Case #29: The depressed man who thought he was out of options

The Case: The depressed man who thought he was out of options
The Question: Are some episodes of depression untreatable?
The Dilemma: What do you do when even ECT and MAOIs do not work?

The Case: 55-year-old with depression not responsive to serotonergic treatment
The Question: (Pharmacogenetics, Part 2): How might psychopharmacology be delivered in the future?
The Dilemma: Can genotyping help predict successful treatment selection

· Provide the case number in the subject line of the Discussion thread.

· List three questions you might ask the patient if he or she were in your office. Provide a rationale for why you might ask these questions.

· Identify people in the patient’s life you would need to speak to or get feedback from to further assess the patient’s situation. Include specific questions you might ask these people and why.

· Explain what physical exams and diagnostic tests would be appropriate for the patient and how the results would be used.

· List three differential diagnoses for the patient. Identify the one that you think is most likely and explain why.

· List two pharmacologic agents and their dosing that would be appropriate for the patient’s antidepressant therapy based on pharmacokinetics and pharmacodynamics. From a mechanism of action perspective, provide a rationale for why you might choose one agent over the other.

· For the drug therapy you select, identify any contraindications to use or alterations in dosing that may need to be considered based on the client’s ethnicity. Discuss why the contraindication/alteration you identify exists. That is, what would be problematic with the use of this drug in individuals of other ethnicities?

· If your assigned case includes “check points” (i.e., follow-up data at week 4, 8, 12, etc.), indicate any therapeutic changes that you might make based on the data provided.

· Explain “lessons learned” from this case study, including how you might apply this case to your own practice when providing care to patients with similar clinical presentations

 Case #29: The depressed man who thought he was out of options

The Case: The depressed man who thought he was out of options
The Question: Are some episodes of depression untreatable?
The Dilemma: What do you do when even ECT and MAOIs do not work?

The Case: 55-year-old wit

h depression not responsive to serotonergic

treatment 
The Question: (Pharmacogenetics, Part 2): How might psychopharmacology be delivered in the future? 
The Dilemma: Can genotyping help predict successful treatment selection

PATIENT FILE

The Case: 55-year-old wit treatment

The

Question

(Pharmacog

h depression not responsive to serotonergic

enetics, Part 2): How might psychopharmacology The Dilemma: Can genotyping help predict successful treatment selection

be delivered in the future?

Pretest self-assessment question (answer at the end of the case)

A 55-year-old patient with depression has the

S/S

genotype for the SERT gene (SLC6A4). Based only on this genetic result, what treatment might be preferred for this patient?

A. SSRI
B. SNRI
C. NoradrenergicTCA

Patient evaluation on intake

• 55-year-old man is admitted to the psychiatric

hospital

because of MDD

Psychiatric history

· MDD symptoms present for approximately five months

· Admits to impaired concentration and a depressed mood with suicidal

thoughts, insomnia, brooding, and feelings of guilt

· This is his first MDE

· He has had no psychotropic drug treatment prior to this hospitalization

Social and personal history

· Separated from spouse and has four sons

· Denies drug or alcohol misuse

Medical history

• Denies acute medical problems

Family history

• There is no family history of mental illness

Patient evaluation on initial visit

· He is diagnosed with single-episode MDD

· First is treated as an inpatient with the NaSSA mirtazapine 45 mg/d but

exhibits no response

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423

PATIENT FILE
Question

Based on this patient’s history and current symptom profile, testing of which of the following genes might be useful?

· SLC6A4(SERT)

· SLC6A4and

COMT

· SLC6A4,COMT,and

MTHFR

· SLC6A4,COMT,MTHFR,andvoltage-dependentcalciumchannelL-type,

alpha-1c subunit (CACNA1C)

· SLC6A4,COMT,MTHFR,CACNA1C,andD2receptor(DRD2)

Attending physician’s mental notes: initial evaluation

• Testing of any of these genes may provide information that could be considered in the management of this patient

· –  SLC6A4, 5HTTLPR Long(L)/Short(S) promoter insertion/deletion

(rs63749047) and L(A)/L(G) (rs25531) polymorphism

· This patient is homozygous (i.e., has two copies) for S/S

· May indicate individuals who are more likely to exhibit

unsatisfactory or no response to previous SSRI treatment or who

have developed treatment-emergent side effects on SSRIs

· S/S signifies bad alleles

· –  COMT, 158 Val>Met (472 G>A, rs4680)

· This patient is homozygous for (158 Val/Val,

472 G/G)

· May indicate individuals with depression who are more likely to

experience associated cognitive symptoms such as slowness
of information processing, difficulty with executive functioning, and problem solving

