Memantine Augmentation: Not Ready for Prime Time

A meta-analysis pools six trials and finds mostly noise, with one hopeful subgroup

STUDY: Lyndon S et al, CNS Drugs 2026 Jul 22

STUDY TYPE: Systematic review and meta-analysis

FUNDING: Independent

Background

Roughly half of OCD patients don’t get adequate relief from first-line treatment with SSRIs and exposure therapy. Antipsychotic augmentation helps but brings metabolic baggage. Memantine, an NMDA receptor antagonist already approved for Alzheimer’s, targets a different pathway: glutamate signaling in the brain circuits thought to drive obsessions and compulsions. Earlier meta-analyses called it effective, but those pooled a small handful of mostly positive trials.

The Study

• Six double-blind, placebo-controlled trials, 288 adults with OCD total
• Adjunctive memantine (10 or 20 mg/day) versus placebo, added to an SSRI or clomipramine
• 8 to 16 weeks of treatment, with OCD severity (Y-BOCS) as the main outcome

Results

Overall, memantine didn’t beat placebo. The pooled difference in Y-BOCS scores was 3.74 points in memantine’s favor, but the confidence interval crossed zero (-9.95 to 2.47), and heterogeneity between trials was enormous.

That heterogeneity traced back to who was studied. In two trials that enrolled patients already resistant to adequate serotonergic treatment, memantine showed a much larger effect, roughly 9 points on the Y-BOCS. In the four trials that started patients on a new SSRI alongside memantine or placebo, the drug added almost nothing, about 1 point. The resistant-patient signal didn’t reach statistical significance, but that’s not surprising with only two trials behind it.

Response rates (at least 35% symptom reduction) numerically favored memantine, but the estimate was wildly unstable, with a risk ratio of 3.62 and a confidence interval spanning 0.16 to 80.71, essentially uninformative.

Side Effects

Tolerability looked good. Rates of any adverse event, discontinuation for adverse events, and all-cause dropout were similar between memantine and placebo. No one discontinued due to side effects across the four trials that reported it.

Limitations

Only six trials, all conducted in Iran, several in the same city. Treatment-resistance criteria varied across trials and weren’t always reported. Certainty of evidence was rated very low for the main efficacy outcomes.

Practice Implications

This isn’t a green light for using memantine broadly in OCD and starting it alongside a new SSRI adds nothing based on current data. But for patients who’ve already failed adequate SSRI or clomipramine trials plus exposure therapy, and for whom antipsychotic augmentation is unappealing or poorly tolerated, memantine remains a reasonable off-label conversation. If you try it, set a clear stop rule: check the Y-BOCS at 8 and 12 weeks, and discontinue if you don’t see meaningful improvement, since the tolerability is good but the evidence for benefit is still thin.