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Serotonin Receptor 2A (HTR2A) Gene Polymorphism Predicts Treatment Response to Venlafaxine XR in Generalized Anxiety Disorder

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Serotonin Receptor 2A (HTR2A) Gene Polymorphism Predicts Treatment Response to Venlafaxine XR in Generalized Anxiety Disorder The Pharmacogenomics Journal (2013) 13, 21–26 & 2013 Macmillan Publishers Limited. All rights reserved 1470-269X/13 www.nature.com/tpj ORIGINAL ARTICLE Serotonin receptor 2A (HTR2A) gene polymorphism predicts treatment response to venlafaxine XR in generalized anxiety disorder FW Lohoff1,2, TD Aquino1, Generalized anxiety disorder (GAD) is a chronic psychiatric disorder with 2 2 significant morbidity and mortality. Antidepressant drugs are the preferred S Narasimhan , PK Multani , choice for treatment; however, treatment response is often variable. Several 1 1 B Etemad and K Rickels studies in major depression have implicated a role of the serotonin receptor gene (HTR2A) in treatment response to antidepressants. We tested the 1Mood & Anxiety Disorders Section, Department of Psychiatry, University of Pennsylvania School of hypothesis that the genetic polymorphism rs7997012 in the HTR2A gene Medicine, Philadelphia, PA, USA and predicts treatment outcome in GAD patients treated with venlafaxine XR. 2Department of Psychiatry, Psychiatric Treatment response was assessed in 156 patients that participated in a Pharmacogenetics Laboratory, Center for 6-month open-label clinical trial of venlafaxine XR for GAD. Primary analysis Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, included Hamilton Anxiety Scale (HAM-A) reduction at 6 months. Secondary PA, USA outcome measure was the Clinical Global Impression of Improvement (CGI-I) score at 6 months. Genotype and allele frequencies were compared between Correspondence: groups using w2 contingency analysis. The frequency of the G-allele differed Dr FW Lohoff, Department of Psychiatry, significantly between responders (70%) and nonresponders (56%) at Translational Research Laboratory, Center for Neurobiology and Behavior, University of 6 months (P ¼ 0.05) using the HAM-A scale as outcome measure. Similarly, Pennsylvania School of Medicine, 125 South using the CGI-I as outcome, the G-allele was significantly associated with 31st Street, Room 2213, Philadelphia, improvement (P ¼ 0.01). Assuming a dominant effect of the G-allele, PA 19104, USA. improvement differed significantly between groups (P ¼ 0.001, odds E-mail: [email protected] ratio ¼ 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. The Pharmacogenomics Journal (2013) 13, 21–26; doi:10.1038/tpj.2011.47; published online 18 October 2011 Keywords: pharmacogenetics; HTR2A; anxiety disorders; treatment response; venlafaxine; rs7997012 Introduction Generalized anxiety disorder (GAD) is a highly prevalent chronic psychiatric disorder with significant morbidity and mortality. Currently, antidepressant drugs are the preferred choice for acute and chronic treatment; however, Received 2 May 2011; revised 29 July 1–3 2011; accepted 8 September 2011; treatment response is often variable ranging from 40–70%, with some patients published online 18 October 2011 responding well to medications while others fail treatment. In general, only a HTR2A and antidepressant treatment response in GAD FW Lohoff et al 22 third of GAD patients achieve remission in the acute phase rs7997012 and antidepressant treatment response in MDD, of treatment,4,5 and those patients achieving an initial with similar effect sizes. response often suffer relapse.6,7 The underlying neurobiolo- In this study, we addressed the following question: does gical mechanisms of treatment response remain unknown, the HTR2A rs7997012 variant predict antidepressant treat- and currently all pharmacotherapy for GAD is essentially ment response in patients with anxiety disorders? We show determined on a ‘trial and error basis’. However, growing for the first time a pharmacogenetic effect of the HTR2A evidence suggests that genetic factors influence treatment rs7997012 variant in GAD, suggesting that pharmacogenetic response and tolerability to medication. The majority of effects cross diagnostic categories. Our data document that pharmacogenetic studies of antidepressant drugs have been individuals with the HTR2A rs7997012 SNP G-allele have carried out in populations with major depressive disorder better treatment outcome over time. (MDD)8 while only a few reports exist for anxiety disorders.9 Recent data indicate a potential role of the gene encoding the serotonin receptor 2A (HTR2A) and treatment response Subjects and methods to antidepressant drugs in MDD. Several