Double-Blind, Placebo-Controlled Trial of Topiramate Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder

Background: From 40% to 60% of obsessive-compulsive disorder (OCD) patients fail to tolerate or respond to selective serotonin reuptake inhibitors (SSRIs). Preclinical and neuroimaging studies have shown abnormally high glutamatergic concentrations in OCD patients and an association between decreased caudate glutamatergic concentrations and reduced OCD symptom severity after SSRI treatment. Topiramate inhibits glutamatergic conduction.

Method: Thirty-six adult patients with DSM-IV-defined OCD were randomly assigned to topiramate (n = 18) and placebo (n = 18) groups in this 12-week, double-blind, placebo-controlled, parallel-groups trial. Subjects were taking the maximum SSRI dose they could tolerate for at least 12 weeks and their current dose for at least 6 weeks, which was maintained throughout the study. Primary outcome measures were changes in the Yale-Brown Obsessive Compulsive Scale (YBOCS) total score and compulsions and obsessions subscores. Patients were recruited and followed up between April 1, 2003, and April 13, 2006.

Results: Using mixed regression models (time [weeks] ×— treatment), we found a significant treatment effect on the YBOCS compulsions (P = .014) subscale, but not the obsessions (P = .99) subscale or the total score (P = .11). Over the 12-week trial, the topiramate group (mean endpoint dose = 177.8 ± 134.2 mg/d; range, 50-400 mg/d) showed an average linear decrease of 5.38 points on the compulsions subscale compared to 0.6 points in the placebo group. Thirteen topiramate and 14 placebo subjects completed the study. Topiramate was not well tolerated in this trial: 28% (5/18) of the subjects discontinued the drug for adverse effects, and 39% (7/18) had a dose reduction for this reason.

Conclusions: The results of this first double-blind, placebo-controlled trial of topiramate augmentation for treatment-resistant OCD suggest that topiramate may be beneficial for compulsions, but not obsessions. Modifications in glutamatergic function may be responsible, at least in part, for the improved response in compulsions seen with topiramate.

Trial Registration: clinicaltrials.gov Identifier: NCT00211744

J Clin Psychiatry

Submitted: April 6, 2009; accepted October 19, 2009.

Online ahead of print: August 10, 2010 (doi:10.4088/JCP.09m05266gre).

Corresponding author: Heather A. Berlin, PhD, Mount Sinai School of Medicine, One Gustave L. Levy Pl, Box 1230, New York, NY, 10029 ([email protected]).