Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial
Publication: American Journal of Psychiatry
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.
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Information
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History
Received: 24 March 2013
Revision received: 22 May 2013
Accepted: 17 June 2013
Published online: 1 October 2013
Published in print: October 2013
Authors
Author Contributions
Drs. Murrough and Iosifescu contributed equally to this article.
Funding Information
In the previous 36 months, Dr. Murrough has received research support from Evotec, Janssen Pharmaceuticals, and Avanir. Dr. Iosifescu has received research funding through Icahn School of Medicine at Mount Sinai from AstraZeneca, Brainsway, Euthymics, Neosync, and Roche, and he has received consulting fees from CNS Response, Otsuka, Servier, and Sunovion. Dr. Shah has received honoraria or research support from AstraZeneca, Bristol-Myers Squibb, Evotec, Johnson & Johnson, and Roche Pharmaceuticals. Dr. Charney and Icahn School of Medicine at Mount Sinai have been named on a use patent application of ketamine for the treatment of depression; if ketamine were shown to be effective in the treatment of depression and received approval from the Food and Drug Administration for this indication, Dr. Charney and Icahn School of Medicine at Mount Sinai could benefit financially; Dr. Charney receives research support from NIH, NIH/NIMH, NARSAD, and USAMRAA; he also served on the 2012 Institute of Medicine Committee on DHS Workforce Resilience and was on the 2012 Editorial Board of CNS Spectrums. Dr. Mathew has been named as an inventor on a pending use patent of ketamine for depression; he has relinquished his claim to any royalties and will not benefit financially if ketamine is approved for this use; Dr. Mathew has received consulting fees or research grants/support from Allergan, AstraZeneca, Bristol-Myers Squibb, Cephalon, Corcept, Johnson & Johnson, Naurex, Noven, Roche, and Takeda. The other authors report no financial relationships with commercial interests.
Supplementary Material
Supported by NIMH grant RO1 MH-081870 to Dr. Mathew, by grant UL1 TR000067 from the NIH National Center for Advancing Translational Sciences, by the Department of Veterans Affairs (VA), by a NARSAD Independent Investigator Award and funding from the Brown Foundation, Inc., to Dr. Mathew, by resources and facilities at the Michael E. DeBakey VA Medical Center, and by NIMH Career Development Award 1K23 MH-094707 to Dr. Murrough.Metrics & Citations
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