NeuropharmacologyDec 20, 2022

NMDA receptors as possible treatment targets for depression: Evidence from lab and clinical studies

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 24, 2026

Abstract

Ketamine is a channel blocker of glutamate-gated NMDA receptors that demonstrates fast-acting and sustained antidepressant effects for treatment-resistant depression.

Dysfunction of glutamatergic transmission may be associated with the pathology of depression.
Antidepressant agents that modulate NMDA receptor function could represent breakthroughs in depression treatment compared to conventional monoaminergic antidepressants.
The review summarizes mechanisms by which ketamine exerts antidepressant effects, including NMDA receptor antagonism in specific brain regions.
Different subunits of NMDA receptors may play distinct roles in ketamine's effects on cognitive and psychiatric behaviors in rodent models.
The article discusses potential antidepressant effects of other NMDA receptor modulators observed in animal models and clinical trials.

Simplified

Ketamine, functioning as a channel blocker of the excitatory glutamate-gated N-methyl-d-aspartate (NMDA) receptors, displays compelling fast-acting and sustained antidepressant effects for treatment-resistant depression. Over the past decades, clinical and preclinical studies have implied that the pathology of depression is associated with dysfunction of glutamatergic transmission. In particular, the discovery of antidepressant agents modulating NMDA receptor function has prompted breakthroughs for depression treatment compared with conventional antidepressants targeting the monoaminergic system. In this review, we first summarized the signalling pathway of the ketamine-mediated antidepressant effects, based on the glutamate hypothesis of depression. Second, we reviewed the hypotheses of the synaptic mechanism and network of ketamine antidepressant effects within different brain areas and distinct subcellular localizations, including NMDA receptor antagonism on GABAergic interneurons, extrasynaptic and synaptic NMDA receptor-mediated antagonism, and ketamine blocking bursting activities in the lateral habenula. Third, we reviewed the different roles of NMDA receptor subunits in ketamine-mediated cognitive and psychiatric behaviours in genetically-manipulated rodent models. Finally, we summarized the structural basis of NMDA receptor channel blockers and discussed NMDA receptor modulators that have been reported to exert potential antidepressant effects in animal models or in clinical trials. Integrating the cutting-edge technologies of cryo-EM and artificial intelligence-based drug design (AIDD), we expect that the next generation of first-in-class rapid antidepressants targeting NMDA receptors would be an emerging direction for depression therapeutics. This article is part of the Special Issue on 'Ketamine and its Metabolites'.

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NMDA receptors as possible treatment targets for depression: Evidence from lab and clinical studies

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