Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation
This study (2021), written by a large group of international experts, reviews the state of knowledge around ketamine and esketamine as potential treatments for treatment-resistant depression (TRD). Special attention is given to the risk of suicide after discontinuing (es)ketamine treatment.
Authors
- Roger McIntyre
- Carlos Zarate
- Jonathan Rosenblat
Published
Abstract
Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.
Research Summary of 'Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation'
Introduction
Mcintyre and colleagues frame the paper by noting that a large proportion of people with major depressive disorder do not achieve full symptomatic or functional recovery with conventional monoamine-based antidepressants, and that remission rates in treatment-resistant depression (TRD) are reportedly less than 15% after two prior conventional treatment or augmentation failures. Intranasal esketamine received regulatory approval for TRD in 2019 (and an expanded U.S. indication in 2020 for major depression with suicidal ideation or behaviour), and growing clinical and public interest has accompanied expanding use of ketamine formulations. At the same time, uncertainties remain about long-term efficacy, safety, tolerability, patient selection, abuse liability, and appropriate clinical settings and personnel for safe implementation. This article presents an expert synthesis of the literature on ketamine and esketamine for adults with TRD, focusing on pharmacology, efficacy, safety, tolerability, and practical implementation at the point of care. The authors explicitly state this is not an exhaustive systematic review but rather an international expert opinion that summarises key findings from clinical trials, meta-analyses, regulatory documents, and preclinical work, and identifies areas of consensus and priorities for future research and implementation guidance.
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Study Details
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McIntyre, R. S., Rosenblat, J. D., Nemeroff, C. B., Sanacora, G., Murrough, J. W., Berk, M., Brietzke, E., Dodd, S., Gorwood, P., Ho, R., Iosifescu, D. V., Lopez Jaramillo, C., Kasper, S., Kratiuk, K., Lee, J. G., Lee, Y., Lui, L. M., Mansur, R. B., Papakostas, G. I., . . . Stahl, S. (2021). Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. American Journal of Psychiatry, 178(5), 383-399. https://doi.org/10.1176/appi.ajp.2020.20081251
References (24)
Papers cited by this study that are also in Blossom
Wilkinson, S. T., Ballard, E. D., Bloch, M. H. et al. · American Journal of Psychiatry (2017)
Zanos, P., Gould, T. D. · Molecular Psychiatry (2018)
Williams, N. R., Heifets, B. D., Bentzley, B. S. et al. · Molecular Psychiatry (2019)
Yoon, G., Petrakis, I. L., Krystal, J. H. · JAMA Psychiatry (2019)
Sanacora, G., Frye, M. A., McDonald, W. et al. · JAMA Psychiatry (2017)
Sanacora, G., Schatzberg, A. F. · Neuropsychopharmacology (2021)
Singh, J. B., Fedgchin, M., Daly, E. J. et al. · American Journal of Psychiatry (2016)
Bahji, A., Vazquez, G. H., Zarate, C. A. · Journal of Affective Disorders (2021)
Ionescu, D. F., Lane, R., Lim, P. et al. · Journal of Clinical Psychiatry (2020)
Ionescu, D. F., Qiu, X., Lane, R. et al. · International Journal of Neuropsychopharmacology (2020)
Show all 24 referencesShow fewer
Short, B., Fong, J., Galvez, V. et al. · Lancet Psychiatry (2017)
Luckenbaugh, D. A., Niciu, M. J., Ionescu, D. F. et al. · Journal of Affective Disorders (2014)
Niciu, M. J., Shovestul, B. J., Jaso, B. A. et al. · Journal of Affective Disorders (2018)
Bartova, L., Papageorgiou, K., Milenkovic, I. et al. · European Neuropsychopharmacology (2018)
Murrough, J. W., Burdick, K. E., Levitch, C. F. et al. · Neuropsychopharmacology (2014)
Riva-Posse, P., Reiff, C. M., Edwards, J. A. et al. · Journal of Affective Disorders (2018)
Ionescu, D. F., Bentley, K. H., Eikermann, M. et al. · Journal of Affective Disorders (2019)
Rong, C., Park, C., Rosenblat, J. D. et al. · International Journal of Environmental Research and Public Health (2018)
Salloum, N. C., Fava, M., Freeman, M. P. et al. · Depression and Anxiety (2018)
Dakwar, E., Nunes, E. V., Hart, C. L. et al. · American Journal of Psychiatry (2019)
Dakwar, E., Levin, F. R., Hart, C. L. et al. · American Journal of Psychiatry (2020)
Abdallah, C. G., Averill, L. A., Gueorguieva, R. et al. · Neuropsychopharmacology (2020)
Gastaldon, C., Raschi, E., Kane, J. M. et al. · Psychotherapy and Psychosomatics (2020)
Greenway, K. T., Garel, N., Jerome, L. et al. · Expert Review of Clinical Pharmacology (2020)
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