Serotonin receptor 2A (HTR2A) gene polymorphism predicts treatment response to venlafaxine XR in generalized anxiety disorder

Abstract

Generalized anxiety disorder (GAD) is a chronic psychiatric disorder with significant morbidity and mortality. Antidepressant drugs are the preferred choice for treatment; however, treatment response is often variable. Several studies in major depression have implicated a role of the serotonin receptor gene (HTR2A) in treatment response to antidepressants. We tested the hypothesis that the genetic polymorphism rs7997012 in the HTR2A gene predicts treatment outcome in GAD patients treated with venlafaxine XR. Treatment response was assessed in 156 patients that participated in a 6-month open-label clinical trial of venlafaxine XR for GAD. Primary analysis included Hamilton Anxiety Scale (HAM-A) reduction at 6 months. Secondary outcome measure was the Clinical Global Impression of Improvement (CGI-I) score at 6 months. Genotype and allele frequencies were compared between groups using χ(2) contingency analysis. The frequency of the G-allele differed significantly between responders (70%) and nonresponders (56%) at 6 months (P=0.05) using the HAM-A scale as outcome measure. Similarly, using the CGI-I as outcome, the G-allele was significantly associated with improvement (P=0.01). Assuming a dominant effect of the G-allele, improvement differed significantly between groups (P=0.001, odds ratio=4.72). Similar trends were observed for remission although not statistically significant. We show for the first time a pharmacogenetic effect of the HTR2A rs7997012 variant in anxiety disorders, suggesting that pharmacogenetic effects cross diagnostic categories. Our data document that individuals with the HTR2A rs7997012 single nucleotide polymorphism G-allele have better treatment outcome over time. Future studies with larger sample sizes are necessary to further characterize this effect in treatment response to antidepressants in GAD.

PharmGKB summary

“…In the same cohort of 156 anxious patients, a trend of association was found for the HTR2A rs7997012 G allele with a difference in frequency between responders (70%) and nonresponders (56%) at 6 months ( P =0.05) using the HAM-A score as described above [55]. Furthermore, the G allele was associated with improvement using the CGI-I as the secondary outcome measure ( P =0.001, odds ratio=4.72) [55]. Treatment response in association with the functional variant rs6265 (Val66Met) in the BDNF gene was assessed in 111 of the European-American patients and no significant correlation was found [56].…”

“…However, a slight dominant effect of the A-allele (Met) compared with the G allele (Val) is shown when the CGI-I scale is used as secondary outcome measure [54]. In the same cohort of 156 anxious patients, a trend of association was found for the HTR2A rs7997012 G allele with a difference in frequency between responders (70%) and nonresponders (56%) at 6 months ( P =0.05) using the HAM-A score as described above [55]. Furthermore, the G allele was associated with improvement using the CGI-I as the secondary outcome measure ( P =0.001, odds ratio=4.72) [55].…”

Post-stroke depression and the aging brain

“…In addition, increased functional activity of the amygdala in response to negative stimuli appears to be a mood-congruent phenomenon that is likely moderated by the 5-HT transporter gene ( Slc6a4 ) promoter polymorphism ( 5-Httlpr ) [9]. Lohon and colleagues showed significant gene-gene interaction between Slc6a4 and 5-Httlpr /rs25531 in general anxiety disorder [83]. …”

Overview of pharmacogenomic testing in clinical practice

“…Another variant, rs7997012, was associated with increased antidepressant response in patients carrying a guanine polymorphism (odds ratio 1.92, 95% CI 1.02-3.61) although with wider confidence interval the signal is not as strong 14. Patients carrying the guanine polymorphism also demonstrated better response to and tolerability of venlafaxine in the treatment of generalized anxiety disorder 15. Better tolerability often leads to increased compliance, which is well known to be a challenge in treating the mental health population.…”