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. Noradrenergic TCA
Patient evaluation on intake
55-year-old man is admitted to the psychiatric hospital because of MDD
Psychiatric history
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
Question
Based on this patient’s history and current symptom profile, testing of which of the following genes might be useful?
SLC6A4 (SERT)
SLC6A4 and COMT
SLC6A4, COMT, and MTHFR
SLC6A4, COMT, MTHFR, and voltage-dependent calcium channel L-type, alpha-1c subunit (CACNA1C)
SLC6A4, COMT, MTHFR, CACNA1C, and D2 receptor (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
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 heterozygous for T/C
The T allele may indicate individuals with depression who are more 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:
| Pathway | Gene | Protein | Result |
|---|---|---|---|
| Serotonin | SLC6A4 | SERT, also called serotonin reuptake pump, responsible for termination of serotonin action | S/S |
| Dopamine | DRD2 | D2 receptor, target of antipsychotic drugs, theoretically overactive in psychosis and underactive in Parkinson’s disease | (Ins/Ins) |
| COMT | Enzyme responsible for degradation of DA and NE | (158 Val/Val, 472 G/G) | |
| Glutamate | CACNA1C | Voltage-gated channel for calcium | (G/G) |
| Metabolism | MTHFR | Predominant enzyme that converts inactive folic acid to active folate | (T/C) |
Question
Based on this patient’s symptoms, history, and genetic testing results, which of the following would you prescribe?
Serotonergic antidepressant
Noradrenergic and/or dopaminergic antidepressant
Any antidepressant plus an atypical antipsychotic
Any antidepressant plus a stimulant
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
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
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