Efficacy of Dextromethorphan Augmentation in SSRI‐Resistant Obsessive–Compulsive Disorder: A Randomized Controlled Trial
Ahmad Zolghadriha, Afagh Anjomshoaa, Romina Bagheri
Health science reports May 1, 2026 DOI: 10.1002/hsr2.72055 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Pilot study Peer reviewed |
|---|---|
| Sample size | 40 |
| Population | Adults with moderate to severe obsessive-compulsive disorder (Y-BOCS > 16) and inadequate response to at least 12 weeks of adequate-dose SSRI monotherapy |
| Intervention | Dextromethorphan |
| Dose | 15 mg twice daily |
| Duration | 12 weeks |
| Measures | Yale-Brown Obsessive Compulsive Scale (Y-BOCS) |
| Key findings | Dextromethorphan augmentation reduced OCD symptom severity: Y-BOCS scores dropped from 26.55 at baseline to 16.30 at week 12, while placebo scores remained relatively unchanged, with a significant group-by-time interaction. The authors conclude that dextromethorphan may have potential as an adjunctive treatment, warranting larger, longer-term trials. |
Abstract
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.
Citations in the library
Cites 2
- Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials Expert Opinion on Emerging Drugs January 2, 2021
- Profiling the combination of bupropion and dextromethorphan as a treatment option for major depressive disorder. Expert Review of Neurotherapeutics September 1, 2024