Modulating tonic NMDA receptor currents: mechanistic insights into ketamine, esketamine, and dextromethorphan for major depressive disorder and implications for the discovery and development of investigational agents

Up to 50% of adults with major depressive disorder may experience treatment-resistant depression after using two or more antidepressants.

• Elevated tonic currents mediated by NR2C/D subunits in NMDA receptors are implicated in the pathophysiology of treatment-resistant depression.
• Sustained ambient-glutamate signaling occurs in key limbic regions, as documented by in vivo studies.
• Ketamine, esketamine, and dextromethorphan may produce rapid and sustained antidepressant effects through selective dampening of NR2C/D-mediated tonic currents.
• Ketamine and esketamine's affinity for NR2A/B subunits may lead to dissociative effects, which are not observed with dextromethorphan.
• Future drug discovery could focus on subunit-biased ligands and allosteric modulators to enhance antidepressant efficacy and tolerability.

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