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

Selective dampening of NR2C/D-mediated tonic currents underlie rapid and sustained antidepressant effects of ketamine, esketamine, and dextromethorphan. Separately, ketamine and esketamine's affinity for NR2A/B subunits may constitute the core mechanism driving the dissociative effects which are not observed with dextromethorphan. Future drug discovery should emphasize subunit-biased ligands and allosteric modulators, guided by advanced receptor structural models and translational biomarkers, to enhance antidepressant efficacy and concurrently improve tolerability.