 9-2 9-5
symptoms to hypothetically malfunctioning brain circuits regulated by specific neurotransmitters in
order to rationally select and combine psychopharmacological treatments to eliminate all symptoms
and get the patient to remission.
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Overlapping symptoms of different anxiety disorders
Although there are different diagnostic criteria for different anxiety disorders ( though ),Figures 9-2 9-5
these are constantly changing, and many do not even consider obsessive-compulsive disorder to be
an anxiety disorder any longer (OCD is discussed in on impulsivity). All anxiety disordersChapter 14
have overlapping symptoms of anxiety/fear coupled with worry ( ). Remarkable progressFigure 9-6
has been made in
Figure 9-6. . Anxiety can be deconstructed, or broken down, into the two coreAnxiety: the phenotype
symptoms of fear and worry. These symptoms are present in all anxiety disorders, although what triggers them
may differ from one disorder to the next.
understanding the circuitry underlying the core symptom of anxiety/fear based upon an explosion of
neurobiological research on the amygdala ( through ). The links between theFigures 9-7 9-14
amygdala, fear circuits, and treatments for the symptom of anxiety/fear across the spectrum of
anxiety disorders are discussed throughout the rest of this chapter.
Worry is the second core symptom shared across the spectrum of anxiety disorders ( ).Figure 9-7
This symptom is hypothetically linked to the functioning of cortico-striato-thalamo-cortical (CSTC)
loops. The links between the CSTC circuits, “worry loops,” and treatments for the symptom of worry
across the spectrum of anxiety disorders are discussed later in this chapter (see also Figures 9-15
through , , and ). We shall see that what differentiates one anxiety disorder from9-17 9-26 9-29
another may not be the anatomical localization, or the neurotransmitters regulating fear and worry in
each of these disorders ( and ), but the specific nature of malfunctioning within theseFigures 9-6 9-7
same circuits in various anxiety disorders. That is, in generalized anxiety disorder (GAD),
malfunctioning in the amygdala and CSTC worry loops may be hypothetically persistent, and
unremitting, yet not severe ( ), whereas malfunctioning may be theoretically intermittent butFigure 9-2
catastrophic in an unexpected manner for panic disorder ( ) or in an expected manner forFigure 9-3
social anxiety ( ). Circuit malfunctioning may be traumatic in origin and conditioned inFigure 9-4
posttraumatic stress disorder (PTSD: ).Figure 9-5
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Generalized Anxiety Disorder
Middle-Aged White Male With Anxiety
BACKGROUND INFORMATION
The client is a 46-year-old white male who works as a welder at a local steel fabrication factory. He presents today after being referred by his PCP after a trip to the emergency room in which he felt he was having a heart attack. He stated that he felt chest tightness, shortness of breath, and feeling of impending doom. He does have some mild hypertension (which is treated with low sodium diet) and is about 15 lbs. overweight. He had his tonsils removed when he was 8 years old, but his medical history since that time has been unremarkable. Myocardial infarction was ruled out in the ER and his EKG was normal. Remainder of physical exam was WNL.
He admits that he still has problems with tightness in the chest and episodes of shortness of breath- he now terms these “anxiety attacks.” He will also report occasional feelings of impending doom, and the need to “run” or “escape” from wherever he is at.
In your office, he confesses to occasional use of ETOH to combat worries about work. He admits to consuming about 3-4 beers/night. Although he is single, he is attempting to care for aging parents in his home. He reports that the management at his place of employment is harsh, and he fears for his job. You administer the HAM-A, which yields a score of 26.
Client has never been on any type of psychotropic medication.
MENTAL STATUS EXAM
The client is alert, oriented to person, place, time, and event. He is appropriately dressed. Speech is clear, coherent, and goal-directed. Client’s self-reported mood is “bleh” and he does endorse feeling “nervous”. Affect is somewhat blunted, but does brighten several times throughout the clinical interview. Affect broad. Client denies visual or auditory hallucinations, no overt delusional or paranoid thought processes readily apparent. Judgment is grossly intact, as is insight. He denies suicidal or homicidal ideation.
The PMHNP administers the Hamilton Anxiety Rating Scale (HAM-A) which yields a score of 26.
