Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression.
Courtney M Vecera, Alan C. Courtes, Gregory Jones, Jair C Soares, Rodrigo Machado‐Vieira
Pharmaceuticals November 7, 2023 DOI: 10.3390/ph16111572 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Ketamine esketamine D-cycloserine apimostinel dextromethorphan-bupropion brexanolone |
| Topics | Depression |
| Keywords | Gaba Antidepressants Glutamate Pharmacotherapies Targets |
| Key findings | NMDA receptor antagonism, particularly with ketamine and esketamine, shows the most promise among glutamatergic targets for treatment-resistant depression, and synthetic neurosteroid analogs like brexanolone are the most promising GABA modulators. |
Abstract
Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with various studies describing between 1 and 4 failures of antidepressant therapies, with or without electroconvulsive therapy (ECT). That is why TRD is such a growing concern among clinicians and researchers, and it explains the necessity for investigating novel therapeutic targets beyond conventional monoamine pathways. An imbalance between two primary central nervous system (CNS) neurotransmitters, L-glutamate and γ-aminobutyric acid (GABA), has emerged as having a key role in the pathophysiology of TRD. In this review, we provide an evaluation and comprehensive review of investigational antidepressants targeting these two systems, accessing their levels of available evidence, mechanisms of action, and safety profiles. N-methyl-D-aspartate (NMDA) receptor antagonism has shown the most promise amongst the glutamatergic targets, with ketamine and esketamine (Spravato) robustly generating responses across trials. Two specific NMDA-glycine site modulators, D-cycloserine (DCS) and apimostinel, have also generated promising initial safety and efficacy profiles, warranting further investigation. Combination dextromethorphan-bupropion (AXS-05/Auvelity) displays a unique mechanism of action and demonstrated positive results in particular applicability in subpopulations with cognitive dysfunction. Currently, the most promising GABA modulators appear to be synthetic neurosteroid analogs with positive GABAA receptor modulation (such as brexanolone). Overall, advances in the last decade provide exciting perspectives for those who do not improve with conventional therapies. Of the compounds reviewed here, three are approved by the Food and Drug Administration (FDA): esketamine (Spravato) for TRD, Auvelity (dextromethorphan-bupropion) for major depressive disorder (MDD), and brexanolone (Zulresso) for post-partum depression (PPD). Notably, some concerns have arisen with esketamine and brexanolone, which will be detailed in this study.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | Review | |
| 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 | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
Cited by 8
- Neuroprotective Role of Ketamine in Reducing Neuroinflammation and Enhancing Neuroplasticity Against a Cortisol-Induced In Vitro Stress Model. Molecular Neurobiology June 5, 2025
- Ketamine's Influence on Magnetoencephalography Patterns During a Working Memory Task in Treatment-Resistant Depression: An Exploratory Study. Bipolar Disorders April 2, 2025
- SAL0114: a novel deuterated dextromethorphan-bupropion combination with improved antidepressant efficacy and safety profile. Frontiers in Pharmacology 2024
- Esketamine’s therapeutic effect on anhedonia in adolescents: a post-hoc of a randomized controlled trial BMC Psychiatry October 7, 2026
- AMPA receptor modulation in depression: from molecular mechanisms of plasticity to therapeutic translation Pharmacological Reports June 12, 2026
and 3 more in the library
Cites 55
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
and 50 more in the library