· Val/Val equates to bad alleles

· –  CACNA1C, G>A rs1006737

· This patient is homozygous for

(G/G)

· The A allele (not carried by this patient) may indicate individuals

with

mood disorders

who are more likely to experience frequent

relapses and recurrences

· G/G alleles are good

· –  DRD2, -141C insertion/deletion (rs1799732)

· This patient is homozygous for

(Ins/Ins)

· May indicate individuals who are more likely to benefit from

augmentation with an atypical antipsychotic in the event that they do not respond to an antidepressant (compared to those who carry the Del allele)

· Ins/Ins alleles are good

· –  MTHFR, 677 C>T

◦ This patient is heterozygous for T/C

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PATIENT FILE

· TheTallelemayindicateindividualswithdepressionwhoaremore likely to experience associated cognitive symptoms, especially in those who also express the Val variant of the COMT gene

· T/C equates to fair alleles (Remember T/T is the poorest allelic combination for risk for MDD)

Case outcome: initial visit

· No psychotherapy is offered

· No further prescription is issued

· In considering the potential future of psychopharmacology, the patient

has his saliva sample or cheek swab analyzed for five genes, with the following results:

Table 29.1. Risk genes in another patient with MDD

Pathway Serotonin

Dopamine

Glutamate

Metabolism

Gene Protein

SLC6A4 SERT, also called serotonin reuptake pump,

responsible for termination

of serotonin action

DRD2

D2 receptor, target of antipsychotic drugs,

theoretically overactive in psychosis and underactive in Parkinson’s disease

COMT Enzyme responsible for degradation of DA and NE

CACNA1C

Voltage-gated channel for

calcium
MTHFR Predominant enzyme that

converts inactive folic acid to active folate

Result

S/S
(Ins/Ins)

(158 Val/Val, 472 G/G)

(G/G)

(T/C)

Question

Based on this patient’s symptoms, history, and genetic testing results, which of the following would you prescribe?

• Serotonergicantidepressant
• Noradrenergicand/ordopaminergicantidepressant • Anyantidepressantplusanatypicalantipsychotic • Anyantidepressantplusastimulant

Attending physician’s mental notes: initial evaluation (continued)

• Carrying both the SLC6A4 S/S and the COMT Val/Val genotype theoretically would reduce this patient’s likelihood of responding to an SSRI; thus, choosing an agent with predominantly noradrenergic and/or dopaminergic properties may be preferable
– Consider an NDRI like bupropion-XL (Wellbutrin-XL)

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425

PATIENT FILE

– Consider a TCA with greater NRI potential like desipramine (Norpramin), nortriptyline (Pamelor), or protriptyline (Vivactil)

• Theoretically, it is plausible that the effect of the COMT Val allele on DA neurotransmission, possibly combined with the effect of the MTHFR T allele, could be a central explanation for the severe cognitive impairments of this patient, particularly with regard to his executive dysfunction (“prefrontal dopamine” hypothesis)

– This finding might further support adding antidepressant agents or augmentation strategies with more robust dopaminergic mechanisms of action

Case outcome: interim visit at four weeks

· He is switched to the TCA, nortriptyline (Pamelor), 200 mg/d

· This is considered a high dose, but his serum levels were previously

lower while taking usual doses, so that this dose was required for his levels to reach the therapeutic range of 50–150 mcg/ml

· –  Nortriptyline is chosen because, as a carrier of the S/S alleles for

SLC6A4, this patient may be less likely to respond to SSRI treatment than individuals with the L(A) alleles

◦ This way, a noradrenergic drug is used

· –  Being a carrier of the Val/Val allele for COMT also theoretically

suggests that he would be less likely to respond to an SSRI

· Quetiapine (Seroquel) is next chosen as an augmenting agent due to his

delusions of guilt

· –  50mg/d titrating to 100mg/d given at bedtime

· –  Being homozygous for the Ins allele for DRD2 could theoretically

suggest that he may respond better to atypical antipsychotic

augmentation in comparison to those individuals with the Del allele

· Lorazepam (Ativan) 2 mg/d is prescribed as needed for agitation or insomnia

· He experiences a good response to this regimen and is released from

hospital

· If his symptoms relapse, augmentation with

L-methylfolate

could be

considered as it would address his MTHFR solo T allele more directly

Case debrief

· This patient suffered from an index MDD episode with likely psychotic features

· He had no previous treatment, but his serious symptoms required inpatient hospitalization

· Genetic testing was ordered; suggested where his theoretical neurobiological vulnerabilities might lie and also indicated what antidepressant class (SSRI) might be the least helpful first and which class might be more helpful (TCA, antipsychotics)