Diagnosis: Generalized anxiety disorder
RESOURCES
§ Hamilton, M. (1959). Hamilton Anxiety Rating Scale. Psyctests, doi:10.1037/t02824-0
Begin Zoloft 50 mg po daily
Begin Imipramine 25 mg po BID
Begin Buspirone 10 mg po BID
Antipsychotic agents
This chapter will explore antipsychotic drugs, with an emphasis on treatments for schizophrenia.
These treatments include not only conventional antipsychotic drugs, but also the newer atypical
antipsychotic drugs that have largely replaced the older conventional agents. Atypical antipsychotics
are really misnamed, since they are also used as treatments for both the manic and depressed
phases of bipolar disorder, as augmenting agents for treatment-resistant depression, and “off-label”
for various other disorders, such as treatment-resistant anxiety disorders. The reader is referred to
standard reference manuals and textbooks for practical prescribing information, such as drug doses,
because this chapter on antipsychotic drugs will
Figure 5-1. . ThroughoutQualitative and semi-quantitative representation of receptor binding properties
this chapter, the receptor binding properties of the atypical antipsychotics are represented both graphically and
semi-quantitatively. Each drug is represented as a blue sphere, with its most potent binding properties depicted
along the outer edge of the sphere. Additionally, each drug has a series of colored boxes associated with it.
Each colored box represents a different binding property, and binding strength is indicated by the size of the box
and the number of plus signs. Within the colored box series for any particular antipsychotic, larger boxes with
more plus signs (positioned to the left) indicate stronger binding affinity, while smaller boxes with fewer plus
signs (positioned to the right) represent weaker binding affinity. The series of boxes associated with each drug
are arranged such that the size and positioning of a box reflect the binding potency for a particular receptor. The
vertical dotted line cuts through the dopamine 2 (D ) receptor binding box, with binding properties that are more2
potent than D on the left and those that are less potent than D on the right. All binding properties are based on2 2
the mean values of published K (binding affinity) data ( ). The semi-quantitative depictioni http://pdsp.med.unc.edu
used throughout this chapter provides a quick visual reference of how strongly a particular drug binds to a
particular receptor. It also allows for easy comparison of a drug’s binding properties with those of other atypical
antipsychotics.
emphasize basic pharmacologic concepts of mechanism of action and not practical issues such as
how to prescribe these drugs (for that information see for example Stahl’s Essential
, which is a companion to this textbook).Psychopharmacology: the Prescriber’s Guide
Antipsychotic drugs exhibit possibly the most complex pharmacologic mechanisms of any drug class
within the field of clinical psychopharmacology. The pharmacologic concepts developed here should
help the reader understand the rationale for how to use each of the different antipsychotic agents,
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based upon their interactions with different neurotransmitter systems ( ). Such interactionsFigure 5-1
can often explain both the therapeutic actions and the side effects of various antipsychotic
medications and thus can be very helpful background information for prescribers of these therapeutic
agents.
Conventional antipsychotics
What makes an antipsychotic “conventional”?
In this section we will discuss the pharmacologic properties of the first drugs that were proven to
effectively treat schizophrenia. A list of many conventional antipsychotic drugs is given in .Table 5-1
These drugs are usually called antipsychotics, but they are sometimes also called conventional
antipsychotics, or antipsychotics, or antipsychotics. The earliestclassical typical first-generation
effective treatments for schizophrenia and other psychotic illnesses arose from serendipitous clinical
observations more than
Table 5-1 Some conventional antipsychotics still in use
60 years ago, rather than from scientific knowledge of the neurobiological basis of psychosis, or of
the mechanism of action of effective antipsychotic agents. Thus, the first antipsychotic drugs were
discovered by accident in the 1950s when a drug with antihistamine properties (chlorpromazine) was
serendipitously observed to have antipsychotic effects when this putative antihistamine was tested in
schizophrenia patients. Chlorpromazine indeed has antihistaminic activity, but its therapeutic actions
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in schizophrenia are not mediated by this property. Once chlorpromazine was observed to be an
effective antipsychotic agent, it was tested experimentally to uncover its mechanism of antipsychotic
action.
