Original ArticlesTolcapone in obsessive-compulsive disorder: a randomized double-blind placebo-controlled crossover trialGrant, Jon E.a; Hook, Roxanneb; Valle, Stephaniea; Chesivoir, Evea; Chamberlain, Samuel R.b,,cAuthor Information aUniversity of Chicago, Department of Psychiatry and Behavioral Neuroscience, Chicago, Illinois, USA bDepartment of Psychiatry, University of Cambridge, Cambridge, UK cDepartment of Psychiatry, Faculty of Medicine, University of Southampton; and Southern Health NHS Foundation Trust, Southampton, UK. Received 1 March 2021 Accepted 26 April 2021 ClinicalTrials.gov Identifier: NCT03348930 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.intclinpsychopharm.com Correspondence to Jon E. Grant, JD, MD, MPH, Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Pritzker School of Medicine, 5841 S. Maryland Avenue, MC-3077, Chicago, IL 60637, USA, Tel: +773 834 1325; e-mail: [email protected] International Clinical Psychopharmacology: September 2021 - Volume 36 - Issue 5 - p 225-229 doi: 10.1097/YIC.0000000000000368 Buy SDC Metrics Abstract Despite the availability of evidence-based treatments for obsessive-compulsive disorder (OCD), not all patients experience sufficient benefit or are able to tolerate them. Tolcapone is a catechol-O-methyl-transferase (COMT) enzyme inhibitor that augments cortical dopaminergic transmission. Conduct a proof of concept study to examine whether a COMT inhibitor would reduce OCD symptoms to a greater extent than placebo. We conducted a randomized, placebo-controlled, double-blind crossover trial in adults with OCD (N = 20). Participants were assessed at baseline, after 2 weeks of tolcapone, and again after 2 weeks of placebo on measures of OCD symptom severity and psychosocial functioning. There was a 1-week washout period between the 2-week treatment phases. Two weeks of tolcapone was associated with significant improvement in OCD versus two weeks of placebo (t = 2.194, P = 0.0409). The mean percentage decreases in the total Yale–Brown obsessive-compulsive scale (YBOCS) scores for the entire sample over the corresponding 2-week period were 16.4% for tolcapone and 3.6% for placebo. These data indicate that brain penetrant COMT inhibitors merit further investigation as a candidate new treatment for OCD. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.