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 antiobsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n ¼ 15) 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 (n ¼ 8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n ¼ 7). One-week post-infusion, 50% of those receiving ketamine (n ¼ 8) met criteria for treatment response (X35% Y-BOCS reduction) vs 0% of those receiving placebo (n ¼ 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.

853. Effect of a Novel NMDA Receptor Modulator, Rapastinel (formerly GLYX-13) in OCD: Proof-Of-Concept

“…6 Specifically, rapastinel did not increase psychotomimetic effects following dosing in this sample of OCD patients, unlike ketamine in prior studies. 1,[3][4][5] In this small open-label sample, rapastinel had acute effects on obsessions and compulsions, anxiety and depression. However, rapastinel did not have significant effects on OCD symptoms one week post-infusion.…”

“…To have clinical utility, glutamate modulators should refine molecular targets for rapid and sustained action while minimizing side effects. Mechanistic preclinical data suggests drugs like rapastinel 17 and ketamine's metabolite hydroxynorketamine 1,8 that act on AMPA receptor modulation pathways may be promising therapeutic strategies.…”

Avances en el tratamiento farmacológico del trastorno obsesivo-compulsivo.

“…La ketamina, otro antagonista no competitivo de los receptores NMDA, administrada vía EV reduce significativamente los síntomas obsesivo-compulsivos en ausencia de ISRS, de acuerdo a un estudio controlado con placebo; la mejoría ocurre en minutos y se mantiene al menos 1 semana luego de la infusión (50). Asimismo, un reporte de caso sugiere que la ketamina es útil en TOC refractario y produce un efecto máximo a partir de los 30 min de iniciada la infusión (51).…”

Pharmacotherapy for obsessive-compulsive disorder (OCD): predicting response and moving beyond serotonin re-uptake inhibitors

“…One study [15] reported that there were more sexual, aggressive, and religious obsessions in responders of a memantine augmentation trial. Further support for the glutamatergic system playing a role in the development of OCD symptoms arises from studies showing the effectiveness of ketamine in rapidly reducing OCD symptoms [16]. The studies are too small to determine which participants respond to the treatment and which participants do not.…”