CLINICS 2012;67(4):335-340 CLINICAL SCIENCE DOI:10.6061/clinics/2012(04)06 Endophenotypes and serotonergic polymorphisms associated with treatment response in obsessive- compulsive disorder Fa´ bio M. Corregiari, Ma´ rcio Bernik, Quirino Cordeiro, Homero Vallada Hospital das Cl´ınicas da Faculdade de Medicina da Universidade de Sa˜ o Paulo, Instituto de Psiquiatria, S a˜o Paulo/SP, Brazil. OBJECTIVES: Approximately 40-60% of obsessive-compulsive disorder patients are nonresponsive to serotonin reuptake inhibitors. Genetic markers associated with treatment response remain largely unknown. We aimed (1) to investigate a possible association of serotonergic polymorphisms in obsessive-compulsive disorder patients and therapeutic response to selective serotonin reuptake inhibitors and (2) to examine the relationship between these polymorphisms and endocrine response to intravenous citalopram challenge in responders and non-responders to serotonin reuptake inhibitors and in healthy volunteers. METHODS: Patients with obsessive-compulsive disorder were classified as either responders or non-responders after long-term treatment with serotonin reuptake inhibitors, and both groups were compared with a control group of healthy volunteers. The investigated genetic markers were the G861C polymorphism of the serotonin receptor 1Db gene and the T102C and C516T polymorphisms of the serotonin receptor subtype 2A gene. RESULTS: The T allele of the serotonin receptor subtype 2A T102C polymorphism was more frequent among obsessive-compulsive disorder patients (responders and non-responders) than in the controls (p,0.01). The CC genotype of the serotonin receptor subtype 2A C516T polymorphism was more frequent among the non-responders than in the responders (p,0.01). The CC genotype of the serotonin receptor subtype 1Db G681C polymorphism was associated with higher cortisol and prolactin responses to citalopram (p,0.01 and p,0.001, respectively) and with a higher platelet-rich plasma serotonin concentration among the controls (p,0.05). However, this pattern was not observed in the non-responders with the same CC genotype after chronic treatment with serotonin reuptake inhibitors. This CC homozygosity was not observed in the responders. KEYWORDS: Pharmacogenetics; Serotonin Receptor Subtype 1Db; Serotonin Receptor Subtype 2A; Citalopram; Challenge Test. Corregiari FM, Bernik M, Cordeiro Q, Vallada H. Endophenotypes and serotonergic polymorphisms associated with treatment response in obsessive- compulsive disorder. Clinics. 2012;67(4):335-340. Received for publication on December 3, 2011; First review completed on December 12, 2011; Accepted for publication on December 15, 2011 E-mail: marcio.bernik@uol.com.br Tel.: 55 11 2661-6988 INTRODUCTION Despite the efficacy of serotonin reuptake inhibitors (SRIs) in treating obsessive-compulsive disorder (OCD) (1), 40-60% of these patients are unresponsive to treatment (2). Individual genetic differences may play a role in determin- ing both clinical responses to medications and adverse side effects. However, few genetic factors have been identified, and the mechanisms underlying clinical failure remain largely unknown (3). One way to assess the brain serotonergic system is through the identification of endophenotypes with a variety of tests, such as the neuroendocrine challenge test. In a Copyright 2012 CLINICS – This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non- commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. No potential conflict of interest was reported. previous study (4), our group reported that cortisol response to citalopram in OCD patients who are responsive to SRIs was comparable to the response of the control subjects who had no mental disorders. In contrast, OCD patients who were therapeutically unresponsive after several long-term SRI trials demonstrated a blunted cortisol response to citalopram. The goal of the present study was (1) to investigate whether there is an association of serotonergic polymorph- isms and treatment response to SRIs in OCD patients and (2) to examine the association between the selected polymorph- isms and endocrine responses to an acute intravenous (IV) citalopram challenge. SUBJECTS AND METHODS Samples Outpatients who met the DSM-IV5 diagnostic criteria for OCD and were between 18 and 65 years of age were classified according to their therapeutic response to long-term SRI 335