Early in the testing process, chlorpromazine and other antipsychotic agents were all found to cause
“neurolepsis,” known as an extreme form of slowness or absence of motor movements as well as
behavioral indifference in experimental animals. The original antipsychotics were first discovered
largely by their ability to produce this effect in experimental animals, and are thus sometimes called
“neuroleptics.” A human counterpart of neurolepsis is also caused by these original (i.e.,
conventional) antipsychotic drugs and is characterized by psychomotor slowing, emotional quieting,
and affective indifference.
Figure 5-2. . Conventional antipsychotics, also called first-generation antipsychotics or typicalD antagonist2
antipsychotics, share the primary pharmacological property of D antagonism, which is responsible not only for2
their antipsychotic efficacy but also for many of their side effects. Shown here is an icon representing this single
pharmacological action.
D receptor antagonism makes an antipsychotic conventional2
By the 1970s it was widely recognized that the key pharmacologic property of all “neuroleptics” with
antipsychotic properties was their ability to block dopamine D receptors ( ). This action has2 Figure 5-2
proven to be responsible not only for the antipsychotic efficacy of conventional antipsychotic drugs,
but also for most of their undesirable side effects, including “neurolepsis.”
The therapeutic actions of conventional antipsychotic drugs are hypothetically due to blockade of D2
receptors specifically in the mesolimbic dopamine pathway ( ). This has the effect ofFigure 5-3
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reducing the hyperactivity in this pathway that is postulated to cause the positive symptoms of
psychosis, as discussed in ( and ). All conventional antipsychotics reduceChapter 4 Figures 4-12 4-13
positive psychotic symptoms about equally well in schizophrenia patients studied in large multicenter
trials if they are dosed to block a substantial number of D receptors there ( ).2 Figure 5-4
Unfortunately, in order to block adequate numbers of D receptors in the mesolimbic dopamine2
pathway to
Figure 5-3. . In untreated schizophrenia, the mesolimbicMesolimbic dopamine pathway and D antagonists2
dopamine pathway is hypothesized to be hyperactive, indicated here by the pathway appearing red as well as by
the excess dopamine in the synapse. This leads to positive symptoms such as delusions and hallucinations.
Administration of a D antagonist, such as a conventional antipsychotic, blocks dopamine from binding to the D2 2
receptor, which reduces hyperactivity in this pathway and thereby reduces positive symptoms as well.
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Figure 5-4. . All known antipsychoticsHypothetical thresholds for conventional antipsychotic drug effects
bind to the dopamine 2 receptor, with the degree of binding determining whether one experiences therapeutic
and/or side effects. For most conventional antipsychotics, the degree of D2 receptor binding in the mesolimbic
pathway needed for antipsychotic effects is close to 80%, while D2 receptor occupancy greater than 80% in the
dorsal striatum is associated with extrapyramidal side effects (EPS) and in the pituitary is associated with
hyperprolactinemia. For conventional antipsychotics (i.e,. pure D2 antagonists) it is assumed that the same
number of D2 receptors is blocked in all brain areas. Thus, there is a narrow window between the threshold for
antipsychotic efficacy and that for side effects in terms of D2 binding.
quell positive symptoms, one must simultaneously block the same number of D receptors2
throughout the brain, and this causes undesirable side effects as a “high cost of doing business” with
conventional antipsychotics ( through ). Although modern neuroimaging techniquesFigures 5-5 5-8
are able to measure directly the blockade of D receptors in the dorsal (motor) striatum of the2
nigrostriatal pathway, as shown in , for conventional antipsychotics it is assumed that theFigure 5-4
same number of D receptors is blocked in all brain areas, including the ventral limbic area of2
striatum known as the nucleus accumbens of the mesolimbic dopamine pathway, the prefrontal
cortex of the mesocortical dopamine pathway, and the pituitary gland of the tuberoinfundibular
dopamine pathway.
Neurolepsis
D receptors in the mesolimbic dopamine system are postulated to mediate not only the positive2
symptoms of psychosis, but also the normal reward system of the brain, and the nucleus accumbens
is widely considered to be the “pleasure center” of the brain. It may be the final common pathway of
all reward and reinforcement, including not only normal reward (such as the pleasure of eating good
food, orgasm, listening to music) but also the artificial reward of substance abuse. If D receptors are2
stimulated in some parts of the mesolimbic pathway, this can lead to the experience of pleasure.
