AMPA receptor modulation in depression: from molecular mechanisms of plasticity to therapeutic translation
Wojciech Ziemichód, Natalia Kajka, Klaudia Kister, Karolina Kasprzak, Kaja Karakuła, Dariusz Juchnowicz
Pharmacological Reports June 12, 2026 DOI: 10.1007/s43440-026-00871-5 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Narrative review Peer reviewed |
|---|---|
| Intervention | AMPAkines |
| Topics | Neuroplasticity Depression |
| Keywords | Ampa receptor Glutamatergic Long-term potentiation Neurotransmission Nmda receptor Glutamate receptor Excitatory postsynaptic potential Allosteric regulation Pharmacology Metaplasticity |
| Key findings | AMPAkines represent a potentially promising class of rapid-acting antidepressants, although significant translational hurdles remain. |
Abstract
The glutamatergic system, particularly N-methyl-D-aspartate (NMDA) receptors, has long been a significant focus of research into new strategies for treating depression, and the clinical success of ketamine, an NMDA receptor antagonist, has been a significant breakthrough. In parallel, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, another key component of the glutamatergic system, have been studied for decades, and renewed interest stems from evidence linking their activation to the rapid antidepressant effects and synaptic plasticity observed after ketamine administration. Among pharmacological agents targeting AMPA receptors, the class of positive allosteric modulators, AMPAkines, has attracted particular interest. These compounds act by prolonging AMPA receptor channel open time, thereby enhancing excitatory neurotransmission and upregulating brain-derived neurotrophic factor (BDNF) expression. Preclinical studies consistently demonstrated antidepressant-like effects of low-impact AMPAkines, which offer a favorable safety profile in contrast to high-impact compounds that carry seizure risk. Although preliminary clinical trials support these findings, their limited scope highlights persistent translational challenges. These include a narrow therapeutic window, suboptimal pharmacokinetic properties, and the limited predictive validity of animal models. AMPAkines thus represent a potentially promising class of rapid-acting antidepressants, although significant translational hurdles remain. This narrative review aims to synthesize evidence on the role of AMPA receptors in neuroplasticity, the therapeutic potential of AMPA receptor modulators (AMPAkines) in influencing neuroplasticity, and their potential therapeutic applications in depression.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | 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 | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
Cites 4
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Esketamine disinhibits brain networks in depression: Evidence from oscillatory and aperiodic activity. Progress in Neuro-Psychopharmacology and Biological Psychiatry July 5, 2025
- Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression. Pharmaceuticals November 7, 2023