REVIEW OF: Jelovac A et al, JAMA Psychiatry 2025;82(12):1216–1224

STUDY TYPE: Randomized, double-blind, active-placebo pragmatic trial

Ketamine is increasingly used off-label for depression, often in a series of infusions, but does it really outperform a control treatment when added to standard inpatient care? This study enrolled 65 adults hospitalized for major depression and randomized them to receive up to eight twice-weekly intravenous infusions of ketamine (0.5 mg/kg) or the active placebo midazolam (0.045 mg/kg) along with usual treatment. Symptoms were tracked during the infusion phase and for six months after.

Midazolam was selected as the control because it offers some psychoactive effects that help preserve blinding. But importantly, prior studies have suggested that benzodiazepines, including midazolam, may transiently reduce anxiety or dysphoria, which could obscure ketamine’s antidepressant effects (Wilkinson ST et al, Neuropsychopharmacology 2019;44(7):1233–1238).

By the end of treatment, response and remission were somewhat higher with ketamine (47% and 44%) than with midazolam (33% and 30%), but the difference did not reach statistical significance. Self-rated symptoms, cognition, quality of life, and costs were also similar. The study fell short of its planned enrollment due to constraints related to the COVID-19 pandemic.

The article did not specifically analyze suicidal ideation outcomes, though prior ketamine literature suggests antisuicidal effects within hours to days, especially in patients with severe depression.

CARLAT TAKE

Ketamine didn’t statistically outperform midazolam, but let’s not write it off. The study had strengths, including its randomized design and long follow-up, but two key limitations stand out. Midazolam isn’t an inert placebo; it can have short-term mood-modulating effects that make it harder to detect ketamine’s true antidepressant properties. And the smaller sample size, related to COVID-19 disruptions, reduced the study’s power to pick up more subtle differences. Still, ketamine produced higher response and remission rates, suggesting that a larger, adequately powered trial might have detected a clearer benefit. This study tempers the early enthusiasm but doesn’t close the door, and ketamine may still play a role for some patients with severe or treatment-resistant depression.