Case outcome: initial visit

No psychotherapy is offered

No prescription is issued

In considering the potential future of psychopharmacology, the patient has his saliva or cheek swab analyzed and is tested for risk genes for MDD

His results came back as listed in Table 28.1

Table 28.1. Risk genes for MDD

Pathway		Gene		Protein		Result
Serotonin		SLC6A4		SERT, also called serotonin reuptake pump, responsible for termination of serotonin action		L(A)/L(A)
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/T)

Question

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

Serotonergic antidepressant

Dopaminergic antidepressant

Any antidepressant plus an atypical antipsychotic

Any antidepressant plus a stimulant

A prodopaminergic antidepressant plus L-methylfolate

ECT

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

Carrying both the COMT 158 Val/Val and the MTHFR 677 T/T genotype theoretically could result in increased degradation of DA in the prefrontal cortex, leading to decreased DA signaling there and associated cognitive dysfunction

Theoretically, it is plausible that the effect of the COMT Val allele on DA neurotransmission, which is further enhanced by the epistatic genetic interaction with the MTHFR T allele, could be a central explanation for the severe cognitive impairments of this patient, particularly with regard to his executive functions (“prefrontal dopamine” hypothesis)

• – This patient cannot synthesize as much DA for later use (MTHFR T allele)

• – This patient breaks down DA at a higher rate (COMT 158 Val/Val allele)

• – The net effect is less globally available DA in the CNS

In addition, these genotypes might also be a good theoretical explanation for the “psychiatric parkinsonism” symptoms: lack of drive and concentration, memory disorder, psychomotor retardation, slower thinking (bradyphrenia) and movement (bradykinesia)

• – The development of EPS in this patient on a rather low dose of risperidone (3 mg/d) is another sign of low DA function

• – The patient’s genetic test results suggest that although he could respond to a serotonergic antidepressant (despite having failed monotherapy), a prodopaminergic drug might best address his symptoms as his “psychiatric parkinsonism” features might reflect poor dopaminergic clinical functioning

• – Prodopaminergic options include NDRI, MAOI, and possibly augmentation with a stimulant or wakefulness-promoting agent

The patient’s genetic test results might also suggest that he should not receive augmentation with an antipsychotic, as these agents are DA antagonists and he may not tolerate these very well, and thus potentially exhibit further EPS or cognitive decline

To compensate the decreased capacity to convert folic acid to methylfolate (MTHFR: 677 T/T), L-methylfolate (Deplin) might be a beneficial augmentation strategy

• – L-methylfolate (Deplin) is approved as a medical food capable of boosting antidepressant effectiveness