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PATIENT FILE

· Instead of randomly choosing an antidepressant, or even choosing one based on clinical experience, preliminary genetic tests may allow the psychopharmacologist to choose more accurately the most promising agent for the patient to try first

· This may save weeks of non-response to unlikely agents

· This may deliver good clinical effectiveness and also save weeks of

depressive symptom suffering waiting for antidepressant effects to occur

Take-home points

· Genetic testing as a clinical tool is still in its infancy, but has the potential to inform treatment decisions

· Genotyping may be especially useful for patients who do not respond to or tolerate a drug as expected

· Caution is essential when adopting genetic testing into the selection of treatments in clinical practice

Two-minute tutorial

A short tutorial on the scientific background of this case

· SLC6A4: the patient is homozygous for the Short promoter alleles, S/S

· –  Compared to patients with the L allele, the S allele results in

decreased SERT expression, decreased presynaptic serotonin

reuptake, and higher synaptic serotonin

· –  Individuals with the S or L(G) alleles may be less likely to respond to

SSRI-based antidepressant therapy, may be more likely to experience adverse effects from SSRIs, and may respond to SSRI therapy more slowly

· –  In individuals with unsatisfactory response to SSRI therapy and who possess the Short(S) (or the L(G)) alleles, treatment with alternative (non-SSRI) antidepressant mechanisms may be considered

· –  Greater caution is recommended when initiating or discontinuing SSRI in individuals with the Short(S) (or L(G)) allele

· In summary, patients with the S allele or L(G) alleles have less SERT/reuptake pump availability, and therefore are less likely to respond to SSRI antidepressants

· This patient does have one of these genotypes and likely has inadequate SERTs, and will not respond clinically to SSRI treatment, hence SSRIs were not considered from the start!

· DRD2: the patient is homozygous for the -141C insertion allele (Ins/Ins)

· –  Insertion/deletions of -141C in the DRD2 promoter may influence

striatal DA binding and antipsychotic drug response

· –  Individuals who carry the Del allele (Del/Ins or Del/Del) demonstrate less satisfactory antipsychotic drug response compared to patients

with the homozygous Ins/Ins genotype

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427

PATIENT FILE

– Del allele carriers are also at higher risk of atypical antipsychotic- induced weight gain

· In summary, this finding is important in our current patient as he is psychotic, he carries the Ins allele, and has a good chance of responding to antipsychotics

· This might lead the clinician to use an atypical antipsychotic augmentation strategy earlier in care despite risks of movement or metabolic disorders

· CACNA1C: the patient is homozygous for the rs1006737 G allele (G/G)

· –  CACNA1C gene alterations may lead to calcium channel

disturbances, excess neuronal excitability, and excess glutamate

· –  These alterations may lead to increased depolarization of selective

limbic regions associated with mood and perception

· –  These dysregulated calcium channels may lead to paroxysmal

decompensations with increased risk of relapse in patients with

mood disorders

· –  The CACNA1C rs1006737 A allele has been associated with elevated

rates of mood disorder recurrence
◦ In summary, this finding might suggest less vulnerability to

recurrent mood episodes
◦ This patient has the G allele and likely is not genetically

vulnerable to mood cycling and frequent decompensation, thus

improving his long-term prognosis

· COMT: the patient is homozygous for the 158 Valine allele (158 Val/Val,

472 G/G)

· –  The COMT 158 Val allele is a high-activity allele, leading to increased

COMT activity

· –  The COMT enzyme is responsible for degrading DA, and the Val allele

has higher enzyme activity and thus decreases DA levels in the prefrontal cortex, which may lead to cognitive and working memory deficits where optimal DA levels and activity are needed

· –  Patients with the homozygous Val/Val genotype may be less likely to respond to SSRI treatments

· –  Individuals with cognitive symptoms who possess the COMT Val allele may theoretically benefit from agents that increase DA availability

· In summary, Val alleles allow for increased COMT activity, decreased DA availability, and resultant cognitive problems

· In this patient, he was exhibiting these symptoms, and choosing a DA-facilitating psychotropic may have been warranted

· Inthisparticularcase,anoradrenergicTCAwaschosenfirst,given the genetic findings, suggesting avoidance of the SSRI class

· This TCA might increase NE in the CNS despite COMT aggressively degrading it

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PATIENT FILE

· MTHFR: the patient is heterozygous for the 677 T/C allele (677 T/C)

