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.
Expert Opinion on Therapeutic Targets January 28, 2026 DOI: 10.1080/14728222.2026.2619757 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Esketamine Ketamine |
| Keywords | Nmda receptor subunits Antidepressant mechanisms Dextromethorphan Tonic activity |
| Citations | 1 |
| Key findings | Selective dampening of NR2C/D-mediated tonic NMDA receptor currents underlies the rapid and sustained antidepressant effects of ketamine, esketamine, and dextromethorphan in treatment-resistant depression. |
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.
Comparable studies
Other narrative reviews on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Long-term safety of ketamine and esketamine in treatment of depression | 2022 | Review | |
| Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms. | 2024 | Review | |
| Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review. Patients with depression | 2024 | Narrative review | |
| The Possible Application of Ketamine in the Treatment of Depression in Alzheimer’s Disease | 2022 | Review |