Serial Ketamine Infusions Fail to Show Benefit as Adjunctive Therapy for MDD
Serial ketamine infusions failed to outperform a psychoactive placebo as an adjunctive therapy to usual inpatient care for depression, according to results from the KARMA-Dep 2 trial. Researchers shared their findings in JAMA Psychiatry.
“Serial ketamine infusions are being increasingly adopted as off-label treatment for major depression in routine clinical practice, yet robust psychoactive placebo-controlled trial evidence for short- and long-term efficacy and safety remains limited,” wrote Ana Jelovac, PhD, Department of Psychiatry, School of Medicine, Trinity College Dublin, St Patrick’s University Hospital, Dublin, Ireland, and study coauthors.
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The double-blind trial included 65 participants who were hospitalized for a major depressive episode and had a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score of 20 or higher. Participants were randomized 1:1 to receive up to 8 twice-weekly intravenous infusions of ketamine (0.5mg/kg) or midazolam (0.045mg/kg) over 6 months of follow-up.
Researchers primarily assessed the difference in end-of-treatment MADRS scores between the 2 treatment groups, but also investigated self-rated depressive symptoms, quality of life, and several additional secondary outcomes.
In their final analysis, which included 62 of the total participants, the researchers found that the end-of-treatment MADRS scores did not differ significantly between the ketamine (n=32) and midazolam (n=30) groups, with an adjusted mean difference of −3.16 points (95% CI, −8.54 to 2.22; P = .25; Cohen d, −0.29).
There were also no significant differences observed in the secondary efficacy and quality-of-life outcomes.
“Despite widespread clinical enthusiasm based on early reports of large rapid antidepressant effects of single ketamine infusions, our finding of a small between-group difference falls below both the effect sizes reported in prior open-label or saline-controlled studies, and the minimal clinically important difference for the MADRS,” the authors wrote. “This underscores the need for a cautious interpretation of earlier, less rigorously controlled research.”
In their discussion, the researchers also highlighted the difficulty of maintaining blinding in a ketamine trial due to the agent’s distinct dissociative effects. “…While midazolam was selected to mitigate unblinding, this was not successful, raising the possibility that even the small observed effect reflects expectancy rather than a specific treatment effect,” they cautioned.