Memantine Augmentation in Obsessive-Compulsive Disorder: A Systematic Review and Meta-analysis

Obsessive-compulsive disorder (OCD) remains challenging to treat despite established treatments.

Since glutamatergic dysregulation is implicated in OCD, we systematically reviewed and meta-analysed randomized controlled trials (RCTs) comparing adjunctive memantine versus placebo for OCD.

We searched CENTRAL, Embase, MEDLINE, PsycINFO, PubMed, Web of Science, Scopus, and trial registries from inception to September 2025 for RCTs of adjunctive memantine in adults with OCD [PROSPERO: CRD420251147106]. The primary outcome was endpoint Yale-Brown Obsessive Compulsive Scale score. Random-effects models used REML estimation with Hartung-Knapp-Sidik-Jonkman confidence intervals. Risk of bias was assessed with RoB 2 and certainty of evidence with GRADE.

Six RCTs (n = 288; 8-16 weeks; 5-20 mg/day) met inclusion criteria. Overall, memantine did not produce a statistically significant symptom reduction versus placebo (pooled mean difference -3.74 points, 95% confidence interval [CI] -9.95 to 2.47), with high heterogeneity (I² = 97.9%). Trials in treatment-resistant populations showed a larger but imprecise estimate (≈ -8.85 points), whereas non-resistant trials showed minimal added benefit (≈ -1.26 points); this subgroup observation was based on two RCTs, and meta-regression was underpowered and non-significant. Responder outcomes favored memantine but were statistically unstable (risk ratio [RR] 3.62, 95% CI 0.16-80.71). Tolerability outcomes did not identify clear excess adverse events, excess discontinuations for adverse events, or higher all-cause discontinuation (RR 1.04, 95% CI 0.82-1.31).

Memantine is not supported for routine use in unselected OCD. In treatment-resistant OCD, current evidence supports a hypothesis-generating signal that may justify cautious off-label discussion when established augmenters are unsuitable. An adequately powered RCT in refractory OCD is warranted.