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Original Investigation |

Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder:  A Randomized Clinical Trial

Adriana Feder, MD1; Michael K. Parides, PhD2; James W. Murrough, MD1,3; Andrew M. Perez, MD4; Julia E. Morgan, BA1; Shireen Saxena, MScPH5; Katherine Kirkwood, MS2; Marije aan het Rot, PhD6; Kyle A. B. Lapidus, MD, PhD1,3; Le-Ben Wan, MD, PhD1; Dan Iosifescu, MD1,3; Dennis S. Charney, MD1,3,7
[+] Author Affiliations
1Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
2Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, New York
3Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York
4Department of Anesthesiology, Icahn School of Medicine at Mount Sinai, New York, New York
5School of Public Health, Charité–Universitätsmedizin Berlin, Berlin, Germany
6Department of Psychology, University of Groningen, Groningen, the Netherlands
7Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York
JAMA Psychiatry. 2014;71(6):681-688. doi:10.1001/jamapsychiatry.2014.62.
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Importance  Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of posttraumatic stress disorder (PTSD), a chronic and disabling condition.

Objective  To test the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms in patients with chronic PTSD.

Design, Setting, and Participants  Proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, conducted at a single site (Icahn School of Medicine at Mount Sinai, New York, New York). Forty-one patients with chronic PTSD related to a range of trauma exposures were recruited via advertisements.

Interventions  Intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and midazolam (0.045 mg/kg).

Main Outcomes and Measures  The primary outcome measure was change in PTSD symptom severity, measured using the Impact of Event Scale–Revised. Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression–Severity and –Improvement scales, and adverse effect measures, including the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale.

Results  Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity, compared with midazolam, when assessed 24 hours after infusion (mean difference in Impact of Event Scale–Revised score, 12.7 [95% CI, 2.5-22.8]; P = .02). Greater reduction of PTSD symptoms following treatment with ketamine was evident in both crossover and first-period analyses, and remained significant after adjusting for baseline and 24-hour depressive symptom severity. Ketamine was also associated with reduction in comorbid depressive symptoms and with improvement in overall clinical presentation. Ketamine was generally well tolerated without clinically significant persistent dissociative symptoms.

Conclusions and Relevance  This study provides the first evidence for rapid reduction in symptom severity following ketamine infusion in patients with chronic PTSD. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with this disabling condition.

Trial Registration  clinicaltrials.gov Identifier: NCT00749203

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Figure 1.
Consolidated Standards of Reporting Trials Patient Flowchart

PTSD indicates posttraumatic stress disorder.

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Figure 2.
Changes in Posttraumatic Stress Disorder and Depressive Symptom Levels During the First Period

Change in the Impact of Event Scale–Revised (IES-R) total score, the IES-R mean subscale scores, and the Montgomery-Asberg Depression Rating Scale (MADRS) score over 1 week for the first period (n = 41). Error bars represent standard errors. For this study, the IES-R was modified to inquire about symptoms over the previous 24 hours (instead of the previous 7 days).

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Figure 3.
Emergence of Psychotic, Dissociative, and Manic Symptoms During the First Period

Change in the Brief Psychiatric Rating Scale (BPRS) Positive Symptoms subscale score (4 items corresponding to the positive symptoms of psychosis), the Clinician-Administered Dissociative States Scale (CADSS) score, and the Young Mania Rating Scale (YMRS) item-1 score (elevated mood) over 1 week for the first period (n = 41). Error bars represent standard errors. On the CADSS, 27 of 39 participants (69%) reported at least 1 dissociative symptom of at least moderate intensity while receiving ketamine, and 13 of 31 participants (42%) reported at least 1 dissociative symptom of at least moderate intensity while receiving midazolam, measured 40, 120, and 240 minutes after infusion.

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