The KARMA-Dep2 trial delivered a shocking headline: up to eight serial ketamine infusions were no better than the midazolam placebo for hospitalized adults with moderate to severe depression. In an era of intense hope for ketamine’s rapid antidepressant effects, this result demands a closer look.

This episode critically dissects why this large, pragmatic trial may have failed to show a significant difference, focusing on a central challenge in ketamine research: blinding.

The core question remains: Does midazolam give a truly realistic estimate of ketamine’s effect, or does chasing the “perfect blind” with an active placebo simply obscure the real-world value of a drug whose unique, powerful experience is inseparable from its clinical benefit?

Resources:

Wilkinson, S. T., Farmer, C., Ballard, E. D., Mathew, S. J., Grunebaum, M. F., Murrough, J. W., Sos, P., Wang, G., Gueorguieva, R., & Zarate, C. A., Jr. (2019). Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant. Neuropsychopharmacology, 44, 1233–1238. https://doi.org/10.1038/s41386-019-0317-8

Dwyer, J. B., Landeros-Weisenberger, A., Johnson, J. A., Londono Tobon, A., Flores, J. M., Nasir, M., Couloures, K., Sanacora, G., & Bloch, M. H. (2021). Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression: A Randomized Midazolam-Controlled Trial. American Journal of Psychiatry, 178(4), 352–362. https://doi.org/10.1176/appi.ajp.2020.20010018

Jelovac, A., McCaffrey, C., Terao, M., Shanahan, E., Whooley, E., McDonagh, K., McDonogh, S., Loughran, O., Shackleton, E., Igoe, A., Thompson, S., Mohamed, E., Nguyen, D., O’Neill, C., Walsh, C., & McLoughlin, D. M. (2025). Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression: The KARMA-Dep 2 Randomized Clinical Trial. JAMA Psychiatry. https://doi.org/10.1001/jamapsychiatry.2025.3019