Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept

Abstract

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 anti-obsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n=15) with near-constant 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 (p<0.005) 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 (n=8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n=7). One-week post-infusion, 50% of those receiving ketamine (n=8) met criteria for treatment response (≥35% Y-BOCS reduction) vs 0% of those receiving placebo (n=7). 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.

Figures

Figure 1

Consort diagram showing flow of patients through the study. Enrollment, randomization, and completion of two treatment phases (n=15).

Figure 2

Change in obsessions over 1-week post-infusion type (ketamine or saline) by order of administration (first or second). Obsessions measured by the OCD-VAS scores for each infusion type (ketamine or saline) by order of administration (first or second) over 1 week. An OCD-VAS score of 10 represents constant, intrusive obsessions and 0 represents no obsessions. Dark lines represent patients given ketamine and dashed lines represent patients given saline. Square boxes depict phase 1 (filled square is ketamine first and open square is saline first) and circles depict phase 2 (filled circle is ketamine second and open circle is saline second). Error bars indicate SE. aCarryover effects of ketamine were assessed by comparing the baseline score of saline second with mean baseline of the other three groups (saline first, ketamine first, and ketamine second); these carryover effects were significant (see ‘Test of Carryover Effects' section). To examine data independent of carryover effect, only phase 1 data were analyzed: ketamine first (filled square) was compared with saline first (open square) at mid-infusion, 230 min, and day 7 post-infusion. *p<0.05; **p<0.005.

Figure 3

Side effects for phases 1 and 2 combined. Change in side-effects of (a) dissociation, CADSS, (b) positive psychotic symptoms, BPRS, and (c) mania, YMRS. Dark lines represent patients given ketamine (n=15) and dashed lines represent patients given saline (n=15). Each figure displays mean scores for each scale over time.