The role of glutamatergic modulation in the mechanism of action of ketamine, a prototype rapid-acting antidepressant drug.
Pharmacological Reports October 2018 DOI: 10.1016/j.pharep.2018.02.011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Esketamine Ketamine |
| Keywords | Ampa receptor Antidepressant Nmda receptor Mglu receptor |
| Key findings | The review argues that ketamine's rapid antidepressant effect in treatment-resistant depression involves NMDA receptors, AMPA receptors, synaptogenesis, and modulation of glutamate transmission by mGlu receptor ligands, with enantiomers and metabolites also implicated. It contends that identifying the shared mechanism of rapid-acting antidepressants could help minimize their serious side effects, and that introducing new such drugs will depend on better integration of neuroscience research and clinical practice. |
Abstract
Over the past decade, ketamine has been one of the most commonly studied potential antidepressants. This is because it produces a spectacularly rapid and persistent therapeutic effect in people suffering from severe treatment-resistant depression (TRD), for which classical drugs are ineffective. Similar efficacy was demonstrated for scopolamine, a drug belonging to a completely different pharmacological group. This interesting coincidence piqued the interest of psychopharmacologists and prompted them to search for a possible common mechanism of these rapid acting antidepressant drugs (RAADs). A thorough explanation of this mechanism is also important because each of these substances induces serious side effects. Knowing the mechanism responsible for the therapeutic efficacy of RAADs could lead to minimizing, or even avoiding certain undesirable effects. This review provides an overview of the mechanism of action of a prototype RAAD, ketamine, in animal models, with a particular focus on the roles of NMDA receptors, AMPA receptors, synaptogenesis, and modulation of glutamate transmission by other modulators of this system, such as mGlu receptor ligands. Recently studied roles for ketamine enantiomers and metabolites in its rapid antidepressant effect are also considered. Finally, the results of multiple clinical trials are reported and discussed in relation to basic research. This review concludes that success in introducing novel therapeutic RAADs will depend on better cooperation and integration of neuroscience research and clinical practice.
Comparable studies
Other narrative reviews on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| 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 | |
| Long-term safety of ketamine and esketamine in treatment of depression | 2022 | Review | |
| Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms. | 2024 | Review | |
| Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review. Patients with depression | 2024 | Narrative review | |
| The Possible Application of Ketamine in the Treatment of Depression in Alzheimer’s Disease | 2022 | Review |
Citations in the library
Cited by 19
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 2019
- Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression CNS Drugs November 17, 2021
- (R)-Ketamine Induces a Greater Increase in Prefrontal 5-HT Release Than (S)-Ketamine and Ketamine Metabolites via an AMPA Receptor-Independent Mechanism The International Journal of Neuropsychopharmacology July 16, 2019
- Rapid-acting antidepressants. Advances in pharmacology (San Diego, Calif.) 2019
- Rapid-Acting Antidepressants Current Pharmaceutical Design October 19, 2018
and 14 more in the library
Cites 38
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- 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
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
and 33 more in the library