· –  MTHFR is the predominant enzyme that converts inactive, peripheral

folic acid to a CNS-available and -active form of folate called

L-methylfolate

· –  The 677 T allele is associated with decreased MTHFR activity,

causing there to be less L-methylfolate in the CNS

· –  L-methylfolate is involved in the one-carbon cycle, which is required

in the making of monoamine neurotransmitters, and theoretically

may lower transmitter levels as a possible etiology in MDD

· –  The 677 T allele also may lead to increased homocysteine and

decreased methylation capacity that can increase expression of

COMT and lead to reduced DA

· –  Elevated homocysteine and the MTHFR 677 TT genotype have been

associated with increased risk of schizophrenia, and particularly with negative and cognitive symptoms

· In summary, this patient is heterozygous where he has only one T allele. This situation allows for slightly less L-methylfolate production and DA availability than normal, which may contribute to depression symptomatology

· This patient possesses this mild vulnerability and treating with a dopaminergic agent or even L-methylfolate (Deplin) itself may be warranted as an augmentation

·

MTHFR–COMT methylation interaction

· –  Decreased methylation of COMT, caused by decreased function with

the MTHFR 677 T variant, results in decreased DA signaling, and

may ultimately lead to cognitive impairments

· –  This effect is exacerbated in patients who carry both the MTHFR 677

T allele and the high-activity COMT 158 Val/Val genotype, with

increased cognitive impairment

· –  This effect has been demonstrated in schizophrenic patients but not

in healthy controls

· In summary, this patient might be susceptible to this gene–gene

interaction but he does not have schizophrenia

· He is psychotic, depressed, and has cognitive dysfunction,

which may be explained theoretically by this interaction

Patient’s genetic summary

· In Table 29.2, findings in red suggest genetic vulnerabilities

· Black findings may be genetically protective

· Genes (a person’s genotype) code for proteins, i.e., receptors, enzymes,

growth factors, and regulatory factors

· Proteins allow neurocircuits to be active at optimal performance levels

· Neurocircuits that are over- or underactive likely lead to symptoms (a

patient’s phenotype)

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429

PATIENT FILE

· Sometimes these inappropriately hyper- or hypofunctioning neurocircuits can be seen with functional neuroimaging techniques such as fMRI or PET scans (called an endophenotype)

· If a patient inherits enough of these subtle molecular vulnerabilities (gene mutations), then s/he will collect abnormal proteins, develop abnormally functioning neurocircuits, and show different psychiatric symptoms that may coalesce into a syndrome or categorical DSM-5 diagnosis

Table 29.2. Genetic vulnerabilities in another patient with MDD

Pathway Serotonin
Dopamine
Glutamate
Metabolism

Gene SLC6A4

DRD2
COMT
CACNA1C
MTHFR
MTHFR–COMT methylation interaction

Comments

Carriers of the Short(S) or L(G) alleles may be less likely to respond to SSRIs, or may respond more slowly, and may be more likely to experience adverse effects from SSRIs

Del allele carriers (Del/Ins or Del/Del) may demonstrate less satisfactory antipsychotic drug response compared to Ins/Ins individuals Patients with the homozygous Val/Val genotype may be less likely to respond to SSRI treatments

The A allele has been associated with elevated rates of mood disorder recurrence

Presence of the 677 T allele (C/T or T/T) is associated with decreased MTHFR activity, leading to increased homocysteine and decreased methylation capacity Methylation pathways regulate the metabolism of neurotransmitters, particularly DA. In low methylation states, such as that caused by the MTHFR T allele, DA is degraded at a higher rate. This effect is exacerbated in patients who carry both the MTHFR 677 T allele and the high-activity COMT 158 Val/Val genotype

Patient result

S/S
(Ins/Ins)
(158 Val/Val, 472 G/G)
(G/G)
(T/C)

This patient has a gene– gene interaction that may worsen symptoms

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PATIENT FILE

Posttest self-assessment question and answer

A 55-year-old patient with depression has the S/S genotype for the SERT gene (SLC6A4). Based only on this genetic result, what treatment might be preferred for this patient?

A. SSRI
B. SNRI
C. NoradrenergicTCA
Answer: C
Carriers of the Short(S) alleles for the SLC6A4 gene may be less likely to respond to SSRIs, or may respond more slowly, and may be more likely to experience adverse effects from SSRIs. Therefore, choosing an SSRI first may be fraught with inefficacy or intolerability, thus wasting time clinically while trying to obtain a treatment response. Choosing an SNRI would carry similar problems in that SNRIs have full serotonin reuptake inhibition (SRI) function as part of their dual mechanism of action. Choosing a noradrenergic TCA, would avoid this SRI mechanism and be a logical first treatment choice.

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PATIENT FILE

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