Regular ketamine infusions offer new hope for treatment-resistant bipolar depression

by Paul Arnold, Medical Xpress

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edited by Lisa Lock, reviewed by Robert Egan

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People living with treatment-resistant bipolar disorder still have options to manage their condition. However, the choices are often limited, may take weeks to work or fail to provide full relief. That has led to a search for faster, more effective alternatives.

In a study published in the journal JAMA Psychiatry, scientists led by Dr. Joshua Rosenblat at the University Health Network in Toronto report that serial ketamine infusions can safely and effectively reduce severe depression symptoms in people with treatment-resistant bipolar disorder.

What is unusual is that while this fast-acting anesthetic has shown antidepressant effects, there are also concerns that it might trigger mania or psychosis in bipolar patients.

To address those long-standing fears, the team needed to design a carefully controlled trial.

What the data revealed

Researchers ran a double-blind study with 68 adults with treatment-resistant bipolar I or II depression. Over two weeks, participants received four infusions of either low-dose ketamine or midazolam, a sedative. All patients maintained their regular regimens of mood stabilizers or antipsychotics.

As the trial progressed, a clear difference emerged between responses to the two medications. "We found clinically meaningful and statistically significant antidepressant effects with ketamine compared to midazolam," the study authors wrote in their paper.

Depression scores, as measured on the MADRS [Montgomery-Åsberg Depression Rating Scale], fell during treatment, with the ketamine group showing greater improvements than the control group. By day 14, this gap was statistically significant.

At this stage, depression scores in the ketamine group were an average of 7.3 points lower than those in the midazolam group. Around 35% of ketamine participants saw their symptoms cut by at least half, compared with 11.8% in the midazolam group.

The difference between the groups remained significant for a week after the final infusion, although depression symptoms gradually returned after ketamine treatment stopped.

Another promising result was that no participant developed mania, hypomania or psychosis, and there were no suicide attempts. "Ketamine was not associated with treatment-emergent mania or psychosis." One participant in each group did develop mixed features, meaning they experienced some hypomanic symptoms without meeting the criteria for hypomania.

The challenge ahead

The paper's findings are encouraging. However, the study was small, and outcomes were measured for only two weeks plus a short follow-up period. Consequently, there are no data about whether ketamine is safe or effective when used repeatedly over longer periods for treatment-resistant bipolar disorder.

For researchers, the next challenge is figuring out how to turn this temporary relief into a lasting solution.

Written for you by our author Paul Arnold, edited by Lisa Lock, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You'll get an ad-free account as a thank-you.

Publication details

Diana K. Orsini et al, Serial Ketamine Infusions for Treatment-Resistant Bipolar Depression, JAMA Psychiatry (2026). DOI: 10.1001/jamapsychiatry.2026.2658

Journal information: JAMA Psychiatry

Clinical categories

PsychiatryPsychology & Mental health Who's behind this story?

Paul Arnold

BSc Biology from University of London. BBC documentary producer with world travel experience. Freelances from southern Spain. Full profile →

Lisa Lock

BA art history, MA material culture. Former museum editor, paramedic, and transplant coordinator. Editing for Science X since 2021. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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