JAMA Psychiatry

Repeated ketamine infusions fail to outperform midazolam in hospitalized depression

October 27, 2025

Study details: The KARMA-Dep 2 trial (NCT04939649) was a pragmatic, randomized, double-blind, midazolam-controlled study conducted at a single academic center. Adults hospitalized with moderate to severe depression received up to eight IV infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) over four weeks, alongside usual inpatient care. Primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to 24 hours after final infusion. Secondary outcomes included response/remission rates, relapse, safety, cognitive effects, quality of life, and cost-effectiveness, with a 24-week follow-up.

Results: Among 62 analyzed participants, ketamine wasn't significantly more effective than midazolam in reducing depressive symptoms or improving secondary outcomes. The between-group difference in MADRS score was small (3.2 points) and not clinically meaningful. Remission rates in the ketamine arm (43.8%) were comparable to prior open-label studies. Both treatments were generally safe, with similar rates of adverse events and serious adverse events in each group.

Clinical impact: Serial ketamine infusions didn't demonstrate significant superiority over midazolam as adjunctive therapy for inpatient depression. These findings challenge earlier reports of large rapid antidepressant effects and highlight the importance of rigorous blinding and active comparators in ketamine trials. Caution is warranted in interpreting open-label or saline-controlled studies when considering ketamine’s role in clinical practice.

Source:

Jelovac A, et al. (2025, October 22). JAMA Psychiatry. Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression: The KARMA-Dep 2 Randomized Clinical Trial. https://pubmed.ncbi.nlm.nih.gov/41123905/