Glutamatergic Modulators for Major Depression from Theory to Clinical Use.
CNS Drugs November 1, 2024 DOI: 10.1007/s40263-024-01114-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Narrative review Peer reviewed |
|---|---|
| Interventions | Esketamine Dextromethorphan-bupropion |
| Topics | Depression |
| Keywords | Depression treatment Mental health Antidepressants Brain chemistry |
| Citations | 58 |
| Key findings | Glutamate-targeted antidepressants, including esketamine and dextromethorphan-bupropion, have been FDA-approved for treating major depressive disorder, supporting the importance of glutamatergic signaling in depression therapy. |
Abstract
Major depressive disorder (MDD) is a chronic, burdensome, highly prevalent disease that is characterized by depressed mood and anhedonia. MDD is especially burdensome as approved monoamine antidepressant treatments have weeks-long delays before clinical benefit and low remission rates. In the past 2 decades, a promising target emerged to improve patient outcomes in depression treatment: glutamatergic signaling. This narrative review provides a high-level overview of glutamate signaling in synaptogenesis and neural plasticity and the implications of glutamate dysregulation in depression. Based on this preclinical evidence implicating glutamate in depression and the rapid improvement of depression with ketamine treatment in a proof-of-concept trial, a range of N-methyl-D-aspartate (NMDA)-targeted therapies have been investigated. While an array of treatments has been investigated in registered phase 2 or 3 clinical trials, the development of most of these agents has been discontinued. Multiple glutamate-targeted antidepressants are actively in development, and two are approved. Nasal administration of esketamine (Spravato®) was approved by the US Food and Drug Administration (FDA) in 2019 to treat adults with treatment-resistant depression and in 2020 for adults with MDD with acute suicidal ideation or behavior. Oral combination dextromethorphan-bupropion (AXS-05, Auvelity® extended-release tablet) was FDA approved in 2022 for the treatment of MDD in adults. These approvals bolster the importance of glutamate in depression and represent an exciting breakthrough in contemporary psychiatry, providing new avenues of treatment for patients as first-line therapy or with either poor response or unacceptable side effects to monoaminergic antidepressants.
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 27
- Effectiveness of repeated Esketamine nasal spray administration on anhedonic symptoms in treatment-resistant bipolar and unipolar depression: A secondary analysis from the REAL-ESK study group. Psychiatry Research July 26, 2025
- Beyond NMDA Receptors: A Narrative Review of Ketamine's Rapid and Multifaceted Mechanisms in Depression Treatment. International Journal of Molecular Sciences December 20, 2024
- The Effects of Ketamine and Esketamine on Measures of Quality of Life in Major Depressive Disorder and Treatment-Resistant Depression: A Systematic Review. Journal of Affective Disorders August 1, 2025
- Pharmacological Monotherapy for Depressive Disorders: Current and Future-A Narrative Review. Medicina (Kaunas, Lithuania) March 21, 2025
- New Agents in the Treatment of Psychiatric Disorders: What Innovations and in What Areas of Psychopathology? Pharmaceuticals April 30, 2025
and 22 more in the library
Cites 42
- 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
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
and 37 more in the library