Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial
James W. Murrough, Dan V. Iosifescu, Lee C. Chang, Rayan K. Al Jurdi, Charles E. Green, Andrew M. Perez, Syed Iqbal, Sarah Pillemer, Alexandra L. Foulkes, Asim Shah, Dennis S. Charney, Sanjay J. Mathew
American Journal of Psychiatry August 28, 2013 DOI: 10.1176/appi.ajp.2013.13030392 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Double-blind Peer reviewed |
|---|---|
| Sample size | 73 |
| Population | Patients with treatment-resistant major depression experiencing a major depressive episode |
| Interventions | Ketamine Midazolam |
| Dose | single intravenous infusion |
| Duration | 24 hours after drug administration |
| Topics | Depression Esketamine Ketamine |
| Citations | 1,207 |
| Post-publication review | 3 comments on PubPeer (opens in new tab) · last active December 2014 |
| Key findings | Ketamine produced greater improvement in depression severity than midazolam 24 hours after a single infusion, with a 7.95-point lower MADRS score and a 64% response rate versus 28%. |
Abstract
Objective: Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression.
Method: This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS).
Results: The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively.
Conclusions: Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.