Patient’s genetic summary

In Table 28.2, findings in red suggest genetic vulnerabilities

Genes (a person’s genotype) code for proteins, i.e., receptors, enzymes, growth factors, and genetic regulators

Proteins allow neurocircuits to be active at optimal performance levels

Neurocircuits that are overactive or underactive likely lead to symptoms (a patient’s phenotype or the symptoms we detect during interviews)

Sometimes these inappropriately hyper- or hypofunctioning neurocircuits can be seen with functional neuroimaging techniques such as functional MRI (fMRI) or PET scans (called an endophenotype)

If a patient inherits enough of these subtle molecular vulnerabilities (gene mutations), then s/he could theoretically collect numerous abnormal proteins, develop abnormally functioning neurocircuits, and show different psychiatric symptoms that may coalesce into a syndrome or categorical DSM-5 diagnosis

Findings in black suggest neutral or protective genetic vulnerabilities in this patient

Table 28.2. Genetic vulnerabilities in a patient with MDD

Pathway		Gene		Comments		Patient Result
Serotonin		SLC6A4		Carriers of the Short(S) or L(G) alleles may be less likely to respond to SSRIs, or may respond more slowly, and may be more likely to experience adverse effects from SSRIs		L(A)/L(A)
Dopamine		DRD2		Del allele carriers (Del/Ins or Del/Del) may demonstrate less satisfactory antipsychotic drug response compared to Ins/Ins individuals		(Ins/Ins)
		COMT		Patients with the homozygous Val/Val genotype may be less likely to respond to SSRI treatments		(158 Val/Val, 472 G/G)
		Glutamate		CACNA1C		The A allele has been associated with elevated rates of mood disorder recurrence		(G/G)
		Metabolism		MTHFR		Presence of the 677 T allele (C/T or T/T) is associated with decreased MTHFR activity, leading to increased homocysteine and decreased methylation capacity		(T/T)
				MTHFR–COMT methylation interaction		Methylation pathways regulate the metabolism of neurotransmitters, particularly DA. In low methylation states, such as that caused by the MTHFR T allele, DA is degraded at a higher rate. This effect is exacerbated in patients who carry both the MTHFR 677 T allele and the high-activity COMT 158 Val/Val genotype		Patient has a gene–gene interaction noted

Posttest self-assessment question and answer

A 54-year-old patient has depression with prominent cognitive symptoms and also has the Val/Val genotype for catechol-O-methyltransferase (COMT). Based only on this genetic result, what treatment might be preferred for this patient?

A. SSRI

B. SNRI

C. NDRI

Answer: C

The Val allele, as in this case, codes for a protein (the enzyme COMT) that is now defective. COMT here is now overly active in degrading DA, thus depleting its availability in the synapse. This may lend to the possible etiology of MDD. Antidepressants that increase synaptic DA or dopaminergic neurotransmission may be the most likely to help. An NDRI is the most likely approved agent as it would be the most aggressive at DRI. Off-label stimulant use might be effective as well. Interestingly, the NETs in the frontal cortex also act as DATs. Therefore, the NRI half of the SNRI serves as DRI activity as well. The SSRIs, in general, have little impact on DRI except for minor effects associated with sertraline.

References

1.Arinami T, Gao M, Hamaguchi H, Toru M. A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum Mol Genet 1997; 6:577–82.

2.Baune B, Hohoff C, Berger K, et al. Association of the COMT val158met variant with antidepressant treatment response in major depression. Neuropsychopharmacology 2008; 33:924–32.

3.Casamassima F, Huang J, Fava M, et al. Phenotypic effects of a bipolar liability gene among individuals with major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 2010; 153B:303–9.

4.Ferreira MA, O’Donovan MC, Meng YA, et al. Wellcome Trust Case Control Consortium. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008; 40:1056–8.

5.Gelernter J, Cubells JF, Kidd JR, Pakstis AJ, Kidd KK. Population studies of polymorphisms of the serotonin transporter protein gene. Am J Med Genet 1999; 88:61–6.

6.Heils A, Teufel A, Petri S, et al. Allelic variation of human serotonin transporter gene expression. J Neurochemistry 1996; 66:2621–4.

7.Jönsson EG, Nothen M, Grunhage F, et al. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 1999; 4:290–6.

8.Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry 2010; 15:473–500.

9.Kirchheiner J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004; 9:442–73.

10.Kocabas NA, Faghel C, Barreto M, et al. The impact of catechol-O-methyltransferase SNPs and haplotypes on treatment response phenotypes in major depressive disorder: a case-control association study. Int Clin Psychopharmacol 2010; 25:218–27.

11.Popp J, Leucht S, Heres S, Steimer W. Serotonin transporter polymorphisms and side effects in antidepressant therapy – a pilot study. Pharmacogenetics 2006; 7:159–66.

12.Stahl SM. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide, 5th edn. New York, NY: Cambridge University Press, 2014.

13.Tsai SJ, Gau YT, Hong CJ, et al. Sexually dimorphic effect of catechol-O-methyltransferase val158met polymorphism on clinical response to fluoxetine in major depressive patients. J Affect Disord 2009; 113:183–7.

14.Zhang J-P, Lencz T, Malhotra AK. Dopamine D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis. Am J Psychiatry 2010; 167:763–72.

Patient file

The Case:

55-year-old with depression not responsive to serotonergic treatment

The Question (Pharmacogenetics, Part 2):

How might psychopharmacology be delivered in the future?

The Dilemma:

Can genotyping help predict successful treatment selection

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

MDD symptoms present for approximately five months

Admits to impaired concentration and a depressed mood with suicidal thoughts, insomnia, brooding, and feelings of guilt

This is his first MDE

He has had no psychotropic drug treatment prior to this hospitalization

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

He is diagnosed with single-episode MDD

First is treated as an inpatient with the NaSSA mirtazapine 45 mg/d but exhibits no response

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

• – CACNA1C, G>A rs1006737

  • 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 homozygous for (Ins/Ins)

  • May indicate individuals who are more likely to benefit from augmentation with an atypical antipsychotic in the event that they do not respond to an antidepressant (compared to those who carry the Del allele)

  • Ins/Ins alleles are good

• – MTHFR, 677 C>T

  • 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)