For many people living with bipolar depression, standard treatments do not provide enough relief. Even after trying multiple medications, symptoms can persist, disrupting work, relationships, and daily life. New treatment options are urgently needed. 

Researchers led by Dr. Joshua Rosenblat at UHN’s Krembil Brain Institute, Ontario Shores Centre for Medical Health Sciences, and the University of Toronto have found that ketamine may help fill that gap. In a randomized clinical trial published in JAMA Psychiatry, the team found that repeated ketamine infusions significantly reduced symptoms in adults with treatment-resistant bipolar depression. 

While ketamine has been studied extensively in major depressive disorders, evidence in bipolar depression has remained limited. Previous randomized trials in bipolar disorder examined only a single infusion. This study is the first randomized controlled trial to evaluate a short course of repeated ketamine infusions for treatment-resistant bipolar depression.  

The trial enrolled 68 adults with bipolar I or II disorder who were experiencing a moderate to severe depressive episode despite at least two previous treatment attempts. Participants received four intravenous infusions over two weeks, either ketamine or midazolam, a sedative used as an active comparison treatment. They continued taking their prescribed mood stabilizers or antipsychotic medications throughout the study.  

By the end of treatment, participants who received ketamine had significantly lower depression scores than those who received midazolam. More than one-third of participants in the ketamine group met the study's definition of a clinical response, compared with about 12 per cent of those in the comparison group. The benefits continued for approximately one week after the final infusion.  

The study also addressed a challenge that has complicated earlier ketamine research. Because ketamine can produce noticeable short-term effects, participants may be able to guess which treatment they received. To help maintain blinding, the researchers used midazolam as an active placebo. Participants identified their treatment assignment only about half the time after the first infusion, suggesting treatment expectations were unlikely to explain the findings.  

Equally important were the safety results. Researchers observed no cases of mania, hypomania, or psychosis in either treatment group; concerns that have often limited the use and study of ketamine in people with bipolar disorder.  

"Currently available treatments are often ineffective for treatment-resistant bipolar depression, with new treatments urgently needed," says Dr. Rosenblat. "The present trial supports the antidepressant efficacy, safety, and tolerability of serial ketamine infusions for treatment-resistant bipolar depression."  

The researchers note that larger studies with longer follow-ups are still needed. However, the findings provide important evidence that ketamine could become an additional treatment option for people living with one of the most difficult-to-treat forms of depression.  

Dr. Joshua Rosenblat is a Clinician Investigator in the Poul Hansen Family Centre for Depression, UHN’s Krembil Brain Institute and Centre for Mental Health, and an Associate Professor in the Department of Psychiatry and the Department of Pharmacology and Toxicology at the University of Toronto.  

Co-first authors of the study are Diana K. Orsini and Sara Di Luch. The study was conducted by researchers at UHN and Ontario Shores Centre for Mental Health Sciences.  

This research was supported by the Canadian Institutes of Health Research and UHN Foundation. 

Orsini DK, Di Luch S, Tomlinson G, Lovell G, Vasudeva S, Rodrigues NB, Johnson DE, Flint AJ, Llach CD, McIntyre RS, Mansur RB, Karkouti K, Burhan AM, Kaczmarek E, Chisamore N, Bhatia A, Soneji N, Joshi A, Grewal D, Laframboise R, Rosenblat JD. Serial Ketamine Infusions for Treatment-Resistant Bipolar Depression: A Randomized Clinical Trial. JAMA Psychiatry. Published online September 2, 2026. doi:10.1001/jamapsychiatry.2026.2658.