What is the recommended dose of memantine (N-methyl-D-aspartate (NMDA) receptor antagonist) for the treatment of Obsessive-Compulsive Disorder (OCD)?

Memantine Dosing for OCD

For treatment-resistant OCD, memantine should be dosed at 20 mg/day as augmentation to SSRI therapy, starting at 10 mg/day for the first week and then increasing to 20 mg/day for at least 8 weeks to assess efficacy. 1, 2

Clinical Context and Evidence Base

Memantine is a glutamatergic augmentation strategy specifically reserved for patients with treatment-resistant OCD who have failed adequate trials of SSRIs. 3 The guidelines from Nature Reviews Disease Primers indicate that memantine augmentation can be considered in clinical practice, as several trials have demonstrated efficacy in SSRI augmentation for treatment-resistant OCD. 3

Specific Dosing Protocol

The evidence-based dosing regimen is:

• Week 1: Start at 10 mg/day 2
• Week 2 onwards: Increase to 20 mg/day 1, 2
• Treatment duration: Minimum 8 weeks at target dose to assess response 1

This dosing schedule was used in the highest quality double-blind placebo-controlled trial, which showed that all patients in the memantine group achieved partial or complete response compared to only 32% in placebo. 2

Evidence Quality and Efficacy

The meta-analysis of eight studies involving 125 OCD patients showed a mean reduction of 11.73 points on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), with patients receiving memantine being 3.61 times more likely to respond than those receiving placebo. 1 However, there are important caveats to consider:

• Geographic limitation: The four RCTs in the meta-analysis all emerged from the same geographical area, limiting generalizability. 4
• Methodological concerns: Studies presented completer analyses rather than intention-to-treat analyses, which may overestimate benefits. 4
• Mixed recent evidence: A 2022 double-blind trial showed memantine improved executive function but did NOT show superiority over placebo for OCD symptom reduction. 5

Clinical Application

Memantine should be used as:

• An augmentation agent added to ongoing SSRI therapy (not monotherapy) 1, 2
• Specifically for moderate to severe OCD (Y-BOCS ≥21) 1, 2
• In patients who have failed adequate SSRI trials (at least 12 weeks at optimal dose) 6

Safety Profile

Memantine at 20 mg/day has demonstrated good tolerability with mild and transient side effects. 1, 2, 6 No major adverse effects were observed in clinical trials, and the frequency of side effects was not significantly different from placebo. 2

Important Caveats

Despite promising early evidence, the most recent high-quality trial (2022) failed to show symptom benefit, 5 and a critical analysis questions the validity of earlier positive findings due to methodological limitations. 4 Given this conflicting evidence, memantine augmentation should be considered a third-line option after:

1. Optimizing SSRI dose and duration 7
2. Switching to another SSRI or clomipramine 7
3. Antipsychotic augmentation (risperidone or aripiprazole) 3
4. N-acetylcysteine augmentation (which has the largest evidence base among glutamatergic agents) 3

The decision to use memantine should weigh the mixed evidence against the established safety profile, particularly in patients who have exhausted other augmentation strategies.