A Controlled Trial Finally Tested Ketamine in the Patients Clinics Screen Out
Bipolar patients get screened out of ketamine treatment routinely. The reason is a worry about triggering mania. Until now that worry had almost no controlled evidence behind it, in either direction. A Toronto team has now run the trial, and it was published in JAMA Psychiatry on September 2, 2026.
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| Key Takeaway | Detail |
|---|---|
| The trial | Ket-BD, a double-blind randomized trial from University Health Network and the University of Toronto |
| Who was studied | 68 adults with bipolar I or II and treatment-resistant depression, all on a stable mood stabilizer |
| The protocol | Four 40 minute infusions over two weeks at 0.5 to 0.75 mg/kg, given twice weekly as an add-on |
| The comparator | Midazolam, a sedative used as an active placebo, not a standard antidepressant |
| The result | Depression scores fell 7.3 points further on ketamine. 35.3 percent responded, against 11.8 percent |
| The safety finding | No mania, hypomania, psychosis or suicide attempts in either group |
What the Trial Ran
The study is called Ket-BD. It came out of the Poul Hansen Family Centre for Depression and the Krembil Brain Institute at University Health Network. The University of Toronto and Ontario Shores took part.
Sixty-eight adults aged 21 to 65 were randomized. Just over a third had bipolar I, and just under two thirds had bipolar II. All had failed at least two adequate medication trials and scored at least 21 on the MADRS depression scale.
Everyone stayed on a stable mood stabilizer or antipsychotic. Ketamine was an add-on, never a replacement.
Midazolam Is Why This Trial Counts
The control group did not get saline. They got midazolam, a benzodiazepine sedative, at 0.02 to 0.03 mg/kg on the same schedule.
That choice matters more than any single number here. A saline placebo is easy to spot, because ketamine produces obvious effects. Patients who know they got the real drug tend to report feeling better.
Midazolam makes both groups feel something. It is the harder test, and it is the design most ketamine studies avoid. Read the comparator carefully though. This trial did not measure ketamine against standard antidepressants, and nothing here supports that claim.
The Mania Question, and What 34 Patients Can Answer
No participant in either group experienced mania, hypomania, psychosis or a suicide attempt. Manic symptom scores stayed low throughout. One person in each group developed mixed features.
That is genuinely reassuring, and it is the first controlled look at the question. It is also not proof of safety, and the distinction is worth being precise about.
Thirty-four people received ketamine, over two weeks. Suppose treatment-emergent mania occurs in a small percentage of patients. A sample this size would very likely record zero cases anyway. The trial is underpowered to detect the exact risk it appears to settle.
The Efficacy Numbers
On the primary outcome, depression scores fell 7.3 points further in the ketamine group at day 14. The confidence interval ran from 2.5 to 12.0 points, and the effect size was moderate.
Response, meaning symptoms roughly halved, reached 35.3 percent on ketamine against 11.8 percent on midazolam. Remission reached 17.6 percent against 8.8 percent.
Adverse events clustered on infusion days and were minimal otherwise. Dissociation was higher during ketamine infusions, which is expected.
Two in Three Did Not Respond
The response rate deserves reading in both directions. Tripling the response rate against an active control is a real result.
It also means roughly 65 percent of patients did not respond, and more than 80 percent did not reach remission.
That is worth saying to a patient before a first infusion. It is a meaningful option for a hard population, not a reliable one.
Where the Blinding Broke
The authors report how well the blind held, which is more honesty than most trials offer.
After the first infusion, 47 percent of participants guessed their assignment correctly. By the end of the course, 66 percent did.
So the blind degraded over two weeks. The authors name differential unblinding as a limitation that may have inflated the ketamine result through expectancy. It is the same measurement problem running through this field, which we covered in the review of ketamine assisted psychotherapy evidence.
Four Infusions, Not Six
The protocol used four infusions across two weeks. Most US cash pay practice runs six over two to three weeks, and the authors flag the difference themselves.
That makes three distinct schedules HealingMaps has covered in about a month. A Winston-Salem clinic ran three loading infusions then repeats every six months. A Toronto pain team ran three infusions across twelve weeks. This trial ran four across two.
Nobody is studying the six in three weeks model that the industry actually sells. That gap is starting to look conspicuous.
What It Changes for Intake
Not the screening protocol, at least not yet. One trial of 68 people does not overturn a standing caution, and the authors call for phase 3 replication.
What it changes is the quality of the conversation. A clinic asked about bipolar patients can now point to controlled data rather than to an absence of evidence.
The conditions attached to that data matter. Every participant was on a stable mood stabilizer, ketamine was adjunctive, and follow up ran two weeks. A patient off mood stabilizers is not represented here.
The Bottom Line
This is the strongest evidence yet on a question clinics field constantly. It points in a favorable direction on both effect and safety.
But it is also small, short and partially unblinded. It was funded publicly by the Canadian Institutes of Health Research, with no ketamine industry money involved. Those sentences belong together. For the regulatory picture, see our coverage of the IV ketamine approval pathway.
Patients looking for supervised care can start with our directory of verified ketamine clinics.
This article is for informational purposes and is not medical advice. Ketamine for bipolar depression is an off label use. It was studied here only as an add-on to existing mood stabilizing medication. Discuss treatment options with a qualified clinician.
