Advances in the study of NMDA receptors in depression pathogenesis and the antidepressant efficacy of their antagonists.
Mingrui Chen, Jingyan Jin, Hongsheng Bi, Yihan Zhang, Mingyuan Sun, Xiaobai Li, Yan Wang
Asian Journal of Psychiatry June 1, 2025 DOI: 10.1016/j.ajp.2025.104502 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Ketamine Esketamine Memantine Rapastinel |
| Topics | Depression |
| Keywords | Antidepressants Glutamatergic Nmda receptor antagonists Nmda receptors Depression treatment Neuroscience research Antidepressant mechanisms Brain chemistry |
| Citations | 12 |
| Key findings | NMDA receptor dysfunction is a key pathological mechanism in depression, and ketamine rapidly relieves depressive symptoms by blocking NMDA receptors and activating the mTOR signaling pathway. |
Abstract
N-methyl-D-aspartate receptors (NMDA receptors) play a crucial role as ionotropic glutamate receptors in regulating neuroplasticity, learning, memory, and a range of psychiatric disorders. Studies indicate that dysfunction of NMDA receptors is a key pathological mechanism in depression, where abnormal activation can result in neuronal excitotoxicity, excessive extracellular calcium ion accumulation, and disrupted neuroplasticity. As a non-competitive NMDA receptor antagonist, ketamine quickly relieves depressive symptoms by decreasing the activity of extracellular NMDA receptors and activating the mTOR signaling pathway. The treatment can improve severe depression and suicide thoughts within hours, but its potential for hallucinations, dissociative symptoms, and dependency restricts its broader application. Esketamine has demonstrated improvements in both side effects and efficacy and has received FDA approval, while other compounds with NMDA receptor modulating functions, such as memantine and rapastinel, are also showing potential in exploration. Future studies should concentrate on the molecular mechanisms of NMDA receptors, aiming to develop safer and more effective medications, and refine treatment strategies to offer personalized choices and longer-lasting efficacy for the treatment of 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
Cited by 4
- Comparative network pharmacology analysis of ketamine and xanomeline in major depressive disorder: Shared and distinct molecular mechanisms. Progress in Neuro-Psychopharmacology and Biological Psychiatry June 20, 2026
- Synaptic Plasticity-Intrinsic Excitability and Antidepressant Discovery. Biomedicines June 1, 2026
- State-specific inhibition of NMDA receptors by memantine provides insight into NMDAR channel blocker tolerability Science Advances May 27, 2026
- Abuse liability of dextromethorphan and its combinatory formulation dextromethorphan/bupropion: a pharmacologic perspective. Expert Opinion on Drug Metabolism & Toxicology 2026
Cites 50
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- 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 45 more in the library