Ketamine Showed Antidepressive Effects in Refractory Bipolar Depression

[Ketamine Demonstrates Antidepressant Efficacy in Treatment‑Resistant Bipolar Depression]

• Previous studies have shown that ketamine infusions improve depression symptoms.
• A randomized trial showed that four infusions of ketamine reduced depression symptom severity compared with midazolam in outpatients with treatment-resistant bipolar I or II depression.
• Only 47% of participants correctly guessed which arm of the study they were in, indicating the effectiveness of an active comparator.

Adjunctive ketamine showed significant antidepressive effects in patients with treatment-resistant bipolar depression in a small randomized trial.

Among 63 adult outpatients with treatment-resistant bipolar I or II depression, the mean Montgomery-Åsberg Depression Rating Scale (MADRS) score at 14 days was significantly lower among those who received four infusions of ketamine versus those who received midazolam (between-group difference -7.3 points, 95% CI -12.0 to -2.5, P=0.003), reported Joshua D. Rosenblat, MD, MSc, of the University Health Network in Toronto, and co-authors.

Response rates, defined as a >50% reduction on MADRS, were higher in the ketamine group compared with the midazolam group (35.3% vs 11.8%), as were remission rates, defined as MADRS scores <13 (17.6% vs 8.8%), the authors noted in JAMA Psychiatry.

Of note, a significant between-group difference persisted for 1 week after the last infusion.

“Overall acceptability, safety, and tolerability profiles were positive,” Rosenblat and team wrote. “Ketamine was not associated with treatment-emergent mania or psychosis, a safety concern that has often led to the exclusion of [bipolar disorder] from previous trials and clinical practice.”

“This study would suggest that if other treatments aren’t working for bipolar depression, it would be reasonable to consider ketamine” as a “second-line” option, Rosenblat told MedPage Today.

Previous randomized trials have shown the antidepressant efficacy of serial ketamine infusions for treatment-resistant depression, though one found that ketamine was no better than midazolam for moderate to severe depression in an inpatient setting.

Ketamine has not received FDA approval for any psychiatric indication, nor has it received approval in most countries, with the exception of France, Rosenblat said. However, a related compound, esketamine (Spravato), is approved for treatment-resistant depression in certain situations.

This study was the first randomized trial to assess ketamine in patients with treatment-resistant bipolar depression using a full course of treatment, he noted, though proof-of-concept studies have been done.

Alan F. Schatzberg, MD, a psychiatrist at Stanford Medicine in California, told MedPage Today that he wasn’t surprised by the results. “I think they got a rather clear difference between drug and control,” he said. After treatment stopped, the researchers saw “re-emergence” of depression, “indicating that the drug was being effective.”

More approaches are needed to treat refractory bipolar depression, he noted, but more studies are not needed to support ketamine’s use in “highly refractory” patients.

Rosenblat pointed out that only 47% of participants correctly guessed which arm of the study they were in, which makes this the first ketamine study to “effectively blind” participants with an active comparator.

“This study is the first one to very convincingly say [that] it’s not just because people believe they’re getting ketamine [that] it works,” he added. “The ketamine itself is biologically having an impact that’s leading to a massive antidepressant effect size.”

Greg Rhee, PhD, a pharmacoepidemicologist at the Yale School of Medicine in New Haven, Connecticut, told MedPage Today that “100% complete blinding is not possible,” with ketamine, but the study design employed here (i.e., patient-, rater-, and investigator-blinded) “is quite strong if it is done well.”

For the Ket-BD study conducted at three sites in Ontario, Canada from July 2022 to November 2025, outpatients ages 21 to 65 with a primary bipolar I or II disorder diagnosis with a current moderate-to-severe major depressive episode (MADRS score of 21) were included.

Mean age was 44.4, 55.8% were women, and 82.4% were white. All had at least two failed trials of evidence-based pharmacotherapies.

Participants were randomized 1:1 to receive four flexibly dosed, 40‑minute infusions of ketamine (0.5 to 0.75 mg/kg) or midazolam (0.02 to 0.03 mg/kg) over 2 weeks, with a stable dose of at least one mood stabilizer or antipsychotic.

The primary outcome was the change in depression symptom severity based on MADRS score from baseline to day 14. Safety and tolerability were also assessed.

No cases of mania, hypomania, psychosis, or suicide attempts were observed in either group. One case of mixed features (subthreshold hypomanic symptoms) was seen in each group.

The most important limitation to the study was its sample size and lack of long-term follow-up, Rosenblat said.

He noted that he hopes the study will “move the needle” for policymakers and payers, as access to this treatment is limited.

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