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)

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

• – 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

  • In this particular case, a noradrenergic TCA was chosen first, given the genetic findings, suggesting avoidance of the SSRI class

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

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