Ketamine as an NMDA-modulating therapy in bipolar disorder: rationale and evidence
Frontiers in Psychiatry March 4, 2026 Robert Queissner, F. Fellendorf, E. Z. Reininghaus
Ketamine and its derivative esketamine provide rapid and effective relief from depressive symptoms in treatment-resistant bipolar depression, with a low risk of triggering mania or hypomania. Evidence from randomized controlled trials and real-world studies shows significant improvement in depressive symptoms within hours of administration. Intranasal esketamine demonstrates comparable efficacy and safety in bipolar and unipolar depression, with no reported cases of mania or hypomania. These treatments offer a mechanistically novel alternative to conventional antidepressants, which often work slowly or incompletely and may increase the risk of mood switching. Long-term data are still needed to confirm sustained safety and efficacy.