Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder
This randomised, double-blind, active placebo-controlled crossover proof-of-concept study (n=41) compared the efficacy of ketamine (35mg/70kg) and midazolam (3.15mg/70kg) for the treatment of patients with depressive symptoms associated with chronic PTSD. They found a rapid reduction in symptom severity following intravenous ketamine infusion.
Abstract
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.
Research Summary of 'Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder'
Introduction
Posttraumatic stress disorder (PTSD) is a chronic, disabling condition marked by persistent re‑experiencing, avoidance, and hyperarousal following severe trauma. The authors note that existing pharmacotherapies (for example selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors) often leave many patients with residual symptoms or nonresponse. Emerging preclinical and clinical evidence implicates glutamate in stress responsivity and traumatic memory formation, and intravenous (IV) ketamine—an N‑methyl‑D‑aspartate (NMDA) receptor antagonist—has demonstrated rapid antidepressant effects at sub‑anesthetic doses in treatment‑resistant depression, suggesting a potential therapeutic role in PTSD. Feder and colleagues therefore conducted a proof‑of‑concept, randomised, double‑blind, crossover trial to test whether a single sub‑anesthetic IV ketamine infusion would rapidly reduce core PTSD symptoms compared with an active placebo (midazolam). Their primary hypothesis was that ketamine would produce a significantly greater reduction in PTSD symptom severity 24 hours after infusion; a secondary hypothesis was that ketamine would produce a rapid antidepressant effect in patients with PTSD.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Author
- APA Citation
Feder, A., Parides, M. K., Murrough, J. W., Perez, A. M., Morgan, J. E., Saxena, S., Kirkwood, K., aan het Rot, M., Lapidus, K. A. B., Wan, L., Iosifescu, D., & Charney, D. S. (2014). Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder. JAMA Psychiatry, 71(6), 681. https://doi.org/10.1001/jamapsychiatry.2014.62
References (2)
Papers cited by this study that are also in Blossom
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
Mcghee, L. L., Maani, C. V., Garza, T. H. et al. · Journal of Trauma Injury Infection and Critical Care (2008)
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Cavarra, M., Falzone, A., Ramaekers, J. G. et al. · Frontiers in Psychology (2022)
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Olson, D. E. · Journal of Neurochemistry (2021)
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O'brien, B., Lijffijt, M., Wells, A. et al. · Pharmaceuticals (2019)
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Schenberg, E. E. · Frontiers in Pharmacology (2018)
Cameron, L. P., Benson, C. J., Dunlap, L. E. · ACS Chemical Neuroscience (2018)
Girgenti, M. J., Ghosal, S., Lopresto, D. et al. · Neurobiology of Disease (2017)
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