Efficacy of Dextromethorphan Augmentation in SSRI‐Resistant Obsessive–Compulsive Disorder: A Randomized Controlled Trial

ABSTRACT Background and Aims Obsessive–compulsive disorder (OCD) is a chronic condition associated with marked functional impairment and high rates of treatment resistance. Converging evidence implicates glutamatergic dysregulation in OCD pathophysiology. Dextromethorphan (DXM), an N‐methyl‐ d ‐aspartate (NMDA) receptor antagonist with additional monoaminergic and sigma‐1 receptor activity, may modulate this system. This study evaluated the safety and efficacy of DXM augmentation in adults with moderate to severe OCD receiving stable SSRI treatment. Methods In this randomized, double‐blind, placebo‐controlled pilot trial 40 adults with moderate to severe OCD (Y‐BOCS > 16) and inadequate response to at least 12 weeks of adequate‐dose SSRI monotherapy were assigned to DXM (15 mg twice daily) or matched placebo, in addition to their ongoing SSRI, for 12 weeks. OCD symptom severity was assessed using the Yale–Brown Obsessive Compulsive Scale (Y‐BOCS) at baseline, week 4, and week 12. Repeated‐measures analysis of variance (ANOVA) was used to examine changes over time. The primary outcome was the time × group interaction in Y‐BOCS. Secondary outcomes were not assessed. Trial registration: IRCT20221227056943N1; Ethics approval: IR.ZUMS.REC.1401.236. Results Baseline demographic and clinical characteristics were similar between groups. The DXM group showed a significant reduction in Y‐BOCS scores from 26.55 ± 6.19 at baseline to 16.30 ± 6.94 at week 12, whereas the placebo group remained relatively unchanged. Repeated‐measures ANOVA revealed a significant group × time interaction ( p < 0.001, partial η ² = 0.662) and significant main effects of both group ( p = 0.042) and time ( p < 0.001). DXM was well tolerated with no side effects. No secondary outcomes were measured in this pilot study. Conclusion Dextromethorphan augmentation significantly reduced OCD symptom severity in patients with partial response to SSRIs, supporting its potential role as an adjunctive treatment. These findings warrant larger, longer‐term trials to confirm efficacy, determine optimal dosing, and clarify neurobiological mechanisms.