Convergent Mechanisms Underlying Rapid Antidepressant Action
Open accessAbstract
Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of the mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergone pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine, pro-drug of the glycine B NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists [i.e., GLYX-13 (rapastinel)], metabotropic glutamate receptor 2/3 (mGluR 2/3) antagonists, GABA A receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.
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Ketamine has been reported to have anti-suicidal and anti-anhedonic actions.
“Furthermore, ketamine has been reported to also have anti-suicidal and anti-anhedonic actions.14,19,20”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [20]
Ketamine is metabolized extensively via CYP2B6- and CYP3A4-mediated N-demethylation to norketamine, which then undergoes further catabolism to hydroxynorketamines and dehyronorketamine.
“Ketamine is metabolized extensively in the body via CYP2B6- and CYP3A4-mediated N-demethylation to norketamine. Norketamine then undergoes further catabolism to hydroxynorketamines (HNKs) and dehyronorketamine.20”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [20]
Chronic stress models respond quickly to acute fast-acting antidepressants such as ketamine.
“They also respond quickly to acute administration of fast-acting antidepressant compounds like ketamine [45].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [45]
Ketamine has strong antidepressant-like actions in preclinical models, including restoring reward behavior, promoting spine formation, restoring synaptic strength, and promoting pro-synaptic gene expression.
“Ketamine also exerts strong antidepressant-like actions in preclinical models, including restoration of reward behavior in chronically stressed animals, promotion of dendritic spine formation, restoration of synaptic strength, and promotion of expression of pro-synaptic genes [45].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [45]
Ketamine has antidepressant effects in many antidepressant-relevant tests in experimental animals.
“Moreover, antidepressant effects of ketamine have been demonstrated in many antidepressant-relevant tests in experimental animals (e.g. 9, 10–14); also see 15.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [15]
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References 365 · Cited by 171
Research works printed but not linked: 11
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- Authors
- Zanos, P., Thompson, S. M., Duman, R. S., Zarate, C. A., & Gould, T. D.
- Affiliations
- University of Maryland, Baltimore (US)
- Yale University (US)
- National Institutes of Health (US)
- Corresponding author
- Zanos, Panos
- Venue
- CNS Drugs
- Published
- 2018-03
- Volume
- 32
- Issue
- 3
- Pages
- 197-227
- ISSN
- 1172-7047 (ISSN-L)
- 1179-1934
- PMC
- PMC6005380
- OpenAlex
- W2790010984
- Cited by
- 171
- References
- 365
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 12 · 2023: 16 · 2022: 14 · 2021: 29 · 2020: 23 · 2019: 25 · 2018: 24 · 2016: 1
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- CNS Drugs (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (MH107615, MH086828)
- Harrington Discovery Institute Scholar-Innovator grant
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Keywords
- ketamine, rapid-acting antidepressants, depression, NMDA receptor, hydroxynorketamine, BDNF signaling, AMPA receptors, mTOR, scopolamine, GABA-A receptor modulators, serotonin receptors, suicidal behavior, anhedonia
- MeSH terms
- Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Humans, Time Factors
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