Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments
Bashkim Kadriu, Laura Musazzi, Ioline D. Henter, Morgan C Graves, Maurizio Popoli, Carlos A. Zarate
The International Journal of Neuropsychopharmacology November 14, 2018 DOI: 10.1093/ijnp/pyy094 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Ketamine N-methyl-D-aspartate receptor antagonists glycine binding site ligands metabotropic glutamate receptor modulators other glutamatergic modulators |
| Topics | Ketamine |
| Keywords | Glutamatergic Nmda receptor Antidepressant Metabotropic glutamate receptor Neurotransmission Pharmacology Hippocampus |
| Citations | 164 |
| Key findings | Dysfunctional glutamatergic neurotransmission may underlie the pathophysiology of major depressive disorder and bipolar depression, and ketamine elicits fast-acting antidepressant effects in treatment-resistant depression. |
Abstract
The underlying neurobiological basis of major depressive disorder remains elusive due to the severity, complexity, and heterogeneity of the disorder. While the traditional monoaminergic hypothesis has largely fallen short in its ability to provide a complete picture of major depressive disorder, emerging preclinical and clinical findings suggest that dysfunctional glutamatergic neurotransmission may underlie the pathophysiology of both major depressive disorder and bipolar depression. In particular, recent studies showing that a single intravenous infusion of the glutamatergic modulator ketamine elicits fast-acting, robust, and relatively sustained antidepressant, antisuicidal, and antianhedonic effects in individuals with treatment-resistant depression have prompted tremendous interest in understanding the mechanisms responsible for ketamine's clinical efficacy. These results, coupled with new evidence of the mechanistic processes underlying ketamine's effects, have led to inventive ways of investigating, repurposing, and expanding research into novel glutamate-based therapeutic targets with superior antidepressant effects but devoid of dissociative side effects. Ketamine's targets include noncompetitive N-methyl-D-aspartate receptor inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid throughput potentiation coupled with downstream signaling changes, and N-methyl-D-aspartate receptor targets localized on gamma-aminobutyric acid-ergic interneurons. Here, we review ketamine and other potentially novel glutamate-based treatments for treatment-resistant depression, including N-methyl-D-aspartate receptor antagonists, glycine binding site ligands, metabotropic glutamate receptor modulators, and other glutamatergic modulators. Both the putative mechanisms of action of these agents and clinically relevant studies are described.
Comparable studies
Other narrative reviews on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms | 2018 | Review | |
| Mechanisms of Ketamine Action as an Antidepressant | 2018 | 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 | |
| Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) | 2013 | Review | |
| A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | 2017 | Review and consensus statement |
Citations in the library
Cited by 42
- Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Journal of Affective Disorders September 23, 2020
- Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites Translational Psychiatry November 7, 2019
- Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants The International Journal of Neuropsychopharmacology November 16, 2020
- Practical recommendations for the management of treatment-resistant depression with esketamine nasal spray therapy: Basic science, evidence-based knowledge and expert guidance The World Journal of Biological Psychiatry November 3, 2020
- Novel antidepressant drugs: Beyond monoamine targets CNS Spectrums September 30, 2021
and 37 more in the library
Cites 54
- 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
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
and 49 more in the library