Advancing past ketamine: emerging glutamatergic compounds for the treatment of depression.
Florian Freudenberg, Christine Reif-Leonhard, Andreas Reif
European Archives of Psychiatry and Clinical Neuroscience August 29, 2024 DOI: 10.1007/s00406-024-01875-z (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Esketamine Ketamine |
| Keywords | Ampa Nmda Rapid acting antidepressant Depression mdd Clinical depression Neurotransmitters glutamate Gaba Brain chemicals Neural signaling Antidepressants rapid-acting antidepressants |
| Citations | 10 |
| Key findings | Beyond (es)ketamine, several glutamatergic agents such as arketamine, esmethadone, and nitrous oxide show promise as rapid-acting antidepressants based on clinical trial data. |
Abstract
Changes in glutamatergic neuroplasticity has been proposed as one of the core mechanisms underlying the pathophysiology of depression. In consequence components of the glutamatergic synapse have been explored as potential targets for antidepressant treatment. The rapid antidepressant effect of the NMDA receptor antagonist ketamine and subsequent approval of its S-enantiomer (i.e. esketamine), have set the precedent for investigation into other glutamatergic rapid acting antidepressants (RAADs). In this review, we discuss the potential of the different glutamatergic targets for antidepressant treatment. We describe important clinical outcomes of several key molecules targeting components of the glutamatergic synapse and their applicability as RAADs. Specifically, here we focus on substances beyond (es)ketamine, for which meaningful data from clinical trials are available, including arketamine, esmethadone, nitrous oxide and other glutamate receptor modulators. Molecules only successful in preclinical settings and case reports/series are only marginally discussed. With this review, we aim underscore the critical role of glutamatergic modulation in advancing antidepressant therapy, thereby possibly enhancing clinical outcomes but also to reducing the burden of depression through faster therapeutic effects.
Comparable studies
Other narrative reviews on ketamine 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 | |
| Ketamine: a paradigm shift for depression research and treatment | 2019 | Review | |
| Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review |
Citations in the library
Cited by 6
- Arketamine: a scoping review of its use in humans. European Archives of Psychiatry and Clinical Neuroscience December 16, 2024
- Integrating multi-receptor and neuron–glia mechanisms of ketamine's antidepressant action: a convergence framework for understanding efficacy Frontiers in Molecular Neuroscience October 21, 2026
- Comparative network pharmacology analysis of ketamine and xanomeline in major depressive disorder: Shared and distinct molecular mechanisms. Progress in Neuro-Psychopharmacology and Biological Psychiatry June 20, 2026
- Esketamine Exposure Affects Neurodevelopment and Glutamate-NMDAR Signaling in Zebrafish Larvae. Journal of Biochemical and Molecular Toxicology May 1, 2026
- All roads lead to glutamate: NMDA and AMPA receptors as targets for rapid-acting antidepressants. Pharmacological Research October 1, 2025
and 1 more in the library
Cites 47
- 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
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics Frontiers in Psychiatry September 10, 2021
and 42 more in the library