Repeated ketamine infusions no better than midazolam for depressed inpatients

The question

Do repeated intravenous ketamine infusions reduce depression more than midazolam (a sedative used as an active placebo) when added to normal hospital psychiatric care?

What they did

The KARMA-Dep 2 trial ran at one academic centre in Ireland between September 2021 and August 2024. Adults admitted to hospital with a major depressive episode (unipolar or bipolar) and a Montgomery-Asberg Depression Rating Scale (MADRS) score of at least 20 were randomly assigned, 1 to 1, to up to 8 twice-weekly infusions of either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg). Both groups continued their usual medication and inpatient care. The main outcome was the change in clinician-rated depression scores from the start to the end of treatment, and people were followed for 6 months.

What they found

Of 65 people randomized (average age 53.5 years; 37, or 59.7%, male), 62 were included in the final analysis. At the end of treatment, MADRS depression scores did not differ significantly 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). Self-reported depression scores were essentially identical between groups (adjusted mean difference -0.002; P > .99). There were no significant differences in other secondary outcomes either, including thinking and memory, health care costs and quality of life. Most patients and raters correctly guessed which treatment had been given.

The fine print

The trial included only 65 people at a single hospital, so it may have been too small to detect a modest benefit. Blinding largely failed: most patients and raters guessed the assignment correctly, which can affect ratings in either direction. Everyone was also receiving usual inpatient care and medication, which may itself improve symptoms and narrow any difference between groups. This summary is based on the abstract only.

What it means

In hospitalized patients already receiving standard psychiatric care, a course of ketamine infusions did not outperform an active comparator on depression scores, which tempers assumptions that repeated ketamine adds clear benefit in that setting.

Evidence grade: Moderate. A double-blind randomized controlled trial with an active comparator, but small (65 people), at a single centre, and most participants and raters correctly guessed who got what.

This summary is based on the study’s published abstract.