Case outcome: interim visit at six weeks

Before the results of his genetic testing are known, sertraline 100 mg/d is reinitiated because of his previous response to it; lorazepam (Ativan) 2 mg/d is also prescribed during the first few weeks

• – As a carrier of the L(A)/L(A) alleles for SCL6A4, this patient may be more likely to respond to SSRI treatment than individuals with the S or L(G) alleles

• – Of the SSRIs, sertraline has the most dopaminergic activity (it has some ability to block the DAT, especially at higher doses)

• – However, the DAT is minimally present in the prefrontal cortex; thus, sertraline may benefit his “psychiatric parkinsonism” due to possible deficiencies of DA in the striatum, but may not address his cognitive symptoms from possible deficiency of DA in the prefrontal cortext

Lithium was next chosen as an augmenting agent due to the frequency of recurrence of depressive episodes, but it was not tolerated (severe tremor) and was stopped after 10 days

• – Although this patient was not bipolar disordered, the cyclic nature of his MDEs suggested a rationale for mood stabilizer use

He experienced sufficient improvement in his mood after four weeks on sertraline (Zoloft) to allow hospital discharge after six weeks

If he continues to experience DA-related symptoms, and does not achieve remission, then the next step could be an augmentation with bupropion, a stimulant, or L-methylfolate

Case debrief

This patient suffers from recurrent MDD, which is now considered to be TRD

He had some previous treatment, but much was subtherapeutically delivered

Genetic testing was ordered; suggested where his neurobiological vulnerabilities might lie and also indicated which antidepressants might be the most helpful first

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

This may save weeks of non-response to agents unlikely to deliver good clinical effectiveness and also save weeks of depressive symptom suffering waiting for antidepressant effects to occur

In this case, the clinician chose to optimize the SSRI and the results were reasonable

If the goal is remission, or if this patient were to relapse, then use of an NDRI or L-methylfolate should be considered as these would also address the theoretically genetic vulnerabilities noticed in his testing

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 drugs 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 Long(A) promoter alleles, L(A)/L(A)

• – Compared to patients with the L allele, the S allele results in decreased SERT expression, decreased presynaptic serotonin reuptake, and higher synaptic serotonin availability results

• – Patients who possess the L allele are also tested for the A>G polymorphism within the L allele itself; compared to the L(A) allele, the L(G) variant allele results in decreased expression of the SERT, and a phenotype similar to that of the S allele

• – 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 much more slowly

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

  • This patient does not have either of these genotypes, but conversely has the Long(A) allele and likely has adequate SERTs to respond positively to SSRI treatment, hence an SSRI was ultimately chosen, albeit at higher doses

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 neuroleptic-induced weight gain

  • In summary, this finding is likely not important in our current patient as he is not psychotic and an antipsychotic agent was not chosen as an augmentation

  • This patient was Ins/Ins and if he were to become psychotically depressed, then he more likely might respond to antipsychotic therapy

  • He would also be at less risk for AAWG

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

• – 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 vulnerability to recurrent mood episodes or cycling in affective disorders

  • This patient has the G allele and likely is not genetically vulnerable to mood cycling and decompensations on the basis of the genotype alone

    • However, his history suggests many unipolar depressive episodes hinting that the cause of his cycling is not related to this allele, or that despite the finding of his G allele, to diminished cycling; he has other vulnerabilities that overwhelm the positives of his G allele

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 NE, and the Val allele more aggressively decreases DA 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

  • Interestingly, his SLC6A4 L(A) allele suggested this patient would be a good responder to an SSRI, but this COMT Val allele suggests the opposite

  • Again, depending on the vulnerabilities a patient inherits, genetic testing can still only make suggestions on how to improve treatment. It will likely not tell the clinician which vulnerability is the most egregious as far as depressive etiology is concerned. Some findings are inevitably contradictory

MTHFR: the patient is homozygous for the 677 T allele (677 T/T)

• – 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 contributing 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 T/T genotype have been associated with increased risk of schizophrenia, and particularly with negative and cognitive symptoms

  • In summary, the T allele allows for less L-methylfolate formation and less DA availability, which may contribute to depression

  • This patient possesses this vulnerability and treating with a dopaminergic agent or even L-methylfolate itself may be warranted

MTHFR–COMT methylation interaction

• – Decreased methylation of COMT, caused by decreased function with the MTHFR 677 T variant as discussed previously, 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 carries both of these genetic vulnerabilities, but does not have schizophrenia

  • He does exhibit marked vegetative depressive symptoms, psychomotor impairment, and cognitive dysfunction