Prediction of Response to Paroxetine and Venlafaxine by Serotonin-Related Genes in Obsessive-Compulsive Disorder in a Randomized, Double-Blind Trial

Objective: Serotonin reuptake inhibitors (SRIs) are the most effective pharmacologic treatment currently available for patients with obsessive-compulsive disorder (OCD). Still, up to 40% to 60% of OCD patients do not respond to SRI treatment. The purpose of the present study was to determine whether polymorphisms of the serotonin transporter (5-HTT), 5-HT_1B, and 5-HT_2A receptor genes affect the efficacy of SRI treatment in OCD.

Method: 91 outpatients with OCD according to DSM-IV criteria consented to the study and were randomly assigned in a 12-week, double-blind trial to receive dosages titrated upward to 300 mg/day of venlafaxine or 60 mg/day of paroxetine. Primary efficacy was assessed by the change from baseline on the Yale-Brown Obsessive Compulsive Scale (YBOCS), and response was defined as a >= 25% reduction on the YBOCS. Responders and nonresponders were stratified according to 5-HTT, 5-HT_1B, and 5-HT_2A genotypes and differentiated in paroxetine- or venlafaxine-treated groups. The study was conducted from August 1998 to July 2002.

Results: In the whole group, 64% of responders carried the S/L genotype of the 5-HTTLPR polymorphism (chi² = 7.17, df = 2, p = .028). In the paroxetine-treated patients, the majority of responders carried the G/G genotype of the 5-HT_2A polymorphism (chi² = 8.66, df = 2, p = .013), whereas in the venlafaxine-treated patients, the majority of responders carried the S/L genotype of the 5-HTTLPR polymorphism (chi² = 9.72, df = 2, p = .008).

Conclusions: The results of this study suggest that response in venlafaxine-treated OCD patients is associated with the S/L genotype of the 5-HTTLPR polymorphism and in paroxetine-treated OCD patients with the G/G genotype of the 5-HT_2A polymorphism.