Effects of adjunctive memantine on executive function and global cognition in bipolar disorder (BD): A randomized, double-blind, placebo-controlled clinical trial.

Hasan Mirzazadeh; Erfan Sadeghi; Sara Mostafavi; Saghar Elmi; Reza Moshfeghinia; Somayyeh Rahimi

doi:10.1016/j.jad.2026.122309

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Effects of adjunctive memantine on executive function and global cognition in bipolar disorder (BD): A randomized, double-blind, placebo-controlled clinical trial.

Hasan Mirzazadeh·Erfan Sadeghi·Sara Mostafavi·Saghar Elmi·Reza Moshfeghinia·Somayyeh Rahimi

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BACKGROUND: Cognitive impairment contributes substantially to disability in bipolar disorder (BD), but effective pharmacologic options remain limited. This trial evaluated whether adjunctive memantine improves global cognition and executive function in BD. METHODS: In this double-blind, placebo-controlled randomized trial, patients with bipolar I disorder (B1D) receiving lithium and olanzapine were assigned to memantine or placebo. Memantine was titrated to 20 mg/day over 6 weeks. Cognitive outcomes were assessed at baseline, week 6, and week 18. Global cognition was measured with the Neurocognitive Assessment Battery (NuCog), and executive function with the Frontal Assessment Battery (FAB). Data were analyzed using generalized estimating equations and Bonferroni-adjusted post-hoc tests. RESULTS: Sixty-three participants were randomized (memantine, n = 31; placebo, n = 32), and all completed follow-up. Groups were comparable at baseline for demographic and clinical variables and for most cognitive measures. Both groups improved over time (P < 0.001), but improvement was greater with memantine for global cognition at week 6 (MD = 9.32; 95% CI, 4.84-13.81; P < 0.001) and week 18 (MD = 12.69; 95% CI, 8.67-16.71; P < 0.001). FAB total scores favored memantine at week 18 (MD = 2.68; 95% CI, 1.76-3.61; P < 0.001), but not at week 6. Domain analyses showed significant benefits for NuCog attention, visuoconstructional ability, memory, and executive function, and for several FAB subscales by week 18. CONCLUSIONS: Adjunctive memantine improved global cognition and, over longer follow-up, executive function in BD. These findings support NMDA receptor modulation as a potential strategy for cognitive dysfunction in BD.

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Hasan Mirzazadeh, Erfan Sadeghi, Sara Mostafavi, Saghar Elmi, Reza Moshfeghinia, Somayyeh Rahimi. 2026-07-24. Effects of adjunctive memantine on executive function and global cognition in bipolar disorder (BD): A randomized, double-blind, placebo-controlled clinical trial.. https://doi.org/10.1016/j.jad.2026.122309

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Journal Article; Randomized Controlled Trial resource Adult subject Antipsychotic Agents subject Bipolar Disorder subject Cognition subject Cognitive Enhancement subject Cognitive impairment subject Dipolar I disorder subject Double-Blind Method subject Drug Therapy, Combination subject Executive Function subject Female subject Humans subject Journal Article subject Male subject Memantine subject

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