Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression: A Randomized Midazolam-Controlled Trial
Abstract
Objective:
Adolescent depression is prevalent and is associated with significant morbidity and mortality. Although intravenous ketamine has shown efficacy in adult treatment-resistant depression, its efficacy in pediatric populations is unknown. The authors conducted an active-placebo-controlled study of ketamine’s safety and efficacy in adolescents.
Methods:
In this proof-of-concept randomized, double-blind, single-dose crossover clinical trial, 17 adolescents (ages 13–17) with a diagnosis of major depressive disorder received a single intravenous infusion of either ketamine (0.5 mg/kg over 40 minutes) or midazolam (0.045 mg/kg over 40 minutes), and the alternate compound 2 weeks later. All participants had previously tried at least one antidepressant medication and met the severity criterion of a score >40 on the Children’s Depression Rating Scale–Revised. The primary outcome measure was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after treatment.
Results:
A single ketamine infusion significantly reduced depressive symptoms 24 hours after infusion compared with midazolam (MADRS score: midazolam, mean=24.13, SD=12.08, 95% CI=18.21, 30.04; ketamine, mean=15.44, SD=10.07, 95% CI=10.51, 20.37; mean difference=−8.69, SD=15.08, 95% CI=−16.72, −0.65, df=15; effect size=0.78). In secondary analyses, the treatment gains associated with ketamine appeared to remain 14 days after treatment, the latest time point assessed, as measured by the MADRS (but not as measured by the Children’s Depression Rating Scale–Revised). A significantly greater proportion of participants experienced a response to ketamine during the first 3 days following infusion as compared with midazolam (76% and 35%, respectively). Ketamine was associated with transient, self-limited dissociative symptoms that affected participant blinding, but there were no serious adverse events.
Conclusions:
In this first randomized placebo-controlled clinical trial of intravenous ketamine in adolescents with depression, the findings suggest that it is well tolerated acutely and has significant short-term (2-week) efficacy in reducing depressive symptoms compared with an active placebo.
Reprinted from Am J Psychiatry 2021; 178:352–362 with permission from American Psychiatric Association Publishing.
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Received: 6 January 2020
Revision received: 22 September 2020
Revision received: 12 November 2020
Accepted: 25 November 2020
Published in print: Spring 2022
Published online: 22 April 2022
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Supported by a Ritvo Pilot Grant (Yale University, awarded to Dr. Dwyer), an AACAP Pilot Award (to Dr. Dwyer), and a Thrasher Pediatric Research Fund Early Career Award (to Dr. Dwyer). NIH grant T32MH018268 provided salary support for Dr. Dwyer, Dr. Londono Tobon, and Dr. Flores.The funding agencies had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Dr. Dwyer has received research support from the Klingenstein Third Generation Foundation, NIMH, and the AACAP Junior Investigator Award, and she has served as a consultant for Axsome Therapeutics. Dr. Flores receives funding as a research and clinical fellow at Yale’s Neuroscience Research Training Program through the Daniel X. and Mary Freedman Foundation. Dr. Couloures’s spouse has served as a consultant for Certara. Dr. Sanacora has served as a consultant for Allergan, Alkermes, AstraZeneca, Avanir Pharmaceuticals, Axsome Therapeutics, Biohaven Pharmaceuticals, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Clexio Biosciences, Denovo Biopharma, Engrail Therapeutics, Epiodyne, Hoffman LaRoche, Intra-Cellular Therapies, Janssen, Lundbeck, Merck, Minerva Pharmaceuticals, Naurex, Navitor Pharmaceuticals, Neurocrine, NeuroRx, Novartis, Noven Pharmaceuticals, Otsuka, Perception Neuroscience, Praxis Therapeutics, Sage Pharmaceuticals, Seelos Pharmaceuticals, Servier Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant, VistaGen Therapeutics, and XW Labs; he has received research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceuticals, Johnson & Johnson, Hoffman LaRoche, Merck, Naurex, Servier, and Usona Institute; he holds equity in Biohaven Pharmaceuticals; and he has received royalties from Yale University from patent licenses with Biohaven Pharmaceuticals. Dr. Bloch has served on scientific advisory boards for Teva Pharmaceuticals and Therapix Biosciences; he receives research support from Biohaven Pharmaceuticals, Janssen Pharmaceuticals, Neurocrine Biosciences, and Therapix Biosciences. The other authors report no financial relationships with commercial interests.
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