The first randomized trial of serial ketamine infusions in bipolar depression finds benefits (and no mania)
STUDY: Orsini DK et al, JAMA Psychiatry 2026
STUDY TYPE: Randomized, double-blind, midazolam-controlled clinical trial
FUNDING: Canadian Institutes of Health Research
Background
Ketamine has solid evidence as a rapid antidepressant in major depression, but bipolar patients have routinely been excluded from trials over fear it triggers mania. Ketamine for bipolar depression had only been tested as a single infusion until now.
The Study
- 68 adults with treatment resistant bipolar I or II depression (MADRS 21+, 2+ failed treatments) at 3 Ontario sites.
- Randomized to 4 infusions of ketamine or midazolam (active placebo) over 2 weeks, added to a mood stabilizer or antipsychotic. The use of midazolam is a strength, as it improves the blinding of the trial.
- Primary outcome: MADRS change at day 14, watching for mania or psychosis.
Results
Ketamine improved depression by two weeks. The MADRS score fell significantly more with ketamine than midazolam, a 7.3-point difference (95% CI, 2.5-12.0; P = .003; Cohen d = 0.7).
Response: 35% with ketamine vs 12% with midazolam; remission: 18% vs 9%. The improvements, however, faded about a week after the last infusion.
Side Effects
No cases of mania, hypomania, or psychosis occurred in either group; one case of subthreshold mixed features occurred in each arm. Ketamine caused more dissociation, but fewer than half of participants correctly guessed their treatment after the first dose.
Limitations
Small (68 randomized, 63 analyzed). Treatment lasted only 2 weeks.
Practice Implications
- Ketamine has a role in bipolar depression. I recommend short-term use, paired with psychotherapy to build lasting behavioral change. Learn how to do that in Difficult to Treat Depression.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
