Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling.
Stephen M Stahl, Sara de Martin, Andrea Mattarei, Ezio Bettini, Luca Pani, Clotilde Guidetti, Franco Folli, Marc De Somer, Sergio Traversa, Charles E Inturrisi, Marco Pappagallo, Marco Gentilucci, Andrea Alimonti, Maurizio Fava, Paolo L. Manfredi
International Journal of Molecular Sciences October 13, 2022 DOI: 10.3390/ijms232012196 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Intervention | Esmethadone (REL-1017) |
| Topics | Depression Esketamine Ketamine Neuroplasticity |
| Keywords | N-methyl-d-aspartate receptor Rel-1017 D-methadone Dextromethorphan Esmethadone |
| Key points | Proposes that esmethadone and other uncompetitive NMDAR antagonists may restore neural plasticity via preferential tonic block of hyperactive GluN2D subtypes, and that MDD may be caused by upregulated tonic Ca2+ currents through these subtypes reducing synaptic protein availability. |
Abstract
This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.
Comparable studies
Other theoretical and historical papers on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Esketamine and Acceptance and Commitment Therapy (ACT) for Treatment-Resistant Depression: An Intervention-Development Framework and Treatment Manual | 2026 | Theoretical or philosophical paper | |
| Adjunctive dopaminergic enhancement of esketamine in treatment-resistant depression. | 2022 | Theoretical or philosophical paper |
Citations in the library
Cited by 9
- Clinical pharmacological innovation in the treatment of depression. Expert Review of Clinical Pharmacology April 1, 2023
- Rapid onset brain plasticity at novel pharmacologic targets hypothetically drives innovations for rapid onset antidepressant actions. Journal of Psychopharmacology March 1, 2023
- Short-term ketamine use in bipolar depression: a review of the evidence for short-term treatment management Frontiers in Psychiatry December 8, 2023
- Pharmacological Monotherapy for Depressive Disorders: Current and Future-A Narrative Review. Medicina (Kaunas, Lithuania) March 21, 2025
- Depression with comorbid borderline personality disorder - could ketamine be a treatment catalyst? Frontiers in Psychiatry 2024
and 4 more in the library
Cites 19
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- NMDA Antagonist Neurotoxicity: Mechanism and Prevention Science December 6, 1991
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
and 14 more in the library