Thus, if D receptors in the mesolimbic system are blocked, this may not only reduce positive2
symptoms of schizophrenia, but also block reward mechanisms, leaving patients apathetic,
anhedonic, lacking motivation, interest, and joy from social interactions, a state very similar to that of
negative symptoms of schizophrenia. The near shutdown of the mesolimbic dopamine pathway
necessary to improve the positive symptoms of psychosis ( ) may contribute to worseningFigure 5-4
of anhedonia, apathy, and negative symptoms, and this may be a partial explanation for the high
incidence of smoking and drug abuse in schizophrenia.
Antipsychotics also block D receptors in the mesocortical DA pathway ( ), where DA may2 Figure 5-5
already be deficient in schizophrenia (see through ). This can cause or worsenFigures 4-14 4-16
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negative and cognitive symptoms even though there is only a low density of D receptors in the2
cortex. An adverse behavioral state can be produced by conventional antipsychotics, and is
sometimes called the “neuroleptic-induced deficit syndrome” because it looks so much like the
negative symptoms produced by schizophrenia itself, and is reminiscent of “neurolepsis” in animals.
Extrapyramidal symptoms and tardive dyskinesia
When a substantial number of D receptors are blocked in the nigrostriatal DA pathway, this will2
produce various disorders of movement that can appear very much like those in Parkinson’s disease;
this is why these movements are sometimes called drug-induced
Figure 5-5. . In untreated schizophrenia, theMesocortical dopamine pathway and D antagonists2
mesocortical dopamine pathways to dorsolateral prefrontal cortex (DLPFC) and to ventromedial prefrontal cortex
(VMPFC) are hypothesized to be hypoactive, indicated here by the dotted outlines of the pathway. This
hypoactivity is related to cognitive symptoms (in the DLPFC), negative symptoms (in the DLPFC and VMPFC),
and affective symptoms of schizophrenia (in the VMPFC). Administration of a D antagonist could further reduce2
activity in this pathway and thus not only not improve such symptoms but actually potentially worsen them.
parkinsonism. Since the nigrostriatal pathway is part of the extrapyramidal nervous system, these
motor side effects associated with blocking D receptors in this part of the brain are sometimes also2
called extrapyramidal symptoms, or EPS ( and ).Figures 5-4 5-6
Worse yet, if these D receptors in the nigrostriatal DA pathway are blocked chronically ( ),2 Figure 5-7
they can produce a hyperkinetic movement disorder known as tardive dyskinesia. This movement
disorder causes facial and tongue movements, such as constant chewing, tongue protrusions, facial
grimacing, and also limb movements that can be quick, jerky, or choreiform (dancing). Tardive
dyskinesia is thus caused by long-term administration of conventional antipsychotics and is thought
to be mediated by changes, sometimes irreversible, in the D receptors of the nigrostriatal DA2
pathway. Specifically, these receptors are hypothesized to become supersensitive or to “upregulate”
(i.e., increase in number), perhaps in a futile attempt to overcome drug-induced blockade of D2
receptors in the striatum ( ).Figure 5-7
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About 5% of patients maintained on conventional antipsychotics will develop tardive dyskinesia every
year (i.e., about 25% of patients by 5 years), not a very encouraging prospect for a lifelong illness
starting in the early twenties. The risk of developing tardive
Figure 5-6. . The nigrostriatal dopamine pathway isNigrostriatal dopamine pathway and D antagonists2
theoretically unaffected in untreated schizophrenia. However, blockade of D receptors, as with a conventional2
antipsychotic, prevents dopamine from binding there and can cause motor side effects that are often collectively
termed extrapyramidal symptoms (EPS).
dyskinesia in elderly subjects may be as high as 25% within the first year of exposure to conventional
antipsychotics. However, if D receptor blockade is removed early enough, tardive dyskinesia may2
reverse. This reversal is theoretically due to a “resetting” of these D receptors by an appropriate2
decrease in the number or sensitivity of them in the nigrostriatal pathway once the antipsychotic drug
that had been blocking these receptors is removed. However, after long-term treatment, the D2
receptors apparently cannot or do not reset back to normal, even when conventional antipsychotic
drugs are discontinued. This leads to tardive dyskinesia that is irreversible, continuing whether
conventional antipsychotic drugs are administered or not.
