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The Role of Pharmacodynamic Genes in Generalized Anxiety Disorder Treatment

When choosing a medication to treat your patient’s generalized anxiety disorder (GAD), are you aware that there are several genetic biomarkers that may impact the response or tolerability of that drug? On the Genomind® Professional PGx Express™ test you’ll find several pharmacodynamic (PD) genes that impact medications commonly utilized in the treatment of GAD.

How Pharmacodynamic Gene Variation Affects Drug Response

Pharmacodynamics, often described as “what a drug does to the body”, is the study of the biochemical, physiologic, and molecular effects of drugs on the body. Genetic variations in PD genes could result in changes to these processes and thus affect tolerability and/or likelihood of response to drugs. The majority of pharmacogenetic studies of antidepressant medications have been carried out in major depressive disorder (MDD) while only a few reports exist for anxiety disorders. Let’s discuss a few examples of PD gene variations that could affect pharmacologic treatment options for GAD.

How the Serotonin Receptor Gene (HTR2A) Variant Affects Antidepressant Response

HTR2A Gene

  • Physiological Role: The serotonin receptor 2A gene, abbreviated HTR2A, encodes one of the serotonin receptor subtypes involved in mediating second messenger cascades.
  • Significance: Neurobiological data suggests that HTR2A plays an important role in antidepressant drug action. Variations in the HTR2A gene may influence antidepressant response.

Several studies in MDD have documented a role of this variant in treatment response to antidepressants. Falk Lohoff and colleagues (2013) hypothesized that this genetic polymorphism could predict treatment outcomes in 112 GAD patients treated with venlafaxine XR. The authors found that patients carrying the G allele at HTR2A were more likely to see an improvement in Hamilton Anxiety Scale (HAM-A) and Clinical Global Impression of Improvement (CGI-I) score at 6 months in comparison to patients with the A/A genotype. Interestingly, the pharmacogenetic effect was increasingly statistically significant as time progressed, with a mean HAM-A difference between the A/A group and the G/A + G/G group of 4.8 at 6 months. Lohoff and colleagues concluded that variants in the HTR2A gene may predict treatment outcomes to antidepressant drugs, independent of the underlying DSM-IV diagnostic category.

How the Serotonin Transporter Gene (SLC6A4) Variant Affects SSRI Drug Response

SLC6A4 GeneSLC6A4 Gene Variant

  • Physiological Role: The serotonin transporter gene, abbreviated SLC6A4, encodes for the protein responsible for the reuptake of serotonin from synapses. Variation in this gene leads to differential expression of serotonin transporters. 
  • Significance: Antidepressant activity of selective serotonin reuptake inhibitor (SSRI) medications is achieved through inhibition of this protein.

Distinct variations in SLC6A4 have been identified to impact the likelihood of response to and side effect risk with SSRIs due to altered transporter activity. In the example risk variant above, serotonin transporter expression is impaired. Individuals with these variations may have reduced reuptake of synaptic serotonin, and several studies of depressive disorders have shown that Caucasian individuals with risk variations may be more likely to have a poor response, and/or increased risk for adverse events during treatment with SSRI medications, as compared to individuals who do not possess these variants. 

It should be noted that a majority of these studies were done in major depressive disorder, however, comorbid anxiety was not an exclusionary criterion in many of these studies. While these results may not generalize to GAD, it should be recognized that nearly 50% of patients with GAD have comorbid major depressive disorder.

In Conclusion

These are just a few of the many pharmacodynamic genes that can influence drug response and tolerability in psychiatry. Having insight into an individual’s PD genes can offer a more personalized approach that takes into account both the clinical factors and the patient’s genetics.

The Genomind® Professional PGx Express™ test analyzes 13 additional PD genes that can provide further guidance when prescribing medications for several psychiatric diagnoses including major depressive disorder, generalized anxiety disorder, obsessive compulsive disorder, pain, drug dependency, bipolar disorder and schizophrenia.

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References

  1. Karczewski, KJ, Daneshjou R, Altman RB. Chapter 7: Pharmacogenomics. PLoS Comput Biol. 2012;8(12):e1002817.
  2. Lohoff, F.W., et al., Serotonin receptor 2A (HTR2A) gene polymorphism predicts treatment response to venlafaxine XR in generalized anxiety disorder. Pharmacogenomics J, 2013. 13(1): p. 21-6.
  3. Niitsu, T., et al., Pharmacogenetics in major depression: a comprehensive meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry, 2013. 45: p. 183-94.
  4. Porcelli S, Fabbri C, Serretti A. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. Eur Neuropsychopharmacol. 2012. 22(4):239-58.
  5. Abejuela HR, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Algorithm for Generalized Anxiety Disorder. Harv Rev Psychiatry. 2016 Jul-Aug;24(4):243-56.

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