Patient’s genetic summary

In Table 29.2, findings in red suggest genetic vulnerabilities

Black findings may be genetically protective

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

Proteins allow neurocircuits to be active at optimal performance levels

Neurocircuits that are over- or underactive likely lead to symptoms (a patient’s phenotype)

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

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

Table 29.2. Genetic vulnerabilities in another 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		S/S
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/C)
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		This patient has a gene–gene interaction that may worsen symptoms

Posttest self-assessment question and answer

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

Answer: C

Carriers of the Short(S) alleles for the SLC6A4 gene may be less likely to respond to SSRIs, or may respond more slowly, and may be more likely to experience adverse effects from SSRIs. Therefore, choosing an SSRI first may be fraught with inefficacy or intolerability, thus wasting time clinically while trying to obtain a treatment response. Choosing an SNRI would carry similar problems in that SNRIs have full serotonin reuptake inhibition (SRI) function as part of their dual mechanism of action. Choosing a noradrenergic TCA, would avoid this SRI mechanism and be a logical first treatment choice.

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:

23-year-old with first depression…that’s it!

The Question:

How might psychopharmacology be delivered in the future: neuropharmacogenetic imaging?

The Dilemma:

Can genotyping and functional neuroimaging help predict successful treatment selection

Pretest self-assessment question

A 23-year-old patient with her first depression has the S/S genotype for the SERT gene, the Del/Del alleles for the D2 receptor gene, the Val/Val alleles for the COMT gene, the T/T alleles for the MTHFR gene, and the A/A alleles for the CACNA1C gene. She also had a brain fMRI completed and it shows that her right insular cortex was hypoactive. Based only on these genetic results and neuroimaging findings, what treatment might be preferred for this patient?

A. SSRI

B. An atypical antipsychotic

C. Lithium

D. NDRI like bupropion

E. A noradrenergic TCA like desipramine

F. A mood stabilizer like lamotrigine

G. A folate-boosting product such as L-methylfolate

H. CBT

Patient evaluation on intake

23-year-old woman states that she feels “sad, down, and amotivated”

Admits to all MDD symptoms except for suicidality for the last two to three months

There was no psychosocial trigger and she reported that “life was going well”

Psychiatric history

There is no premorbid psychiatric history

This is her first MDE

There has been no prior psychotropic drug treatment before this hospitalization for suicidal thinking

There are no other comorbid psychiatric disorders present

Social and personal history

Graduated college with a business degree and has a good job as a manager in a local company

This job is going very well and with minimal stress

She is in a long-term relationship with a supportive boyfriend

There are no financial concerns

Her upbringing was relatively stress free and her parents are supportive

Denies any drug or alcohol misuse

Medical history

Denies acute medical problems

Takes no medications

Family history

There is no family history of psychiatric disorder

Patient evaluation on initial visit

She is diagnosed with single-episode MDD

Question

Based on this patient’s history and current symptom profile, testing of which of the following might be useful?

SLC6A4 (SERT) gene

COMT gene

MTHFR gene

Calcium channel, voltage-dependent L-type alpha, 1c subunit (CACNA1C) gene

D2 receptor gene (DRD2)

fMRI of the insular cortex

Attending physician’s mental notes: initial evaluation

This patient is asking for a precise answer as to what type of treatment will “help her the most, the fastest, and harm her the least”

• – All antidepressants are equal per regulatory agencies

• – Her genetic testing is daunting in that she has the bad alleles for every gene (see Table 30.1)

  • She is less likely to respond to SSRI and may have more side effects

  • Her high-activity COMT will degrade DA more completely

  • She may be vulnerable to more cognitive depressive symptoms

  • She is less likely to respond to atypical antipsychotic augmentation

  • She may experience many recurring depressive episodes

Testing of any of these genes may provide information that could be considered in the management of this patient

• – SLC6A4, 5HTTLPR

  • 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

• – COMT

  • 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

• – CACNA1C, G>A rs1006737

  • This patient is homozygous for (A/A)

  • The A allele may indicate individuals with mood disorders who are more likely to experience frequent relapses and recurrences

• – DRD2, -141C insertion/deletion (rs1799732)

  • This patient is homozygous for (Del/Del)

  • May indicate individuals who are less 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 Ins allele)

• – MTHFR, 677 C>T

  • This patient is heterozygous for T/T

  • 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

As this is her index depressive episode, treating her to remission quickly and avoiding relapses and recurrences is the primary goal, similar to an index episode of schizophrenia or mania

It seems that no medication is an ideal choice and genetic testing really has failed to guide prescribing toward a clear, concise choice of antidepressant

Testing via fMRI suggests depression exists when the DLPFC is hypoactive and the limbic system is hyperactive

• – This patient has this typical depression finding in her limbic area, which may help aid in diagnosis but does not help in treatment selection

• – This patient also has a novel finding that her right insular cortex is hypoactive

  • Initial studies suggest that this hypoactivity predicts a response to CBT but not SSRI

  • Alternatively, if hyperactivity were detected, then response to SSRI is favored and CBT would likely be ineffective