IV Ketamine Reduced Symptoms in Bipolar Depression Trial
Key Takeaways
- In adult outpatients with treatment-resistant bipolar I or II depression receiving stable mood stabilizer or antipsychotic treatment, adjunctive IV ketamine was associated with a significantly greater reduction in depressive symptoms than midazolam at day 14.
- No cases of mania, hypomania, psychosis, or suicide attempts were observed in either group during the acute trial period.
- Mixed features occurred once in each group during the randomized comparison.
- After the first infusion, 31 of 66 participants (47%) correctly guessed treatment allocation.
The Ket-BD randomized trial, reported by Orsini et al in JAMA Psychiatry, was an investigator-led, double-blind, midazolam-controlled study conducted at 3 sites in Ontario, Canada. Eligible participants were adult outpatients aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of bipolar I or II disorder, a current moderate to severe major depressive episode, a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 21, and at least 2 failed trials of evidence-based pharmacotherapies.
Participants were randomized 1:1 to 4 flexibly dosed 40-minute infusions over 2 weeks of ketamine 0.5-0.75 mg/kg or midazolam 0.02-0.03 mg/kg, added to a stable dose of at least 1 mood stabilizer or antipsychotic. The primary outcome was change in observer-rated MADRS score from baseline to day 14; 68 participants were randomized, and 63 were included in the final efficacy analysis after 5 withdrew before the primary end point.
Ketamine was associated with a 7.3-point lower day-14 MADRS score than midazolam (95% CI, -12.0 to -2.5; P = .003; Cohen d = 0.7).
Acute psychiatric safety findings remained limited to the trial-period observations, with no cases of mania, hypomania, psychosis, or suicide attempts in either group and one case of mixed features in each group. After the first infusion, 31 of 66 participants (47%) correctly guessed treatment allocation.
Interpretation is limited to an acute 2-week infusion course with the primary assessment at day 14 in adult outpatients with bipolar I or II depression who stayed on stable mood stabilizer or antipsychotic treatment. The authors concluded that adjunctive intravenous ketamine was well tolerated and associated with significant antidepressant effects compared with midazolam in treatment-resistant bipolar depression.
Clinician Questions
Which patients with bipolar depression were represented in the Ket-BD trial?
The trial population was limited to adult outpatients with bipolar I or II disorder and a current moderate to severe depressive episode after multiple evidence-based pharmacotherapy failures, all while continuing stable mood stabilizer or antipsychotic treatment. Applicability therefore remains bounded to that outpatient, adjunctive-treatment setting.
How should the active-comparator design frame interpretation of the ketamine signal?
Ketamine was tested against midazolam under double-blind conditions while background mood stabilizer or antipsychotic treatment remained stable, so the reported signal reflects an adjunctive comparison within ongoing bipolar treatment rather than ketamine monotherapy or a placebo-only contrast.
What outcome did investigators use to measure antidepressant effect in treatment-resistant bipolar depression?
The primary outcome was change in depression symptom severity on the observer-rated Montgomery-Åsberg Depression Rating Scale from baseline to the end of treatment at day 14, making this an acute symptom-change end point rather than a longer-term durability measure.