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 Introduction 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. Areas covered 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. Expert opinion 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. Plain Language Summary Many people living with depression do not improve after trying standard antidepressant medications. In recent years, new treatments that affect the brain chemical glutamate have been shown to relieve depressive symptoms rapidly, even in people with treatment-resistant depression. The agents of interest include ketamine, esketamine, and dextromethorphan in the approved combined dextromethorphan-bupropion formulation. However, how these treatments work, and why some cause dissociative side effects while others do not, is still not fully understood. This article reviews evidence suggesting that these drugs act on the brain in two different ways. One involves reducing abnormally high background activity in certain brain cells, which may help restore healthy brain network connections and improve mood. The other affects fast, moment-to-moment brain signaling and appears to be more closely related to side effects such as dissociation. Importantly, antidepressant benefits can occur without dissociation. Understanding these distinct mechanisms may help researchers develop new treatments that work rapidly and effectively while minimizing unwanted side effects, leading to safer and more tolerable options for people living with depression.