small studies of various antidepressant drugs in various MDD samples have Patients for this study participated in an 18-month, one- been previously investigated for polymorphisms in the center, relapse prevention study that comprised three HTR2A gene and treatment response and/or adverse events treatment phases.15 A 6-month open-label venlafaxine XR (for review Kato and Serretti8). While some studies were (VEN) flexible-dose treatment phase (75–225 mg per day) positive others could not confirm previous results; however, (Phase I), a 6-month randomized, double-blind, placebo- new interest in the HTR2A gene was generated by recent controlled relapse phase (Phase II) and a final 6-month findings of pharmacogenetic studies using the large randomized, double-blind, placebo-controlled relapse phase STAR*D sample.10 McMahon et al.11 genotyped 68 candidate (Phase III). Pharmacogenetics analysis was carried out only genes in 1953 patients with MDD from the STAR*D trial who for patients from Phase I. Detailed methodology of the were moderately depressed and treated open-label with clinical trial is described elsewhere.15 Briefly, to be included citalopram for up to 12 weeks. The main finding was a in the study, subjects had to be 18 years or older and meet robust association between the rs7997012 single nucleotide the Diagnostic and Statistical Manual of Mental Disorders, polymorphism (SNP) in the HTR2A gene and treatment Fourth Edition (DSM-IV) criteria for GAD as determined by outcome.11 Since then, several other groups have indepen- the Structured Clinical Interview and a psychiatric evalua- dently replicated the finding (Table 1). Peters et al. (2009) tion. Patients had to have sufficient symptoms to require used the same sample and reconfirmed the association. anxiolytic drug therapy, including a score of X20 on the Lucae et al.12 confirmed an association of the rs7997012 SNP Hamilton Anxiety Scale (HAM-A) at screen and at baseline, and antidepressant treatment response in two samples of the and a score of X4 on the Clinical Global Impressions-Severity German origin. Horstmann et al.13 could also replicate the (CGI-S). Patients were also assessed with the 17-item Hamil- association of the rs7997012 SNP in a sample from Munich, ton Depression Scale (HAM-D). A HAM-D cutoff score of p18 but found stronger support for the HTR2A SNP rs17288723. was used to exclude more seriously depressed patients, and a Uher et al.14 could not confirm the rs7997012 SNP in the cutoff score of o2 on the suicide item of the HAM-D was used genome-based therapeutic drugs for depression sample; to exclude suicidal patients. Patient health was determined by however, they found several other SNPs (rs9316233, physical examination, medical history, and if necessary, rs7324218 and rs2224721) in the HTR2A gene associated laboratory tests and electrocardiogram. with treatment response to antidepressants. Taken together, Exclusion criteria were any current anxiety spectrum several studies document a role of the HTR2A variant DSM-IV diagnosis at the threshold but not sub-threshold Table 1 Positive pharmacogenetic studies of the HTR2A SNP rs7997012 Study Phenotype N Antidepressant Ethnicity Trial length Results OR OR dominant model treatment (weeks) GG+GA vs AA McMahon et al.10 MDD 1953 Citalopram Mixed 12 A/A ¼ 18% reduction 2.26 response *Unavailable (STAR*D) in risk for being nonresponder Peters et al.28 MDD 1953 Citalopram Mixed 12 A-allele associated 1.43 response *Unavailable (STAR*D) 1.52 remission Lucae et al.12 MDD (85%) 186 Various European 6 G-allele associated 1.31 remission 5.99 remission Bipolar (15%) with better outcome Horstmann et al.13 MDD 305 Various European 5 G-allele associated 1.57 remission 2.07 remission with better outcome Lohoff et al., GAD 112 Venlafaxine XR European 24 G-allele associated 1.50 response 3.35 response present study with better outcome 1.88 improvement 4.98 improvement Abbreviations: GAD, generalized anxiety disorder; MDD, major depressive disorder; OR, odds ratio; SNP, single nucleotide polymorphism. * Indicates trend since P value is slightly above 0.05. The Pharmacogenomics Journal HTR2A and antidepressant treatment response in GAD FW Lohoff et al 23 level, current or past history of bipolar disorder, schizo- using  2 contingency analysis. A two-tailed type I error phrenia, other psychotic disorders or dementia. An episode rate of 5% was chosen for the analysis. of major depression in the previous 6 months or depressive symptomatology at intake (HAM-D418), and substance abuse or dependence during the past 6 months were further Results exclusion criteria. Occasional recreational drug or alcohol
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