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		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

• – Consider an NDRI like bupropion-XL (Wellbutrin-XL)

• – 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