Ketamine’s antidepressant trials have almost never included people with bipolar disorder. Researchers worried the drug could trigger mania or psychosis in this population, a concern serious enough that bipolar patients were routinely screened out of trial after trial, even as ketamine became a widely used treatment for other forms of depression. A new trial called Ket-BD, published September 2 in JAMA Psychiatry, is one of the first to test ketamine specifically in people with treatment-resistant bipolar depression instead of excluding them. It found a real benefit. It also found something that complicates how much of that benefit to credit to the drug itself.
Why this population was avoided for so long
The researchers, led by Diana Orsini at the University Health Network’s Krembil Brain Institute in Toronto, affiliated with the University of Toronto, state the exclusion plainly in their own paper: “patient complexity and theoretical safety concerns,” specifically the risk of ketamine triggering mania or psychosis, have kept bipolar patients out of this research. That’s the same underlying logic behind a separate trial, a psilocybin study at UT Houston built specifically around a bipolar population that pharmaceutical trials have historically avoided. Both trials are testing whether that decades-old caution still holds up once someone actually runs the study instead of assuming the risk without testing it.
What the trial found
Ket-BD compared repeated ketamine infusions against midazolam, a sedative that produces its own noticeable effects without being an antidepressant, in patients with treatment-resistant bipolar depression who hadn’t improved on standard treatment. Ketamine outperformed midazolam on depression symptom scores. That’s a real, positive result in a population large trials have simply never tested this directly in before.
The catch, and why it matters
After the first infusion, 47 percent of patients correctly guessed which drug they’d received. The researchers note this happened despite the ketamine group experiencing noticeably more dissociation, the floating, detached feeling ketamine is known to produce, which should have made it easier, not harder, for those patients to correctly guess they’d gotten the real drug instead of the sedative. When roughly half a trial’s participants can tell which treatment they’re on, a real question opens up: how much of the measured benefit reflects ketamine’s antidepressant effect, and how much reflects patients simply expecting to feel better once they realized they’d gotten the active drug. This is the same functional unblinding problem tracked across psychedelic depression trials all year, and Ket-BD is a clean example of it showing up in ketamine research specifically, not just psilocybin or MDMA trials.
A result that lands right after the opposite one
A separate, larger trial published roughly ten months earlier tells a different story in an adjacent population. KARMA-Dep 2, run at St. Patrick’s University Hospital in academic partnership with Trinity College Dublin, tested serial ketamine infusions against the same sedative comparator in hospitalized patients with moderate to severe depression, a group that included both unipolar and bipolar patients. That trial found no significant difference between ketamine and the sedative at all. Two serious, well-designed trials, published close together, using a similar comparator drug, reached opposite conclusions in overlapping populations. That contrast doesn’t mean either trial is wrong. It means the actual effect size, if one exists, is small enough and population-specific enough that it’s hard to detect consistently, exactly the situation where an unblinding problem like the one in Ket-BD becomes harder to rule out as the real explanation.
A confound the researchers flag themselves
More patients in the ketamine group had received ketamine before, compared to the midazolam group. The researchers say this imbalance could have affected the results, since someone who’s had ketamine before may respond differently, psychologically or otherwise, than someone experiencing it for the first time. That’s a real limitation in how the groups were built, not just a theoretical concern.
What happens next
The researchers themselves call for the finding to be replicated in Phase 3 trials, with larger groups of patients and longer treatment periods, before treating this as settled. Orsini reports no financial ties to any company that could benefit from this result, a clean disclosure worth noting given how often depression trial data comes from industry-funded research.
Two true things that pull against each other
This trial does two things at once. It provides real evidence that a population excluded from ketamine research for years can benefit from it, evidence that decades of caution may have been broader than the actual risk warranted. It also shows exactly why that evidence needs careful reading rather than being taken at face value: a trial where nearly half the participants can guess their treatment assignment is a trial where the measured benefit and the expectation of benefit are tangled together in a way this study can’t fully separate. Both things are true. The next trial, larger and built to address this specific unblinding problem directly, will matter more than this one for knowing which explanation is doing the work.