IMPORTANCE: 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.

OBJECTIVE: To assess antidepressant efficacy, safety, tolerability, cost-effectiveness, and quality of life during and after serial ketamine infusions compared with midazolam as an adjunct to usual inpatient care.

DESIGN, SETTING, AND PARTICIPANTS: The KARMA-Dep 2 trial was an investigator-led, double-blind, randomized, midazolam-controlled, pragmatic trial conducted at an academic center in Ireland between September 2021 and August 2024. Participants included adults (=18 years) hospitalized with a DSM-5 major depressive episode (unipolar or bipolar) and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score =20.

INTERVENTIONS: Participants were randomized 1:1 to receive up to 8 twice-weekly intravenous infusions of either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) as an adjunct to usual-care pharmacotherapy and other aspects of routine inpatient psychiatric care. Participants were followed up for 6 months.

MAIN OUTCOMES AND MEASURES: The primary outcome was change in depression symptom severity measured by the observer-rated MADRS score from baseline to end of treatment. Secondary outcomes included self-reported depression severity, safety, tolerability, health care costs, and quality of life.

RESULTS: Of 65 randomized participants (mean [SD] age, 53.5 [18.6] years; 37 [59.7%] male), 62 were included in the final analysis. In the analysis of primary outcome, end-of-treatment MADRS scores did not significantly differ between the ketamine and midazolam groups (adjusted mean difference, -3.16 points, 95% CI, -8.54 to 2.22; P = .25; Cohen d, -0.29). Similarly, there was no significant between-group difference between Quick Inventory of Depressive Symptoms, Self-Report, scores (adjusted mean difference, -0.002; 95% CI, -2.71 to 2.71; P > .99; Cohen d, -0.0004). There were no significant between-group differences on other secondary outcomes, including cognition, cost-effectiveness, or quality of life. Most patients and raters accurately guessed treatment allocation.

CONCLUSIONS AND RELEVANCE: Serial adjunctive ketamine infusions were not more effective than serial midazolam infusions in reducing depressive symptoms in inpatients receiving usual psychiatric care.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04939649.

Psychiatry rater

Controlled data always beat what we observe: KARMA-Dep 2 trial is a new example.

Psychiatry rater

Important study with negative results. This study may not be directly applicable because it needs to be combined with others, so I could recommend this therapy or not, but it definitely adds to my knowledge as a psychiatrist.