Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies.
Pharmacology & Therapeutics July 1, 2019 DOI: 10.1016/j.pharmthera.2019.02.017 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Esketamine Ketamine Serotonin |
| Citations | 190 |
| Key findings | Ketamine's fast antidepressant-like activity involves adaptations in the glutamate/GABA balance within the medial prefrontal cortex and its connections to the dorsal raphe nucleus, beyond previously proposed mTOR-dependent structural plasticity. |
Abstract
Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptor, displays a fast antidepressant activity in treatment-resistant depression and in rodent models of anxiety/depression. A large body of evidence concerning the cellular and molecular mechanisms underlying its fast antidepressant-like activity comes from animal studies. Although structural remodeling of frontocortical/hippocampal neurons has been proposed as critical, the role of excitatory/inhibitory neurotransmitters in this behavioral effect is unclear. Neurochemical and behavioral changes are maintained 24h after ketamine administration, well beyond its plasma elimination half-life. Thus, ketamine is believed to initiate a cascade of cellular mechanisms supporting its fast antidepressant-like activity. To date, the underlying mechanism involves glutamate release, then downstream activation of AMPA receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis in the medial prefrontal cortex (mPFC), a brain region strongly involved in ketamine therapeutic effects. However, these mPFC effects are not restricted to glutamatergic pyramidal cells, but extend to other neurotransmitters (GABA, serotonin), glial cells, and brain circuits (mPFC/dorsal raphe nucleus-DRN). It could be also mediated by one or several ketamine metabolites (e.g., (2R,6R)-HNK). The present review focuses on evidence for mPFC neurotransmission abnormalities in major depressive disorder (MDD) and their potential impact on neural circuits (mPFC/DRN). We will integrate these considerations with results from recent preclinical studies showing that ketamine, at antidepressant-relevant doses, induces neuronal adaptations that involve the glutamate-excitatory/GABA-inhibitory balance. Our analyses will help direct future studies to further elucidate the mechanism of action of fast-acting antidepressant drugs, and to inform development of novel, more efficacious therapeutics.
Comparable studies
Other narrative reviews on serotonin, most cited first.
Citations in the library
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- Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials Pharmacological Reports April 16, 2020
- Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression CNS Drugs November 17, 2021
- Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice Nature Communications May 12, 2022
- Glutamatergic receptor and neuroplasticity in depression: Implications for ketamine and rapastinel as the rapid-acting antidepressants. Biochemical and Biophysical Research Communications 2022
- Effect of Ketamine on Limbic GABA and Glutamate: A Human In Vivo Multivoxel Magnetic Resonance Spectroscopy Study Frontiers in Psychiatry September 8, 2020
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Cites 38
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- 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
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