International Journal of Psychiatry in Clinical Practice, 2009; 13: 345 348 SHORT REPORT Response to serotonin reuptake inhibitors in OCD is not influenced by common CYP2D6 polymorphisms FILIP C.W. VAN NIEUWERBURGH1, DAMIAAN A.J.P. DENYS2, HERMAN G.M. WESTENBERG3 & DIETER L.D. DEFORCE1 1Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium, 2AMC, University of Amsterdam, Amsterdam, The Netherlands, and 3UMC, University of Utrecht, Utrecht, The Netherlands Abstract The cornerstone of pharmacotherapy for OCD is serotonin reuptake inhibition, either with clomipramine or with selective serotonin reuptake inhibitors (SSRIs). In spite of the success of serotonin reuptake inhibiting drugs, nearly half of OCD patients do not respond to treatment. Treatment response may be affected by genetic polymorphisms of the P450 metabolic system. The four most common enzyme-activity reducing polymorphisms of the P450 CYP2D6 enzyme were determined in 91 outpatients with primary OCD according to DSM-IV criteria, receiving dosages titrated upward to 300 mg/day of venlafaxine or 60 mg/day of paroxetine, using a fixed dosing schedule. Our results show that the investigated CYP2D6 polymorphisms are not a decisive factor in the response to paroxetine and venlafaxine treatment in OCD in spite of their highly significant effect on the blood levels of these medicines. Key Words: Obsessive-compulsive disorder, OCD, CYP2D6, venlafaxine, paroxetine, polymorphisms, response, blood levels, plasma levels Introduction Serotonin reuptake inhibitors (SRIs) are the most effective pharmacological treatment currently avail- able for patients with obsessive-compulsive disorder (OCD). Still, up to 40 60% of OCD patients do not respond to SRI treatment [1]. We recently reported the pharmacogenetic effect of the 44-bp insertion/ deletion 5-HTTLPR polymorphism and the 5- HT2A 1438G/A polymorphism in serotonin-related genes on the efficacy of venlafaxine and paroxetine treatment of OCD [2]. Our findings suggest that these polymorphisms influence the pharmacody- namics of venlafaxine and paroxetine. Polymorph- isms in the P450 CYP2D6 enzyme are known to change the pharmacokinetics of venlafaxine and paroxetine [3]. In an effort to characterize whether this pharmacokinetic factor influences the response to paroxetine or venlafaxine treatment, we deter- mined four common polymorphisms of the P450 CYP2D6 enzyme in 91 OCD patients. We investi- gated the effect of the studied polymorphisms on the blood levels of paroxetine and (O-desmethyl)venla- faxine and on the response to paroxetine treatment or venlafaxine treatment. Methods Ninety-one outpatients gave written informed consent for participation in this study, which had been approved by the University of Utrecht Medical Ethical Review committee (Utrecht, The Nether- lands). The studied population is described in detail by Denys et al. [2]. Severity of obsessive-compulsive symptoms was rated with the Yale Brown Obsessive Compulsive Scale (YBOCS), depressive symptoms with the Hamilton Rating scale for Depression (HAM-D) and anxiety with the Hamilton Rating Scale for Anxiety (HAM-A). Only patients with a score of at least 18 on the YBOCS, or at least 12 if only obsessions or only compulsions were present, were included. Patients with a major depressive Correspondence: Professor Dieter Deforce, Laboratory of Pharmaceutical Biotechnology, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium. E-mail: dieter.deforce@ugent.be (Received 28 November 2008; accepted 17 March 2009) ISSN 1365-1501 print/ISSN 1471-1788 online # 2009 Informa UK Ltd. DOI: 10.3109/13651500902903016