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Articles   |    
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial
James W. Murrough, M.D.; Dan V. Iosifescu, M.D.; Lee C. Chang, M.D.; Rayan K. Al Jurdi, M.D.; Charles E. Green, Ph.D.; Andrew M. Perez, M.D.; Syed Iqbal, M.D.; Sarah Pillemer, B.A.; Alexandra Foulkes, M.S.; Asim Shah, M.D.; Dennis S. Charney, M.D.; Sanjay J. Mathew, M.D.
Am J Psychiatry 2013;170:1134-1142. doi:10.1176/appi.ajp.2013.13030392
View Author and Article Information

Drs. Murrough and Iosifescu contributed equally to this article.

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.

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.

The authors thank J. Moral, D. Reich, J. Joseph, S. Caress, R. de la Garza II, C. Levitch, J. Mahoney, T. Newton, P. Atluri, and M. Suresh.

The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

ClinicalTrials.gov identifier, NCT00768430 (http://clinicaltrials.gov/show/NCT00768430).

From the Department of Psychiatry, the Department of Neuroscience, the Department of Anesthesiology, the Department of Pharmacology and Systems Therapeutics, and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York; the Department of Anesthesiology and the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston; the Michael E. DeBakey VA Medical Center, Houston; and the Center for Clinical Research and Evidence-Based Medicine, University of Texas Medical School at Houston.

Presented at the 51st annual meeting of the American College of Neuropsychopharmacology, Hollywood, Fla., Dec. 8–12, 2012; the 2013 annual meeting of the Anxiety and Depression Association of America, La Jolla, Calif., April 4–7, 2013; the 68th Annual Scientific Convention of the Society of Biological Psychiatry, May 16–18, 2013; and the 166th annual meeting of the American Psychiatric Association, San Francisco, May 18–22, 2013.

Address correspondence to Dr. Mathew (sjmathew@bcm.edu).

Copyright © 2013 by the American Psychiatric Association

Received March 24, 2013; Revised May 22, 2013; Accepted June 17, 2013.

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.

Abstract Teaser
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FIGURE 1. Change in Depression Severity Over Time in Patients With Treatment-Resistant Major Depression Given a Single Infusion of Ketamine or Midazolama

a Modified intention-to-treat group. MADRS scores range from 0 to 60, with higher scores indicating a greater severity of symptoms.

b Reduction in MADRS score 24 hours after infusion was the primary outcome measure and was significantly greater for the ketamine group than for the midazolam group (p≤0.002).

FIGURE 2. Response Rates Over Time in Patients With Treatment-Resistant Major Depression Given a Single Infusion of Ketamine or Midazolama

a Modified intention-to-treat group. Response at each time point was defined as a decrease from baseline of at least 50% in score on the Montgomery-Åsberg Depression Rating Scale.

FIGURE 3. Time to Relapse for Responders at Day 7 Among Patients With Treatment-Resistant Major Depression Given a Single Infusion of Ketamine or Midazolama

a Response was defined as a decrease from baseline of at least 50% in score on the Montgomery-Åsberg Depression Rating Scale (MADRS). Relapse was defined as a MADRS score of 20 or higher maintained for two consecutive visits and meeting criteria for a major depressive episode for 1 week.

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TABLE 1.Characteristics of Patients With Treatment-Resistant Major Depression Given a Single Infusion of Ketamine or Midazolama
Table Footer Note

a Modified intention-to-treat group.

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b Scores range from 0 to 84, with higher scores indicating a greater severity of symptoms.

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c Scores range from 0 to 60, with higher scores indicating a greater severity of symptoms.

Table Footer Note

d Scores range from 0 to 27, with higher scores indicating a greater severity of symptoms.

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TABLE 2.Clinical Status at 24 Hours of Patients With Treatment-Resistant Major Depression Given a Single Infusion of Ketamine or Midazolama
Table Footer Note

a Modified intention-to-treat group.

Table Footer Note

b Significantly lower score in the ketamine group (t=3.34, df=68, p≤0.001).

Table Footer Note

c Significantly lower score in the ketamine group (t=6.69, df=68, p≤0.01).

Table Footer Note

d Significantly higher proportion in the ketamine group (p≤0.006, exact logistic regression).

Table Footer Note

e Significantly higher proportion in the ketamine group (p≤0.004, ordinal logistic regression).

Table Footer Note

f Significantly higher proportion in the ketamine group (p≤0.001, ordinal logistic regression).

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TABLE 3.Adverse Events in Patients With Treatment-Resistant Major Depression Given a Single Infusion of Ketamine (N=47) or Midazolam (N=25)
Table Footer Note

a From the modified version of the Patient Rated Inventory of Side Effects (26), excluding sleep and sexual functioning domains.

Table Footer Note

b Measured at 40 minutes, 120 minutes, and 240 minutes after the infusion.

Table Footer Note

c Measured at 24 hours, 48 hours, 72 hours, and 7 days after the infusion.

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TABLE 4.Blood Pressure of Patients With Treatment-Resistant Major Depression Following a Single Infusion of Ketamine or Midazolam
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