Ketamine as an NMDA-modulating therapy in bipolar disorder: rationale and evidence.

Background: Bipolar depression remains a leading cause of morbidity, functional impairment, and suicide risk in bipolar disorder. Conventional pharmacotherapies often provide delayed or incomplete relief and may increase the risk of treatment-emergent affective switching. Recent evidence highlights the therapeutic potential of NMDA receptor antagonists, particularly ketamine and its S-enantiomer esketamine, as rapid-acting antidepressants. Methods: This narrative review synthesizes findings from randomized controlled trials, systematic reviews, and real-world studies investigating ketamine and esketamine in treatment-resistant bipolar depression. Emphasis was placed on antidepressant efficacy, safety, and the risk of mood destabilization. Results: Across multiple trials, ketamine produced rapid and robust antidepressant effects, with significant improvement in depressive symptoms within hours of administration. Data confirmed high response rates in treatment-resistant bipolar depression, while rapid-onset benefits with minimal switch risk. Further there is evidence on comparable efficacy and safety of intranasal esketamine in bipolar and unipolar depression, with no cases of mania or hypomania. Conclusions: Ketamine and esketamine represent mechanistically novel and clinically effective treatments for bipolar depression. Their rapid antidepressant action and low switch liability distinguish them from traditional antidepressants. Esketamine, with its favorable tolerability and intranasal administration, offers a promising adjunctive option for treatment-resistant bipolar depression. Long-term data are warranted to optimize maintenance strategies and confirm sustained safety and efficacy.