New targets for rapid antidepressant action.
Rodrigo Machado‐Vieira, Ioline D. Henter, Carlos A. Zarate
Progress in Neurobiology December 23, 2015 DOI: 10.1016/j.pneurobio.2015.12.001 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Ketamine Memantine Dextromethorphan AZD6765 CP-101 606/traxoprodil MK-0657 GLYX-13 AZD2066 RO4917523/basimglurant Scopolamine ALKS-5461 CP-316 311 |
| Topics | Depression |
| Keywords | Brain Animals Humans Antidepressive agents Treatment outcome Evidence-based medicine Drug discovery Glutamate Rapid Bipolar disorder Antidepressant |
| Key findings | The review reports that ketamine produces rapid and robust antidepressant effects, while most other NMDA receptor antagonists studied in major depressive disorder show relatively modest antidepressant effects compared with ketamine, though some have more favorable characteristics. It argues that glutamate and its receptors are implicated in the pathophysiology of depression and in the development of novel therapeutics, and surveys additional glutamatergic and non-glutamatergic targets awaiting or undergoing clinical study. |
Abstract
Current therapeutic options for major depressive disorder (MDD) and bipolar disorder (BD) are associated with a lag of onset that can prolong distress and impairment for patients, and their antidepressant efficacy is often limited. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, and in the development of novel therapeutics for this disorder. The rapid and robust antidepressant effects of the N-methyl-d-aspartate (NMDA) antagonist ketamine were first observed in 2000. Since then, other NMDA receptor antagonists have been studied in MDD. Most have demonstrated relatively modest antidepressant effects compared to ketamine, but some have shown more favorable characteristics. This article reviews the clinical evidence supporting the use of novel glutamate receptor modulators with direct affinity for cognate receptors: (1) non-competitive NMDA receptor antagonists (ketamine, memantine, dextromethorphan, AZD6765); (2) subunit (GluN2B)-specific NMDA receptor antagonists (CP-101,606/traxoprodil, MK-0657); (3) NMDA receptor glycine-site partial agonists (GLYX-13); and (4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant). We also briefly discuss several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy that have yet to be studied clinically; these include α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA) agonists and mGluR2/3 negative allosteric modulators. The review also discusses other promising, non-glutamatergic targets for potential rapid antidepressant effects, including the cholinergic system (scopolamine), the opioid system (ALKS-5461), corticotropin releasing factor (CRF) receptor antagonists (CP-316,311), and others.
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 32
- Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression Molecular Brain June 16, 2020
- New Treatment Strategies of Depression: Based on Mechanisms Related to Neuroplasticity Neural Plasticity 2017
- Rapid-acting antidepressants. Advances in pharmacology (San Diego, Calif.) 2019
- Glutamatergic Modulators for Major Depression from Theory to Clinical Use. CNS Drugs November 1, 2024
- Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials Expert Opinion on Emerging Drugs January 2, 2021
and 27 more in the library
Cites 32
- 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
- Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study Biological Psychiatry November 4, 2015
- Do the dissociative side effects of ketamine mediate its antidepressant effects? Journal of Affective Disorders February 18, 2014
and 27 more in the library