Neuropsychopharmacology (2013) 38, 2475–2483

Carolyn I Rodriguez*,1,2, Lawrence S Kegeles1,2, Amanda Levinson2, Tianshu Feng1,2, Sue M Marcus1,2,3, Donna Vermes1,2, Pamela Flood4 and Helen B Simpson1,2

1New York State Psychiatric Institute, New York, NY, USA; 2Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY, USA; 3Department of Biostatistics, Columbia University, Mailman School of Public Health, New York, NY, USA; 4Department of Anesthesia, University of California at San Francisco, San Francisco, CA, USA

Summary

Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2–3 months lag time before clinically meaningful improvement. New medications with faster onset are needed. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid antiobsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n¼15) with nearconstant obsessions received two 40-min intravenous infusions, one of saline and one of ketamine (0.5 mg/kg), spaced at least 1-week apart. The OCD visual analog scale (OCD-VAS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were used to assess OCD symptoms. Unexpectedly, ketamine’s effects within the crossover design showed significant (po0.005) carryover effects (ie, lasting longer than 1 week). As a result, only the first-phase data were used in additional analyses. Specifically, those receiving ketamine (n¼8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n¼7). One-week post-infusion, 50% of those receiving ketamine (n¼8) met criteria for treatment response (X35% Y-BOCS reduction) vs 0% of those receiving placebo (n¼7). Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at least 1 week in some OCD patients with constant intrusive thoughts. This is the first randomized, controlled trial to demonstrate that a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI and is consistent with a glutamatergic hypothesis of OCD.

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