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Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation
Open accessAbstract
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.
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“Available evidence also indicates that the efficacy of ketamine/esketamine in the acute treat ment of TRD is also apparent in individuals with greater de grees of antidepressant resistance 205 .”
From Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions (2023) · cites this paper as [205]
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“The risks for the foregoing safety concerns would be expected to be mitigated when administering ketamine/esketamine under medical supervision in accordance with best practices 205 .”
From Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions (2023) · cites this paper as [205]
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“This result is in line with a recent review of literature emphasising that tolerance of ketamine is good.32”
From Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial (2022) · cites this paper as [32]
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de Miranda, A. S., Toscano, E. C. D. B., Venna, V. R., Graeff, F. G., & Teixeira, A. L. (2025) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2025.2460674 · Cited by 3
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Pacilio, R. M., & Geller, J. A. (2025) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000001995 · Cited by 2
Alborghetti, M., Lionetto, L., Lombardozzi, G., Montaguti, L., Trovini, G., Donato, D., Costanzi, G., Bernardini, D. D., Catapano, F., Surano, M., et al. (2025) · Current Neuropharmacology · doi:10.2174/011570159x356952241216172603 · Cited by 3
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Racial-Ethnic Disparities in Ketamine and Esketamine Therapy for Major Depressive Disorder
Liu, M., Branning, R., Lee, A., Kaelber, D. C., & Gao, K. (2025) · Psychiatric Services · doi:10.1176/appi.ps.20240559 · Cited by 4
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López‐Díaz, Á., de Lope, L. R., & Vega, D. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.10.036 · Cited by 2
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Soubolsky, A., Visentin, J. D., & Crawley, A. (2023) · Canadian Family Physician · doi:10.46747/cfp.6911777 · Cited by 2
Recommendations for the Usage of Ketamine and Esketamine
Reus, V. I. (2021) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2021.21060555 · Cited by 2
Recent Advances in Psychopharmacology
Poznanski, A. J., & Akinyemi, E. (2022) · Advances in Psychiatry and Behavioral Health · doi:10.1016/j.ypsc.2022.03.009 · Cited by 2
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Self-citationInibidores da monoaminoxidase e cetamina intravenosa: uma associação segura?
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Chapter 20. Psychopharmacology
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Metadata
- Authors
- 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. W., Mansur, R. B., Papakostas, G. I., Subramaniapillai, M., Thase, M., Vieta, E., Young, A. H., Zarate, C. A., & Stahl, S.
- Affiliations
- University Health Network (CA)
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto (McIntyre, Rosenblat, Y. Lee, Lui, Mansur); Department of Psychiatry, University of Toronto, Toronto (McIntyre, Rosenblat, Mansur); Department of Pharmacology, University of Toronto, Toronto (McIntyre); Brain and Cognition Discovery Foundation, Toronto (McIntyre, Subramaniapillai); Canadian Rapid Treatment Center of Excellence, Mississauga, Ontario (Rosenblat, Kratiuk); Department of Psychiatry and Behavioral Sciences, Austin Dell...
- ORCID
- McIntyre, Roger S.
- Rosenblat, Joshua D.
- Nemeroff, Charles B.
- Sanacora, Gerard
- Murrough, James W.
- Brietzke, Elisa
- Dodd, Seetal
- Gorwood, Philip
- Ho, Roger
- Iosifescu, Dan V.
- Kasper, Siegfried
- Kratiuk, Kevin
- Lee, Jung Goo
- Lee, Yena
- Lui, Leanna M.W.
- Mansur, Rodrigo B.
- Papakostas, George I.
- Subramaniapillai, Mehala
- Thase, Michael
- Vieta, Eduard
- Young, Allan H.
- Zarate, Carlos A.
- Stahl, Stephen
- Venue
- American Journal of Psychiatry
- Published
- 2021-05-01
- Volume
- 178
- Issue
- 5
- Pages
- 383-399
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC9635017
- OpenAlex
- W3137976016
- Semantic Scholar
- 3cd087ef6947b39c8c924b7248d9d40de77b9e44
- Cited by
- 731
- References
- 168
- Citations by year
- 2026: 129 · 2025: 167 · 2024: 165 · 2023: 141 · 2022: 83 · 2021: 44
- FWCI
- 13.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Wellcome Trust
- National Institute for Health and Care Research (NIHR202380)
- National Institutes of Health (Z99 MH999999)
- National Institute of Mental Health (ZIAMH002857, ZIAMH002927)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- ketamine, esketamine, treatment-resistant depression, major depressive disorder, drug safety and tolerability, clinical implementation, treatment algorithm, expert consensus
- MeSH terms
- Implementation Science, Antidepressive Agents, Delivery of Health Care, Depressive Disorder, Major, Major Depressive Disorder, Dissociative Disorders, Humans, Hypertension, Ketamine, Monitoring, Physiologic, Personnel Staffing and Scheduling, Psychoses, Substance-Induced, Patient Selection, Excitatory Amino Acid Antagonists, Substance-Related Disorders, Suicidal Ideation, Lower Urinary Tract Symptoms, Depressive Disorder, Treatment-Resistant
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