Efficacy and safety of memantine as adjunctive treatment for manic episodes in bipolar disorder (BD): a randomized, double-blind, placebo-controlled clinical trial

BACKGROUND: Bipolar disorder (BD) is a chronic and recurrent psychiatric illness, and acute manic episodes are associated with marked functional impairment. Mood stabilizers and antipsychotics remain the mainstay of treatment. Dysregulation of glutamatergic neurotransmission and N-methyl-D-aspartate (NMDA) receptor signaling has been implicated in bipolar disorder (BD), providing a rationale for evaluating memantine as an adjunctive treatment for manic episodes in bipolar I disorder (BD-I). METHODS: In this 6-week randomized, double-blind, placebo-controlled trial, adults aged 18-65 years with DSM-5 BD-I and a current manic episode were allocated 1:1 to adjunctive memantine or placebo, alongside lithium and olanzapine. Memantine was titrated from 5 mg/day to 20 mg/day. Manic symptoms were assessed using the Young Mania Rating Scale (YMRS), with secondary outcomes including Clinical Global Impression (CGI) scales and peripheral inflammatory markers. RESULTS: Sixty-three participants were randomized (memantine n = 31; placebo n = 32). Baseline YMRS scores were comparable between groups. Mean YMRS scores decreased significantly in both groups over time; however, no between-group differences were observed at week 2 (P = 0.674), week 4 (P = 0.778), or week 6 (P = 0.466). At week 6, the magnitude of YMRS reduction did not differ significantly between the memantine and placebo groups. CGI-Severity, CGI-Improvement, and CGI-Efficacy Index scores were also similar between groups at all assessment points (all P > 0.05). Changes in white blood cell count, neutrophil count, lymphocyte count, and neutrophil-to-lymphocyte ratio at week 6 and week 18 showed no statistically significant differences between the memantine and placebo arms in either intention-to-treat or per-protocol analyses. CONCLUSIONS: Adjunctive memantine did not provide additional symptomatic or biological benefit beyond lithium and olanzapine in the treatment of acute mania in BD-I. These findings do not support routine use of memantine for acute manic episodes, although further research may be warranted in selected patient subgroups or alternative clinical contexts. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT), IRCT20250430065539N1, 30 April 2025.