The KARMA-Dep 2 Trial — Ketamine No Better Than Midazolam for Inpatient Depression

rajaduttamd
2 hours ago
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Background

Ketamine’s rapid antidepressant effects have fueled growing off-label use in hospitals and private clinics. Yet its true efficacy—especially when compared with active psychoactive placebos—has remained uncertain. The KARMA-Dep 2 randomized clinical trial, led by Ana Jelovac and colleagues at Trinity College Dublin, sought to determine whether serial ketamine infusions improve depressive symptoms beyond those seen with midazolam, a sedative used as an active control to maintain blinding.

Study Design

This double-blind, randomized trial enrolled 65 inpatients (mean age ≈ 53 years) hospitalized for moderate-to-severe DSM-5 major depressive episodes (both unipolar and bipolar). Participants received up to 8 intravenous infusions of either ketamine 0.5 mg/kg or midazolam 0.045 mg/kg, administered twice weekly, alongside standard inpatient care. Follow-up continued for 6 months.

The primary outcome was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to end of treatment. Secondary measures included self-rated depression, cognition, side effects, health-care costs, and quality of life.

Findings

By trial completion, 62 participants were analyzed. The results were strikingly neutral:

No significant difference in MADRS reduction between ketamine and midazolam (adjusted mean difference = –3.16; 95% CI –8.54 to 2.22; P = .25).
No advantage on self-rated depression, cognition, cost-effectiveness, or quality of life.
Response and remission rates were modestly higher in the ketamine group (46.9% and 43.8%) than in midazolam (33.3% and 30%), but differences were not statistically significant.
Adverse events were frequent but comparable: fatigue, sleep disturbance, mild hypertension, and transient dissociation. Serious adverse events occurred in both arms (7 vs 6).

Importantly, blinding largely failed—clinicians and patients could often tell which drug had been administered due to ketamine’s distinct psychoactive effects, potentially biasing results.

Interpretation

KARMA-Dep 2 challenges the popular narrative of ketamine as a uniquely potent antidepressant. When compared against a psychoactive control rather than saline, ketamine’s apparent advantage largely disappeared. The authors emphasize that expectancy effects and functional unblinding likely inflate results in earlier, less-rigorous trials.

While both drugs were safe and tolerable, ketamine was neither more effective nor more cost-efficient as an adjunct to inpatient care. The study calls for innovative trial designs capable of distinguishing true pharmacologic benefit from placebo-linked effects in ketamine research.

Bottom Line

In this large, well-controlled inpatient study, serial ketamine infusions did not outperform midazolam for depression. The findings underscore the importance of rigorous placebo controls and cautious interpretation of the ketamine hype.

Citation:Jelovac A et al. Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression: The KARMA-Dep 2 Randomized Clinical Trial. JAMA Psychiatry. Published online October 22, 2025. doi:10.1001/jamapsychiatry.2025.3019