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

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). 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. 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. 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. Iranian Registry of Clinical Trials (IRCT), IRCT20250430065539N1, 30 April 2025.