Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond
Open accessAbstract
Traditional antidepressants require many weeks to reveal their therapeutic effects. However, the widely replicated observation that a single subanesthetic dose of the N-methyl-D-aspartate glutamate receptor antagonist ketamine produced meaningful clinical improvement within hours, suggested that rapid-acting antidepressants might be possible. The ketamine studies stimulated a new generation of basic antidepressant research that identified new neural signaling mechanisms in antidepressant response and provided a conceptual framework linking a group of novel antidepressant mechanisms. This article presents the path that led to the testing of ketamine, considers its promise as an antidepressant, and reviews novel treatment mechanisms that are emerging from this line of research.
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Dysfunction of synaptic plasticity with neuronal atrophy and cell death contributes to the pathophysiology of depression.
“While synaptic plasticity is a well-known key mechanism in learning and memory (Dayan and Cohen, 2011;Kandel, 2001), unequivocal studies suggest that dysfunction of synaptic plasticity with neuronal atrophy and cell death contribute to the pathophysiology of depression and therapeutic response could be associated with overcoming this deficit (Duman and Aghajanian, 2012;Krystal et al., 2013;Shakesb”
From Serotonin and neuroplasticity – Links between molecular, functional and structural pathophysiology in depression (2017) · cites this paper as Krystal et al., 2013
In “Glutamate and the neurobiology of depression” (page unavailable), the review links disrupted glutamate signaling to dendritic atrophy and synapse loss, which it suggests may contribute to major depression. It mentions activation of pathways associated with cell death, but does not establish neuronal cell death as part of depression’s pathophysiology. The claim also states this proposed contribution more firmly than the review does. (LLM, conf=0.87)
Experimental — accuracy not yet measuredKetamine's antidepressant effect is observed long after ketamine has been metabolized and excreted from the body and after ketamine's sedative and dissociative effects have dissipated.
“Ketamine's antidepressant effect is observed long after ketamine has been metabolized and excreted from the body and after ketamine's sedative and dissociative effects have dissipated (Krystal et al, 2013).”
From Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial (2018) · cites this paper as Krystal et al, 2013
In “NMDA receptor antagonists as rapid-acting antidepressants” (page unavailable), the paper says antidepressant effects emerge after ketamine’s psychotigenic and euphoric effects disappear and may last days or longer. It does not establish that ketamine has been metabolized and excreted by then, or specifically discuss the dissipation of sedative effects. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNovel rapidly acting antidepressants in the glutamate system such as ketamine are thought to exert at least parts of their action by stimulating neuroplasticity.
“Novel rapidly acting antidepressants in the glutamate system such as ketamine are thought to exert at least parts of their action by stimulating neuroplasticity (Krystal et al., 2013).”
From Serotonin and neuroplasticity – Links between molecular, functional and structural pathophysiology in depression (2017) · cites this paper as Krystal et al., 2013
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References 128 · Cited by 406
Research works printed but not linked: 2
- [5]5. Organization, WH. The global burden of diseasse: 2004 update. WHO Press; Geneva, Switzerland: 2008.
- [40]40. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al. A randomized add-on trial of an N-methyl-D-aspartate (NMDA) antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010 in press.
- Authors
- Krystal, J. H., Sanacora, G., & Duman, R. S.
- Affiliations
- Yale University (US)
- Corresponding author
- Krystal, John H.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 73
- Issue
- 12
- Pages
- 1133-1141
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3671489
- OpenAlex
- W2018114814
- Cited by
- 406
- References
- 128
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 21 · 2023: 21 · 2022: 23 · 2021: 28 · 2020: 29 · 2019: 25 · 2018: 30 · 2017: 48 · 2016: 37 · 2015: 55 · 2014: 42 · 2013: 11
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (UL1RR024139)
- Abbott Laboratories
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- State of Connecticut Department of Mental Health and Addiction Services
- Yale University
- Gilead Sciences
- Teva Pharmaceutical Industries
- F. Hoffmann-La Roche
- Sunovion
- Georgia Clinical and Translational Science Alliance (UL1 RR024139)
- Eisai
- Shire
- Astellas Pharma
- Merz Pharmaceuticals
- H. Lundbeck A/S
- Astellas Pharma Global Development
- Pfizer Pharmaceuticals
- National Center for PTSD, U.S. Department of Veterans Affairs
- National Institute on Alcohol Abuse and Alcoholism (P50AA012870)
- National Institute of Mental Health (R01MH085055, R01MH081211, MH 17871, MH093897, R01MH093897, R37MH017871, K02MH076222, R01MH017871)
- National Center for Research Resources (UL1RR024139)
- Janssen Pharmaceuticals
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- rapid-acting antidepressants, ketamine, NMDA receptor antagonists, antidepressant mechanism, antidepressant response, treatment-resistant depression
- MeSH terms
- Animals, Antidepressive Agents, Depression, Humans, Ketamine, Glutamic Acid
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