Ketamine as an NMDA-modulating therapy in bipolar disorder: rationale and evidence
Robert Queissner, F. Fellendorf, E. Z. Reininghaus
Frontiers in Psychiatry March 4, 2026 DOI: 10.3389/fpsyt.2026.1777402 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Narrative review Randomized Peer reviewed |
|---|---|
| Population | Patients with treatment-resistant bipolar depression |
| Interventions | Ketamine Esketamine |
| Topics | Depression Ketamine Esketamine |
| Keywords | Bipolar disorder Antidepressant Tolerability Depression economics Anesthesia Adjunctive treatment Randomized controlled trial Mood disorders Clinical trial Hypomania |
| Key findings | Ketamine and esketamine produce rapid, robust antidepressant effects in treatment-resistant bipolar depression with minimal risk of mood destabilization. |
Abstract
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.