Ketamine: A Paradigm Shift for Depression Research and Treatment
Open accessAbstract
Ketamine is the first exemplar of a rapid-acting antidepressant with efficacy for treatment-resistant symptoms of mood disorders. Its discovery emerged from a reconceptualization of the biology of depression. Neurobiological insights into ketamine efficacy shed new light on the mechanisms underlying antidepressant efficacy.
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Ketamine is now FDA-approved for depression as intranasally delivered S-ketamine.
“Currently, the most widely prescribed psychedelic-related compound is ketamine, a noncompetitive antagonist of NMDARs that has been used safely at high doses as an anesthetic for decades, and is now FDA-approved for depression (intranasally delivered S-ketamine) (Aan Het Rot et al., 2012;Krystal et al., 2019).”
From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Krystal et al., 2019
The treatment-algorithm section discusses esketamine as a treatment for depression, particularly in the context of growing safety and efficacy data. It does not state that intranasal S-ketamine is FDA-approved; searches for FDA approval and intranasal delivery found no supporting passage. No page number is available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredKetamine has been used safely at high doses as an anesthetic for decades.
“Currently, the most widely prescribed psychedelic-related compound is ketamine, a noncompetitive antagonist of NMDARs that has been used safely at high doses as an anesthetic for decades, and is now FDA-approved for depression (intranasally delivered S-ketamine) (Aan Het Rot et al., 2012;Krystal et al., 2019).”
From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Krystal et al., 2019
In “The opportunity: a broader circuitry perspective” (page unavailable), the paper refers to clinical reports of ketamine’s effects in an anesthesia context and distinguishes its depression-study dose from an anesthetizing dose. It does not say that high-dose anesthetic use has been safe for decades. The safety discussion under “What does long-term ketamine treatment look like?” instead identifies risks that require management. (LLM, conf=0.82)
Experimental — accuracy not yet measuredKetamine is a noncompetitive antagonist of NMDARs.
“Currently, the most widely prescribed psychedelic-related compound is ketamine, a noncompetitive antagonist of NMDARs that has been used safely at high doses as an anesthetic for decades, and is now FDA-approved for depression (intranasally delivered S-ketamine) (Aan Het Rot et al., 2012;Krystal et al., 2019).”
From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Krystal et al., 2019
The sections “The opportunity: a broader circuitry perspective” and “Mechanism of action: ketamine as ‘the tip of the iceberg’” identify ketamine as an NMDA receptor antagonist and say it blocks NMDA receptors. Our copy does not specify that ketamine’s antagonism is noncompetitive, so it supports the receptor target but not that classification. (LLM, conf=0.82)
Experimental — accuracy not yet measured
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Cites
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- Authors
- Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S., & Duman, R. S.
- Affiliations
- Yale New Haven Hospital (US)
- Yale University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Krystal, John H.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 101
- Issue
- 5
- Pages
- 774-778
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6560624
- OpenAlex
- W2921561928
- Cited by
- 455
- References
- 2
- Citations by year
- 2026: 55 · 2025: 60 · 2024: 74 · 2023: 62 · 2022: 67 · 2021: 62 · 2020: 52 · 2019: 22
- FWCI
- 31.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- AstraZeneca
- Vistagen Therapeutics
- Merck
- Johnson and Johnson
- Broad Institute
- Yale Center for Clinical Investigation, Yale School of Medicine (UL1 RR024139, P01HL131478)
- National Institute of Mental Health (MH093897, MH045481, MH077681)
- Yale University (OCR 7088 US01, OCR 7451 US01, 00754)
- Boehringer Ingelheim
- Eli Lilly and Company
- Avanir Pharmaceuticals
- Harvard University
- Icahn School of Medicine at Mount Sinai (14/889,746, FSV7, 15/417,689, 15/379,013)
- BlackThorn Therapeutics
- Taiho Pharmaceutical
- Roche
- Janssen Research and Development
- Brain and Behavior Research Foundation
- Bristol-Myers Squibb
- U.S. Department of Veterans Affairs
- National Institute on Alcohol Abuse and Alcoholism
- Sunovion
- Teva Pharmaceutical Industries
- Valeant Pharmaceuticals International
- Topics
- Health Sciences › Medicine › Pharmacology › 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, rapid-acting antidepressants, treatment-resistant depression, mood disorders, antidepressant mechanism, neurobiology of depression
- MeSH terms
- Animals, Antidepressive Agents, Humans, Ketamine, Synaptic Transmission, Excitatory Amino Acid Antagonists
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