Ondansetron augmentation for obsessive-compulsive disorder: A systematic review and meta-analysis of randomized placebo-controlled trials

Clinical Snapshot

Key Findings

• P Value: Not explicitly reported but CI excludes null

• Effect Size: Mean difference 5.53 points improvement vs placebo

• Primary Outcome: Y-BOCS total score improvement at week 8 (primary endpoint)

• Nnt Or Sensitivity: Effect size represents clinically meaningful improvement (>3 points on Y-BOCS considered clinically significant)

• Confidence Interval: 95% CI 3.45-7.60

Clinical Application

Limited by off-label use, QT prolongation monitoring requirements, and lack of established dosing protocols Ondansetron available on PBS for chemotherapy-induced nausea but off-label use for OCD would require specialist justification. TGA safety considerations for QT prolongation relevant. RACGP guidelines do not currently include ondansetron for OCD treatment Adults with treatment-resistant OCD already on optimized first-line therapy (SRIs and/or CBT with ERP)

Abstract

BACKGROUND: A substantial proportion of adults with obsessive-compulsive disorder (OCD) experience persistent symptoms despite optimized first-line treatment with exposure and response prevention and/or serotonin reuptake inhibitors (SRIs). Ondansetron, a selective 5-hydroxytryptamine-3 (5-HT3) receptor antagonist with plausible circuit-level relevance to cortico-striato-thalamo-cortical dysfunction, has been evaluated as an augmentation strategy. Still, evidence is dispersed across small randomized trials. METHODS: We conducted a PRISMA 2020-adherent systematic review and random-effects meta-analysis (PROSPERO: CRD420261302132). Embase (Ovid and Embase.com), MEDLINE, PubMed, and Scopus were searched from inception to 12 February 2026. Eligible studies were randomized, double-blind, placebo-controlled trials of oral ondansetron augmentation in adults (≥ 18 years) with OCD on stable background treatment. The primary outcome was change in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) total score, pooled at prespecified acute windows (week 4, ~week 8 primary, week 12). Secondary outcomes included Y-BOCS obsession and compulsion subscales. Risk of bias was assessed using RoB 2. Random-effects models (DerSimonian-Laird) were used; Wan's method was applied when required. RESULTS: Five trials (total N = 289) were included. Ondansetron augmentation was associated with greater improvement in Y-BOCS total score versus placebo at week 4 (MD 2.63; 95% CI 0.87-4.39; I²=62%); heterogeneity resolved after excluding one influential study (MD 1.94; 0.37-3.51; I²=0%). At week 8 (four trials; N = 244), benefit was larger (MD 5.53; 3.45-7.60; I²=48%) and remained robust in sensitivity analysis (MD 6.76; 5.81-7.71; I²=0%). At week 12 (three trials; N = 200), effects persisted (MD 6.41; 4.28-8.53; I²=55%) with reduced heterogeneity after excluding one study (MD 5.06; 2.82-7.30; I²=0%). In two trials reporting subscales (N = 214), obsessions improved at weeks 4 and 8 (overall MD 2.67; 1.66-3.67; I²=0%), while compulsions showed a smaller, later signal (overall MD 1.02; 0.19-1.86; I²=0%). Safety reporting was variably detailed across trials; known QT-prolongation considerations remain relevant for off-label use. CONCLUSIONS: In randomized, placebo-controlled trials, ondansetron augmentation was associated with greater improvement in clinician-rated OCD severity than placebo over short-term follow-up, with signals emerging by week 4 and persisting through 8-12 weeks. However, these findings should be interpreted cautiously because the evidence base is small, geographically concentrated, and partly influenced by individual studies. The current evidence should therefore be considered preliminary and hypothesis-generating rather than definitive. Larger multicenter trials with standardized background SRI optimization, preregistered outcomes, and rigorous safety monitoring are required before routine clinical adoption can be considered.

References

1. 1.Mohammad, A., Ibrahim, M., Khan, A. M., Pervaiz, U., Aijaz, S., Nasrullah, M. H., & Jamil, H. (2026). Ondansetron augmentation for obsessive-compulsive disorder: A systematic review and meta-analysis of randomized placebo-controlled trials. European Journal of Clinical Pharmacology. https://doi.org/10.1016/S0924-977X(99)00030-9