- Design
- Randomised, double-blind, midazolam-controlled trial, 3 sites
- Population
- 68 adults with treatment-resistant bipolar I or II depression
- Primary outcome
- MADRS change at day 14
- Effect
- −7.3 points vs midazolam (95% CI −12.0 to −2.5); d 0.7
The Ket-BD trial randomised 68 adult outpatients in Ontario with bipolar I or II depression (MADRS 21 or more) who had failed at least two evidence-based treatments. All stayed on at least one mood stabiliser or antipsychotic. They received four 40-minute infusions over two weeks of ketamine 0.5 to 0.75 mg/kg or midazolam as an active placebo.
At day 14, MADRS was 7.3 points lower with ketamine (95% CI −12.0 to −2.5; Cohen d 0.7). There were no cases of mania, hypomania, psychosis or suicide attempt in either group, and one case of mixed features in each.
Bipolar depression has few effective options and antidepressant monotherapy risks switching. This is the first reasonably sized, midazolam-controlled trial of serial ketamine in the condition. It is small, short, and nearly half of participants guessed their allocation after the first infusion, which weakens blinding. Durability beyond two weeks is not known.
For now this supports considering ketamine in specialist settings for patients already on mood stabilisation, not as an outpatient routine.
- Confirm mood stabiliser or antipsychotic cover before any ketamine course.
- Screen for mixed features and recent hypomania; the trial excluded neither but monitored closely.
- Plan follow-up beyond two weeks — relapse after the course is the open question.
- Record blood pressure and dissociation at each infusion.
Why it matters
The fear that ketamine would tip bipolar patients into mania was not borne out in a controlled trial.
Don't overread it
Sixty-eight patients over two weeks cannot establish long-term safety or sustained benefit.
The statistics, in plain English
A 7.3-point MADRS difference is clinically meaningful — around the size seen in trials that changed practice. The interval runs from 2.5 to 12 points, so the true effect could be modest. Nearly half guessed their group, so expectation may have inflated the difference despite the active placebo.
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