Advances in the study of NMDA receptors in depression pathogenesis and the antidepressant efficacy of their antagonists

Asian J Psychiatr. 2025 Apr 19;108:104502. doi: 10.1016/j.ajp.2025.104502. Online ahead of print.

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.

PMID:40300235 | DOI:10.1016/j.ajp.2025.104502