Role of the AMPA receptor in antidepressant effects of ketamine and potential of AMPA receptor potentiators as a novel antidepressant.
Atsushi Suzuki, Hiroe Hara, H. Kimura
Neuropharmacology October 1, 2022 DOI: 10.1016/j.neuropharm.2022.109308 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | TAK-653 AMPA receptor potentiators AMPA |
| Topics | Esketamine Ketamine |
| Key findings | The authors propose that agonist activity of AMPA receptor potentiators is linked not only to bell-shaped dose-response curves and seizure risk but also to reduced synaptic transmission and diminished procognitive effects. They describe their screening approach that identified TAK-653, an investigational AMPA receptor potentiator with low agonist activity, and suggest its profile may overcome the limitations of known AMPA receptor potentiators. |
Abstract
Ketamine exerts rapid and long-lasting antidepressant effects in patients with treatment-resistant depression. However, its clinical use is limited by its undesirable psychotomimetic side effects. Accumulating evidence from preclinical studies has shown that the antidepressant effects of ketamine are dependent on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) activation, which triggers activation of the mechanistic target of rapamycin pathway and brain-derived neurotrophic factor release. Thus, AMPA-R has emerged as a promising new target for novel antidepressants with a rapid onset of action. However, almost all known AMPA-R potentiators carry the risk of a narrow bell-shaped dose-response curve and a poor safety margin against seizures. Our data suggest that agonistic activity is not only related to the risks of bell-shaped dose-response curves and seizures but also to the reduced synaptic transmission and procognitive effects of AMPA-R potentiators. In this review, we describe our original screening approach that led to the discovery of an investigational AMPA-R potentiator with low agonistic activity, TAK-653. We further review the in vitro and in vivo profiles of TAK-653, including its procognitive and antidepressant-like effects, as well as its safety profile, in comparison with known AMPA-R potentiators with agonistic activity and AMPA, an AMPA-R agonist. The low agnostic activity of TAK-653 may overcome limitations of known AMPA-R potentiators.
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 15
- Shared effects of electroconvulsive shocks and ketamine on neuroplasticity: A systematic review of animal models of depression. Neuroscience & Biobehavioral Reviews September 1, 2024
- Advancing past ketamine: emerging glutamatergic compounds for the treatment of depression. European Archives of Psychiatry and Clinical Neuroscience August 29, 2024
- Activation of σ1-Receptors by R-Ketamine May Enhance the Antidepressant Effect of S-Ketamine Biomedicines September 28, 2023
- Synergistic use of deep TMS therapy with IV ketamine infusions for major depressive disorder: a pilot study. Psychopharmacology July 1, 2024
- Discovery of a Novel Orally Active Ketamine Derivative with Dual Analgesic and Antidepressant Activities, Lacking Psychomimetic Effects. ACS Chemical Neuroscience March 5, 2025
and 10 more in the library
Cites 16
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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
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
and 11 more in the library