Abstract

Efficacy of Ketamine in Unmedicated Adults with Obsessive-Compulsive Disorder: A Randomized Controlled Trial

Rodriguez C, Chen C-M, Glover G, Jo B, Spielman D, Williams L, Van Roessel P, DeBattista C, Flood P, Ringold A, Wintermark M, Anderson K, Linkovski O, Lombardi A, Millen A, Pinto A, Raila H, Valentine K, Filippou-Frye M, Hawkins J, McCarthy E, Mukunda P, Varias A, Wilson J, Wright B
61st Annual Meeting of the American College of Neuropsychopharmacology. 2022.

Background: Developing novel, robust Obsessive Compulsive Disorder (OCD) treatments is an urgent public health need, given OCD typically starts in childhood, leads to lifelong morbidity, and costs the economy $2.1 billion (direct costs) and $6.2 billion (indirect costs such as lost productivity) annually. OCD is characterized by an inability to inhibit intrusive thoughts (obsessions) and repetitive behaviors (compulsions). Serotonin reuptake inhibitor (SRI) treatment of OCD exhibits a long lag time (2-3 months) before clinical benefit, and this benefit is typically only partial. Identifying effective, fast-acting treatments will help reduce OCD morbidity and its life effects. We previously reported the rapid OCD symptom reduction of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, versus saline infusions in a proof-of-concept crossover trial (n = 15) in unmedicated adults with OCD. Building on this initial finding, we evaluated the efficacy of ketamine in a larger group of unmedicated OCD patients with improved control conditions (active placebo control condition).

Methods: This was a randomized controlled trial of a single infusion of ketamine compared to an active placebo condition (midazolam, an anesthetic). With institutional review board approval, unmedicated adult patients (age 18-65) with OCD were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) in a 2:1 ratio (total n = 45). Participants met DSM-5 criteria for OCD with at least moderate symptoms (Yale-Brown Obsessive Compulsive Rating Scale score of at least 16). Exclusion criteria included severe depression (17-item Hamilton Depression Rating Scale was less or equal to 18 to enter the study) and comorbid psychiatric or medical conditions that made participation unsafe. The primary outcome was change in OCD severity 1 week after drug administration, as assessed by the Y-BOCS. Duration of effect was explored with weekly Y-BOCS up to 4 weeks post-infusion. We focused on estimating intention to treat effects based on longitudinal mixed effects modeling. For both moderator and mediator investigation, we employed the MacArthur approach embedded in mixed effects modeling.

Results: Regarding the primary outcome, the ketamine group had significantly greater improvement in Y-BOCS score than the midazolam group 1 week after treatment (Cohen’s d = 1.25, p < 0.001). The effects from a single intravenous infusion of ketamine persist up to 3 weeks post-infusion (Cohen’s d = 0.59, p = 0.007), gradually reducing each week and then becoming insignificant by Week 4. We examined age, sex, and race as potential moderators of treatment effects, although none were identified as significant moderators. We also examined change in dissociation as a potential mediator of treatment effect, although it did not turn out to be a significant mediator.

Conclusions: To our knowledge, this is the largest clinical trial to date of ketamine in unmedicated OCD patients. Ketamine demonstrated rapid and durable OCD symptom improvement compared to the active control condition. By using an optimized active placebo design to control for nonspecific anesthetic effects, this study provides new supporting evidence for the specific OCD therapeutic effects of ketamine.