Is there any way to predict those who will be harmed with the development of tardive dyskinesia after
chronic treatment with conventional antipsychotics? Patients who develop EPS early in treatment
may be twice as likely to develop tardive dyskinesia if treatment with a conventional antipsychotic is
continued chronically. Also, specific genotypes of dopamine receptors may confer important genetic
risk factors for developing tardive dyskinesia with chronic treatment using a conventional
antipsychotic. Risk of new cases of tardive
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Figure 5-7. . Long-term blockade of D receptors in the nigrostriatal dopamine pathway canTardive dyskinesia 2
cause upregulation of those receptors, which may lead to a hyperkinetic motor condition known as tardive
dyskinesia, characterized by facial and tongue movements (e.g., tongue protrusions, facial grimaces, chewing)
as well as quick, jerky limb movements. This upregulation may be the consequence of the neuron’s futile attempt
to overcome drug-induced blockade of its dopamine receptors.
dyskinesia, however, can diminish considerably after 15 years of treatment, presumably because
patients who have not developed tardive dyskinesia despite 15 years of treatment with a
conventional antipsychotic have lower genetic risk factors for it.
A rare but potentially fatal complication called the “neuroleptic malignant syndrome,” associated with
extreme muscular rigidity, high fevers, coma, and even death, and possibly related in part to D2
receptor blockade in the nigrostriatal pathway, can also occur with conventional antipsychotic agents.
Prolactin elevation
Dopamine D receptors in the tuberoinfundibular DA pathway are also blocked by conventional2
antipsychotics, and this causes plasma prolactin concentrations to rise, a condition called
hyperprolactinemia ( ). This is associated with conditions called galactorrhea (i.e., breastFigure 5-8
secretions) and amenorrhea (i.e., irregular or lack of menstrual periods). Hyperprolactinemia may
thus interfere with fertility, especially in women. Hyperprolactinemia might lead to more rapid
demineralization of bones, especially in postmenopausal women who are not taking estrogen
replacement therapy. Other possible problems associated with elevated prolactin levels may include
sexual dysfunction and weight gain, although the role of prolactin in causing such problems is not
clear.
The dilemma of blocking D dopamine receptors in all dopamine pathways2
It should now be obvious that the use of conventional antipsychotic drugs presents a powerful
dilemma. That is, there is no doubt that conventional antipsychotic medications exert dramatic
therapeutic actions upon positive symptoms of schizophrenia by blocking hyperactive dopamine
neurons in the mesolimbic dopamine pathway. However, there are dopamine pathways in theseveral
brain, and it appears that blocking dopamine receptors in of them is useful ( ),only one Figure 5-3
whereas blocking dopamine receptors in the remaining pathways may be harmful (Figures 5-4
through ). The pharmacologic5-8
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Figure 5-8. . The tuberoinfundibular dopamineTuberoinfundibular dopamine pathway and D antagonists2
pathway, which projects from the hypothalamus to the pituitary gland, is theoretically “normal” in untreated
schizophrenia. D antagonists reduce activity in this pathway by preventing dopamine from binding to D2 2
receptors. This causes prolactin levels to rise, which is associated with side effects such as galactorrhea (breast
secretions) and amenorrhea (irregular menstrual periods).
quandary here is what to do if one wishes simultaneously to dopamine in the mesolimbicdecrease
dopamine pathway in order to treat positive psychotic symptoms theoretically mediated by
hyperactive mesolimbic dopamine neurons and yet dopamine in the mesocortical dopamineincrease
pathway to treat negative and cognitive symptoms, while leaving dopaminergic tone unchanged in
both the nigrostriatal and tuberoinfundibular dopamine pathways to avoid side effects. This dilemma
may have been addressed in part by the atypical antipsychotic drugs described in the following
sections, and is one of the reasons why the atypical antipsychotics have largely replaced
conventional antipsychotic agents in the treatment of schizophrenia and other psychotic disorders
throughout the world.
