The mechanistic basis for the rapid antidepressant-like effects of ketamine: From neural circuits to molecular pathways.
Progress in Neuro-Psychopharmacology and Biological Psychiatry December 1, 2023 DOI: 10.1016/j.pnpbp.2023.110910 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Esketamine Ketamine |
| Key findings | Ketamine's rapid antidepressant-like effects are mediated through the glutamate system, synaptic plasticity, and interactions among GABAergic, serotonergic systems, and astrocytes. |
Abstract
Conventional antidepressants that target monoaminergic receptors require several weeks to be efficacious. This lag represents a significant problem in the currently available treatments for serious depression. Ketamine, acting as an N-methyl-d-aspartate receptor antagonist, was shown to have rapid antidepressant-like effects, marking a significant advancement in the study of mood disorders. However, serious side effects and adverse reactions limit its clinical use. Considering the limitations of ketamine, it is crucial to further define the network targets of ketamine. The rapid action of ketamine an as antidepressant is thought to be mediated by the glutamate system. It is believed that synaptic plasticity is essential for the rapid effects of ketamine as an antidepressant. Other mechanisms include the involvement of the γ-aminobutyric acidergic (GABAergic), 5-HTergic systems, and recent studies have linked astrocytes to ketamine's rapid antidepressant-like effects. The interactions between these systems exert a synergistic rapid antidepressant effect through neural circuits and molecular mechanisms. Here, we discuss the neural circuits and molecular mechanisms underlying the action of ketamine. This work will help explain how molecular and neural targets are responsible for the effects of rapidly acting antidepressants and will aid in the discovery of new therapeutic approaches for major depressive disorder.
Comparable studies
Other narrative reviews on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms | 2018 | Review | |
| Mechanisms of Ketamine Action as an Antidepressant | 2018 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) | 2013 | Review | |
| A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | 2017 | Review and consensus statement |
Citations in the library
Cited by 10
- Beyond NMDA Receptors: A Narrative Review of Ketamine's Rapid and Multifaceted Mechanisms in Depression Treatment. International Journal of Molecular Sciences December 20, 2024
- Ketamine and its enantiomers for depression: a bibliometric analysis from 2000 to 2023. European Archives of Psychiatry and Clinical Neuroscience April 25, 2024
- S-ketamine ameliorates post-stroke depression in mice via attenuation of neuroinflammation, synaptic restoration, and BDNF pathway activation. Biochemical and Biophysical Research Communications July 8, 2025
- Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets. Cell April 30, 2026
- Role of ketamine in treatment-resistant depression Journal of Education, Health and Sport April 5, 2025
and 5 more in the library
Cites 57
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- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
and 52 more in the library