Role of group II metabotropic glutamate receptors in ketamine's antidepressant actions.
Anna Onisiforou, Polymnia Georgiou, Panos Zanos
Pharmacology, Biochemistry, and Behavior February 1, 2023 DOI: 10.1016/j.pbb.2023.173531 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | mGlu2/3 receptor inhibitors ketamine |
| Dose | sub-threshold doses of mGlu2/3 receptor inhibitors, sub-antidepressant doses of ketamine |
| Topics | Esketamine Ketamine |
| Key findings | The authors argue that mGlu2/3 receptor antagonists and ketamine share convergent mechanisms underlying rapid antidepressant effects, and that combining sub-threshold doses of mGlu2/3 inhibitors with sub-antidepressant ketamine doses produces synergistic antidepressant-relevant behavioral effects. They propose this combinatorial strategy may lower the risk of significant adverse events compared with standard doses, and that deconvoluting ketamine's targets could inform next-generation rapid-acting antidepressants. |
Abstract
Major depression (MDD) is a serious neuropsychiatric disorder afflicting around 16-17 % of the global population and is accompanied by recurrent episodes of sadness and suicidal thoughts. Current pharmacological interventions take several weeks to even months for an improvement in depressive symptoms to emerge, with a significant percentage of individuals not responding to these medications at all, thus highlighting the need for rapid and effective next-generation treatments for MDD. Pre-clinical studies in animals have demonstrated that antagonists of the metabotropic glutamate receptor subtype 2/3 (mGlu2/3 receptor) exert rapid antidepressant-like effects, comparable to the actions of ketamine. Therefore, it is possible that mGlu2 or mGlu3 receptors to have a regulatory role on the unique antidepressant properties of ketamine, or that convergent intracellular mechanisms exist between mGlu2/3 receptor signaling and ketamine's effects. Here, we provide a comprehensive and critical evaluation of the literature on these convergent processes underlying the antidepressant action of mGlu2/3 receptor inhibitors and ketamine. Importantly, combining sub-threshold doses of mGlu2/3 receptor inhibitors with sub-antidepressant ketamine doses induce synergistic antidepressant-relevant behavioral effects. We review the evidence supporting these combinatorial effects since sub-effective dosages of mGlu2/3 receptor antagonists and ketamine could reduce the risk for the emergence of significant adverse events compared with taking normal dosages. Overall, deconvolution of ketamine's pharmacological targets will give critical insights to influence the development of next-generation antidepressant treatments with rapid actions.
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 4
- Targeting metaplasticity mechanisms to promote sustained antidepressant actions. Molecular Psychiatry April 1, 2024
- Ketamine and Hydroxynorketamine as Novel Pharmacotherapies for the Treatment of Opioid Use Disorders. Biological Psychiatry March 15, 2025
- Interaction of hallucinogenic rapid-acting antidepressants with mGlu2/3 receptor ligands as a window for more effective therapies. Pharmacological Reports December 1, 2023
- Selective transcriptomic recovery by ( 2R,6R )-hydroxynorketamine in opioid-abstinent mice: Machine learning identifies predictive biomarkers bioRxiv (Cold Spring Harbor Laboratory) June 8, 2025
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and 55 more in the library