Muscarinic cholinergic blocking properties of conventional antipsychotics
In addition to blocking D receptors in all dopamine pathways ( through ), conventional2 Figures 5-3 5-8
antipsychotics have other important pharmacologic
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Figure 5-9. . Shown here is an icon representing a conventional antipsychoticConventional antipsychotic
drug. Conventional antipsychotics have pharmacological properties in addition to dopamine D antagonism. The2
receptor profiles differ for each agent, contributing to divergent side-effect profiles. However, some important
characteristics that multiple agents share are the ability to block muscarinic cholinergic receptors, histamine H1
receptors, and/or -adrenergic receptors.1
properties ( ). One particularly important pharmacologic action of some conventionalFigure 5-9
antipsychotics is their ability to block muscarinic M -cholinergic receptors ( through ).1 Figures 5-9 5-11
This can cause undesirable side effects such as dry mouth, blurred vision, constipation, and
cognitive blunting ( ). Differing degrees of muscarinic cholinergic blockade may alsoFigure 5-10
explain why some conventional antipsychotics have a lesser propensity to produce extrapyramidal
side effects (EPS) than others. That is, those conventional antipsychotics that cause more EPS are
the agents that have only anticholinergic properties, whereas those conventional antipsychoticsweak
that cause fewer EPS are the agents that have anticholinergic properties.stronger
How does muscarinic cholinergic receptor blockade reduce the EPS caused by dopamine D2
receptor blockade in the nigrostriatal pathway? The reason seems to be based on the fact that
dopamine and acetylcholine have a reciprocal relationship with each other in the nigrostriatal
pathway ( ).
Figure 5-11
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Figure 5-10. . In this diagram, the icon of aSide effects of muscarinic cholinergic receptor blockade
conventional antipsychotic drug is shown with its M anticholinergic/antimuscarinic portion inserted into1
acetylcholine receptors, causing the side effects of constipation, blurred vision, dry mouth, and drowsiness.
Figure 5-11
A. . Dopamine and acetylcholine have a reciprocalReciprocal relationship of dopamine and acetylcholine
relationship in the nigrostriatal dopamine pathway. Dopamine neurons here make postsynaptic connections with
the dendrite of a cholinergic neuron. Normally, dopamine suppresses acetylcholine activity (no acetylcholine
being released from the cholinergic axon on the right).
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B. . This figure shows what happens to acetylcholine activityDopamine, acetylcholine, and D antagonism2
when dopamine receptors are blocked. As dopamine normally suppresses acetylcholine activity, removal of
dopamine inhibition causes an increase in acetylcholine activity. Thus if dopamine receptors are blocked at the
D receptors on the cholinergic dendrite on the left, then acetylcholine becomes overly active, with enhanced2
release of acetylcholine from the cholinergic axon on the right. This is associated with the production of
extrapyramidal symptoms (EPS). The pharmacological mechanism of EPS therefore seems to be a relative
dopamine deficiency and a relative acetylcholine excess.
C. . One compensation for the overactivity that occurs whenD antagonism and anticholinergic agents2
dopamine receptors are blocked is to block the acetylcholine receptors with an anticholinergic agent (M1
receptors being blocked by an anticholinergic on the far right). Thus, anticholinergics overcome excess
acetylcholine activity caused by removal of dopamine inhibition when dopamine receptors are blocked by
conventional antipsychotics. This also means that extrapyramidal symptoms (EPS) are reduced.
Dopamine neurons in the nigrostriatal dopamine pathway make postsynaptic connections with
cholinergic neurons ( ). Dopamine normally acetylcholine release fromFigure 5-11A inhibits
postsynaptic nigrostriatal cholinergic neurons, thus suppressing acetylcholine activity there (Figure
). If dopamine can no longer suppress acetylcholine release because dopamine receptors are5-11A
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being blocked by a conventional antipsychotic drug, then acetylcholine becomes overly active (
).Figure 5-11B
One compensation for this overactivity of acetylcholine is to block it with an anticholinergic agent (
). Thus, drugs with anticholinergic actions will diminish the excess acetylcholine activityFigure 5-11C
caused by removal of dopamine inhibition when dopamine receptors are blocked ( and Figures 5-10
). If anticholinergic properties are present in the same drug with D blocking properties, they5-11C 2
will tend to mitigate the effects of D blockade in the nigrostriatal dopamine pathway. Thus,2
conventional antipsychotics with potent anticholinergic properties have lower EPS than conventional
antipsychotics with weak anticholinergic properties. Furthermore, the effects of D blockade in the2
nigrostriatal system can be mitigated by co-administering an agent with anticholinergic properties.
