paroxetine levels (P 0.036), higher venlafaxine levels (P B0.0005), lower O-desmethylvenlafaxine levels (P 0.017) and higher combined venlafaxine O-desmethylvenlafaxine levels (P 0.007) compared to patients with normal alleles. In contrast with these findings, the allele frequen- cies of the individual polymorphisms are almost identical (data not shown) in the responders and non-responders both for the paroxetine group and the venlafaxine group. Pearson chi-square statistics show no significant differences when comparing venlafaxine and paroxetine response in patients with at least one reduced activity CYP2D6 allele versus patients with normal alleles (see Table I). Additionally, no significant differences could be found comparing response in patients with two reduced activity CYP2D6 alleles versus patients with normal alleles. In the studied population, these Pearson chi-square tests have a post-hoc power to detect an effect size w 0.5 of 0.84. Discussion This is the first study assessing the direct impact of CYP2D6 polymorphisms on pharmacological treat- ment outcome in OCD. Because CYP2D6 duplica- tions (resulting in ultra-rapid metabolizers) and the non-tested CYP2D6 polymorphisms are too un- common to be studied in a population of 91 patients, these polymorphisms were not analyzed. Because patient subgroups based on individual genotypes are too small to perform useful statistical tests in the studied population, the patients were divided in groups with no, at least one or at least two reduced activity alleles. From the results, we conclude 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. Because of a previously reported lack of effect of paroxetine and venlafaxine blood levels on YBOCS response [4], it is expected that the CYP2D6 polymorphisms do not have a major influence on the response. This lack of relationship drug plasma levels and YBOCS response has also been reported for clomipramine, fluoxetine, fluvoxamine and sertraline [11]. On the other hand, a few studies report on a dose response relationship: A larger study observed higher venlafaxine blood levels in responders compared to non-responders, but found no evidence for a relationship between treat- ment outcome and blood levels of paroxetine [12]. Hollander et al reported that paroxetine doses of 40 and 60 mg/day (but not 20 mg/day) are effective in treating acute obsessive-compulsive disorder [13]. Yaryura-Tobias et al indicate that doses of venlafaxine SSRI response in OCD not influenced by CYP2D6 347 less than 225 mg/day are not effective in OCD [14]. Dose response studies of paroxetine and/or venlafax- ine in OCD treatment are scarce. The results in this study show additional evidence that blood concentra- tions are not a major factor in the response to venlafaxine and paroxetine treatment of OCD. Given the fact that venlafaxine and paroxetine are metabolized primarily by the CYP2D6 enzymes given the fact that the most common reduced activity alleles do not have a major effect on response and given the fact that other CYP2D6 polymorphisms are rare, previous and future studies on response to venlafaxine and paroxetine treatment in OCD are unlikely to be confounded by CYP2D6 polymorphisms. Key points . The four most common enzyme-activity redu- cing polymorphisms of the P450 CYP2D6 enzyme were determined in 91 outpatients with primary OCD. . Patients received dosages titrated upward to 300 mg/day of venlafaxine or 60 mg/day of paroxetine, using a fixed dosing schedule. . The investigated CYP2D6 polymorphisms are not a decisive factor in the response to treat- ment in spite of their highly significant effect on the blood levels of these medicines. Acknowledgement None. Statement of Interest The authors do not have any conflict of interest to report regarding this study. References [1] Goodman WK, Ward HE, Murphy TK. Biologic approaches to treatment-refractory obsessive-compulsive disorder. Psy- chiatr Ann 1998;/28(11):/641 9. [2] Denys D, Van Nieuwerburgh F, Deforce D, Westenberg HG. Prediction of response to paroxetine and venlafaxine by serotonin-related genes in obsessive-compulsive disorder in a randomized, double-blind trial. J Clin Psychiatry 2007;/ 68(5):/747 53. [3] Kirchheiner J, Brosen K, Dahl ML, Gram LF, Kasper S, Roots I, et al. Cyp2d6 and cyp2c19 genotype-based dose recommendations for antidepressants: A ﬁrst step towards subpopulation-speciﬁc dosages. Acta Psychiatr Scand 2001;/ 104(3):/173 92. [4] Denys D, van Megen HJGM, van der Wee N, Westenberg HGM. A double-blind switch study of paroxetine and venlafaxine in obsessive-compulsive disorder. J Clin Psychia- try 2004;/65(1):/37 43.