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.

Abstract

Up to 50% of adults with major depressive disorder (MDD) fail to achieve remission after two or more monoaminergic antidepressants and meet criteria for treatment-resistant depression (TRD). Low-dose intravenous ketamine, intranasal esketamine, and oral dextromethorphan represent the first glutamatergic treatments to exhibit rapid and robust efficacy in persons with TRD, yet their precise mechanisms remain unclear. Herein, we amplify an existing hypothesis and integrate preclinical, pharmacological, and clinical evidence implicating elevated tonic N-methyl-D-aspartate (NMDA) receptor currents, mediated predominantly by NR2C/D subunits, in the pathophysiology of TRD. We review in vivo proton magnetic resonance spectroscopy and electrophysiology studies that document sustained ambient-glutamate signaling in key limbic regions. We then synthesize mechanistic data on ketamine's dual pore-trapping and hydrophobic lateral-site binding, esketamine's preferential NR2D blockade, and dextromethorphan's pH-enhanced NR2C selectivity. 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.