This has led to the common strategy of giving anticholinergic agents along with conventional
antipsychotics in order to reduce EPS. Unfortunately, this concomitant use of anticholinergic agents
does not lessen the ability of the conventional antipsychotics to cause tardive dyskinesia. It also
causes the well-known side effects associated with anticholinergic agents, such as dry mouth,
blurred vision, constipation, urinary retention, and cognitive dysfunction ( ).Figure 5-10
Other pharmacologic properties of conventional antipsychotic drugs
Still other pharmacologic actions are associated with the conventional antipsychotic drugs. These
include generally undesired blockade of histamine H receptors ( ) causing weight gain and1 Figure 5-9
drowsiness, as well as blockade of -adrenergic receptors causing cardiovascular side effects such1
as orthostatic hypotension and drowsiness. Conventional antipsychotic agents differ in terms of their
ability to block these various receptors represented in . For example, the popularFigure 5-9
conventional antipsychotic haloperidol has relatively little anticholinergic or antihistaminic binding
activity, whereas the classic conventional antipsychotic chlorpromazine has potent anticholinergic
and antihistaminic binding. Because of this, conventional antipsychotics differ somewhat in their
side-effect profiles, even if they do not differ overall in their therapeutic profiles. That is, some
conventional antipsychotics are more sedating than others, some have more ability to cause
cardiovascular side effects than others, some have more ability to cause EPS than others.
A somewhat old-fashioned way to subclassify conventional antipsychotics is “low potency” versus
“high potency” ( ). In general, as the name implies, low-potency agents require higher dosesTable 5-1
than high-potency agents, but, in addition, low-potency agents tend to have more of the additional
properties discussed here than do the so-called high-potency agents: namely, low-potency agents
have greater anticholinergic, antihistaminic, and antagonist properties than high-potency agents,1
and thus are probably more sedating in general. A number of conventional antipsychotics are
available in long-acting depot formulations ( ).Table 5-1
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Generalized Anxiety Disorder
Middle-Aged White Male With Anxiety
Decision Point One
Begin Zoloft 50 mg orally daily
RESULTS OF DECISION POINT ONE
·
Client returns to clinic in four weeks
· Client informs you that he has no tightness in chest, or shortness of breath
· Client states that he noticed decreased worries about work over the past 4 or 5 days
· HAM-A score has decreased to 18 (partial response)
Select what the PMHNP should do next:
Increase dose to 75 mg orally daily
Increase dose to 100 mg orally daily
No change in drug/dose at this time
Generalized Anxiety Disorder
Middle-Aged White Male With Anxiety
Decision Point One
Begin Tofranil (imipramine) 25 mg orally BID
RESULTS OF DECISION POINT ONE
· Client returns to clinic in four weeks
· Client reports a “slight” decrease in symptoms
· Client’s states that he no longer gets chest tightness, but still has occasional episodes of shortness of breath
· HAM-A score decreased from 26 to 22
Decision Point Two
Select what the PMHNP should do next:
Decision Point Two
Select what the PMHNP should do next:
Increase Tofranil to 50 mg orally BID
Continue current dose and reassess in 4 weeks
Add an augmentation agent such as BuSpar (buspirone) 5 mg orally TID
Generalized Anxiety Disorder
Middle-Aged White Male With Anxiety
Decision Point One
Begin Buspirone 10 mg orally BID
RESULTS OF DECISION POINT ONE
· Client returns to clinic in four weeks
· Client reports slight decrease in symptoms
· Client states that he still feels very anxious
· HAM-A score decreased from 26 to 23
· Decision Point Two
· Select what the PMHNP should do next:
·
· Increase buspirone to 10 mg orally TID
·
· Increase buspirone to 20 mg orally TID
·
· Discontinue buspirone and begin Lexapro 10 mg orally daily
·
