IV Ketamine Shows Antidepressant Benefits in Treatment-Resistant Bipolar Depression: JAMA
Canada: Researchers have found in a new study that intravenous ketamine has potential as a promising treatment option for treatment-resistant bipolar depression (TRBD). Further, adjunctive intravenous ketamine was well tolerated and produced significant antidepressant effects compared with midazolam.
The findings are from the Ket-BD study, an investigator-led, double-blind, randomized clinical trial published in JAMA Psychiatry. The study evaluated whether adding IV ketamine to ongoing mood-stabilizing treatment could safely improve depressive symptoms in adults with treatment-resistant bipolar I or II depression.
The trial was conducted at three sites in Ontario, Canada, between July 2022 and November 2025. It included 68 adults aged 21 to 65 years diagnosed with bipolar I or II disorder and experiencing a moderate-to-severe depressive episode. All participants had a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 21 and had previously failed at least two evidence-based pharmacological treatments.
Participants were randomly assigned to receive either ketamine or midazolam in addition to a stable regimen containing at least one mood stabilizer or antipsychotic. Each group received four 40-minute intravenous infusions over two weeks. Ketamine was administered at a flexible dose of 0.5 to 0.75 mg/kg, while midazolam was given at 0.02 to 0.03 mg/kg.
The primary outcome was the change in depressive symptom severity, measured using the observer-rated MADRS score between baseline and day 14. Researchers also closely monitored participants for treatment-emergent mania, hypomania, mixed symptoms, psychosis, and other safety concerns.
The trial revealed the following findings:
- Of the 68 randomized participants, 63 were included in the final efficacy analysis, while 5 withdrew before the primary endpoint.
- After adjusting for sex, bipolar disorder type, and baseline MADRS score, the ketamine group had significantly lower MADRS scores at day 14 than the midazolam group.
- The adjusted between-group difference was −7.3 MADRS points, with a Cohen d of 0.7, indicating a clinically meaningful antidepressant effect.
- No cases of mania, hypomania, psychosis, or suicide attempts were reported in either group.
- One participant in each group developed mixed features, involving hypomanic symptoms that remained below the threshold for hypomania.
- After the first infusion, 31 of 66 participants (47%) correctly identified their treatment assignment.
The researchers concluded that adjunctive IV ketamine was well tolerated and significantly reduced depressive symptoms compared with midazolam among people with treatment-resistant bipolar depression. The findings suggest that ketamine may offer a potential treatment strategy for this difficult-to-treat population, although further research will be important to establish its longer-term efficacy and safety.
Reference:
Orsini DK, Di Luch S, Tomlinson G, et al. Serial Ketamine Infusions for Treatment-Resistant Bipolar Depression: A Randomized Clinical Trial. JAMA Psychiatry. Published online September 02, 2026. doi:10.1001/jamapsychiatry.2026.2658
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