Signaling pathways underlying the rapid antidepressant actions of ketamine
Open accessAbstract
Currently available medications have significant limitations, most notably low response rate and time lag for treatment response. Recent clinical studies have demonstrated that ketamine, an NMDA receptor antagonist produces a rapid antidepressant response (within hours) and is effective in treatment resistant depressed patients. Molecular and cellular studies in rodent models demonstrate that ketamine rapidly increases synaptogenesis, including increased density and function of spine synapses, in the prefrontal cortex (PFC). Ketamine also produces rapid antidepressant actions in behavioral models of depression, and reverses the deficits in synapse number and behavior resulting from chronic stress exposure. These effects of ketamine are accompanied by stimulation of the mammalian target of rapamycin (mTOR), and increased levels of synaptic proteins. Together these studies indicate that ketamine rapidly reverses the atrophy of spines in the PFC and thereby causes a functional reconnection of neurons that underlies the rapid behavioral responses. These findings identify new targets for rapid acting antidepressants that are safer than ketamine. This article is part of a Special Issue entitled 'Anxiety and Depression'.
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Ketamine administration reverses synaptic loss and depressive-like behavior induced by chronic stress in preclinical models.
“Pioneering preclinical work carried out by Duman et al. indicates that administration of ketamine reverses the synaptic loss and depressive-like behavior induced by chronic stress 15,29,30 .”
From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [29]
mTOR is a serine/threonine kinase that regulates neurogenesis, dendritic spine growth, protein translation initiation, and protein synthesis via phosphorylation of p70S6 kinase and repression of 4E binding proteins.
“Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates neurogenesis, dendritic spine growth, protein translation initiation, and protein synthesis via a phosphorylation of p70S6 kinase and repression of 4E binding proteins (4EBP 173–175).”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [173]
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- Authors
- Duman, R. S., Li, N., Liu, R.-J., Duric, V., & Aghajanian, G.
- Affiliations
- Yale University (US)
- Corresponding author
- Duman, Ronald S.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 62
- Issue
- 1
- Pages
- 35-41
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC3195863
- OpenAlex
- W1964466640
- Cited by
- 537
- References
- 61
- Citations by year
- 2026: 14 · 2025: 24 · 2024: 24 · 2023: 25 · 2022: 38 · 2021: 39 · 2020: 50 · 2019: 28 · 2018: 38 · 2017: 41 · 2016: 48 · 2015: 51 · 2014: 45 · 2013: 41 · 2012: 25
- FWCI
- 4.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH093897)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- ketamine, rapid-acting antidepressants, NMDA receptor antagonism, treatment-resistant depression, synaptogenesis, dendritic spine plasticity, prefrontal cortex, mTOR signaling, chronic stress, synaptic proteins
- MeSH terms
- Animals, Antidepressive Agents, Depression, Gene Expression Regulation, Humans, Ketamine, Models, Biological, Neurons, Synapses, Signal Transduction, Neurogenesis
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