A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder
Abstract
Objective:
Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors’ previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD.
Methods:
Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale–Revised, the Montgomery‐Åsberg Depression Rating Scale (MADRS), and side effect measures.
Results:
The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events.
Conclusions:
This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine’s full potential as a treatment for chronic PTSD.
Reprinted from Am J Psychiatry 2021; 178:193–202, with permission from American Psychiatric Association Publishing. Copyright © 2021
Formats available
You can view the full content in the following formats:
Information & Authors
Information
Published In
History
Published in print: Summer 2023
Published online: 14 July 2023
Authors
Funding Information
Department of Psychiatry, Depression and Anxiety Center for Discovery and Treatment, Icahn School of Medicine at Mount Sinai, New York (Feder, Costi, Rutter, A.B. Collins, Jha, Horn, Kautz, Corniquel, K.A. Collins, Bevilacqua, Murrough, Charney); Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York (Govindarajulu); Nathan Kline Institute for Psychiatric Research, Orangeburg, N.Y. (K.A. Collins); Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine at Mount Sinai, New York (Glasgow, Brallier); Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (Pietrzak); Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York (Murrough, Charney); and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York (Charney).
Drs. Murrough and Charney share senior authorship.
Send correspondence to Dr. Feder ([email protected]).
Supported by an Independent Investigator Award from the Brain and Behavior Research Foundation (principal investigator, Dr. Feder), Technology Development Awards from Mount Sinai Innovation Partners and the Mount Sinai i3 Accelerator, and a donation from Mr. Gerald Greenwald and Mrs. Glenda Greenwald. Additional funding for this study was provided by the Ehrenkranz Laboratory for Human Resilience, a component of the Depression and Anxiety Center for Discovery and Treatment at ISMMS.ClinicalTrials.gov identifier: NCT02397889.Drs. Feder and Charney are co-inventors on an issued patent in the United States and several issued patents outside of the United States, filed by the Icahn School of Medicine at Mount Sinai (ISMMS) for the use of ketamine as therapy for posttraumatic stress disorder; this intellectual property has not been licensed. Dr. Jha has received contract research grant support from Acadia Pharmaceuticals and Janssen Research and Development and honoraria for CME presentations from the North American Center for Continuing Medical Education and Global Medical Education. Dr. K. Collins is a paid independent rater for Medavante-Prophase. Dr. Murrough has provided consultation services or served on advisory boards for Allergan, Boehreinger Ingelheim, Clexio Biosciences, Fortress Biotech, FSV7, Global Medical Education, Impel Neuropharma, Janssen Research and Development, Medavante-Prophase, Novartis, Otsuka, and Sage Therapeutics. Dr. Murrough is also a co-inventor on a patent application filed by ISMMS for the use of ezogabine and other KCNQ channel openers to treat depression and related conditions; this intellectual property has not been licensed. Drs. Murrough and Charney are co-inventors on a patent application filed by ISMMS for the use of intranasally administered neuropeptide Y for the treatment of mood and anxiety disorders; this intellectual property has not been licensed. Dr. Charney is co-inventor on several issued U.S. patents, and several pending U.S. patent applications, filed by ISMMS for the use of ketamine as therapy for treatment-resistant depression and suicidal ideation. ISMMS has entered into a licensing agreement with Janssen Pharmaceuticals and receives payments from Janssen under the license agreement related to these patents; as a co-inventor, Dr. Charney is entitled to a portion of the payments received by the ISMMS. Because esketamine has received regulatory approval for treatment-resistant depression, ISMMS and Dr. Charney, as an employee and a co-inventor, will be entitled to additional payments under the license agreement. Dr. Charney is also a co-inventor on several patents filed by ISMMS for a cognitive training intervention to treat depression and related psychiatric disorders. ISMMS has entered into a licensing agreement with Click Therapeutics and receives payments related to the use of this cognitive training intervention for the treatment of psychiatric disorders. In accordance with the ISMMS Faculty Handbook, Dr. Charney has received a portion of these payments and is entitled to a portion of any additional payments that the medical school might receive from this license with Click Therapeutics. The other authors report no financial relationships with commercial interests.Metrics & Citations
Metrics
Citations
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
There are no citations for this item
View Options
Get Access
Login options
Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.
Personal login Institutional Login Open Athens loginNot a subscriber?
PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.
Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).