Ketamine eases treatment-resistant bipolar depression

Clinical takeaway: Four ketamine infusions eased treatment-resistant bipolar depression without triggering mania or psychosis, though symptoms returned once infusions ended. 

Treatment-resistant bipolar depression leaves clinicians with few places to turn. Patients who fail two or more evidence-based regimens often cycle through additional medication trials with diminishing returns, and depressive episodes drive most of the disability in bipolar disorder. Meanwhile, ketamine clinics have proliferated for treatment-resistant major depression, and many patients with bipolar depression are asking whether that door is open to them. 

FDA approval for ketamine is as an anesthetic, though IV infusions are widely used off-label for treatment-resistant major depression and esketamine's psychiatric indications cover treatment-resistant major depression and depressive symptoms with acute suicidal ideation. Randomized data in bipolar disorder have been limited to single-infusion studies, in part because of a theoretical risk that ketamine could tip patients into mania or psychosis. A new randomized trial is the first to test a serial course in this population, and it works to answer both the efficacy and the safety questions. 

Ketamine outperformed midazolam by 7.3 points on the Montgomery-Åsberg Depression Rating Scale at day 14, roughly double the 3.6-point threshold the investigators prespecified as clinically important. The advantage held across bipolar I and II, and persisted for a week after the final infusion before symptoms began returning toward baseline. That fade fits the pattern seen in major depression, where maintenance infusions are typically needed to hold the response. 

Response rates ran 35.3% with ketamine against 11.8% with midazolam, and remission 17.6% against 8.8%. Safety carried no surprises in the direction that has kept bipolar patients out of ketamine trials: no mania, hypomania, psychosis, or suicide attempts in either arm. One participant per arm developed subthreshold mixed features. Adverse events clustered on infusion days, and dissociation ran higher with ketamine, yet after the first infusion fewer than half of participants correctly guessed which drug they had received. 

The Ket-BD trial randomized 68 adults with bipolar I or II disorder and a moderate to severe depressive episode, each with at least two failed evidence-based pharmacotherapy trials, at three sites in Ontario. Participants received four flexibly dosed 40-minute infusions of ketamine or midazolam over two weeks, adjunctive to a stable mood stabilizer or antipsychotic. Midazolam served as a psychoactive control to protect blinding. 

Investigators call for phase 3 trials with larger samples and longer treatment, and the durability question is the one that matters most for practice. Newer protocols in major depression run six to eight infusions over three to four weeks, and maintenance dosing is likely needed to hold response in bipolar depression as well. Whether payers and clinics extend existing ketamine infrastructure to bipolar patients ahead of additional evidence or an approval for this indication remains to be seen. 

"Currently available treatments are often ineffective for treatment-resistant bipolar depression, with new treatments urgently needed," says Joshua Rosenblat, MD, MSc, clinician investigator at University Health Network's Krembil Brain Institute and associate professor of psychiatry at the University of Toronto. "The present trial supports the antidepressant efficacy, safety, and tolerability of serial ketamine infusions for treatment-resistant bipolar depression." 

Source: Orsini DK, et al. (2026 Sep 2) JAMA Psychiatry. Serial Ketamine Infusions for Treatment-Resistant Bipolar Depression: A Randomized Clinical Trial