Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine.
Biochemical Pharmacology July 1, 2020 DOI: 10.1016/j.bcp.2020.113935 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Pilot study Peer reviewed |
|---|---|
| Topics | Esketamine Ketamine |
| Keywords | R-ketamine or arketamine S-ketamine or esketamine Brain-gut-microbiota axis Brain-spleen axis Transforming growth factor |
| Citations | 232 |
| Key findings | (R)-ketamine has greater potency and longer-lasting antidepressant-like actions in animal models with fewer side effects than (R,S)-ketamine or (S)-ketamine. |
Abstract
Ketamine, an anesthetic developed in the early 1960s, is also a popular abused drug among young people at dance parties and raves and among spiritual seekers, because it produces schizophrenia-like symptoms and dissociation (i.e., out-of-body experience). Regarding mood disorders, ketamine exerts robust antidepressant actions in treatment-resistant patients with depression. Ketamine is a racemic mixture comprising equal parts of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine). The United States (US) Food and Drug Administration approved the J&J (S)-ketamine nasal spray for treatment-resistant depression on March 5, 2019; the spray was then approved in Europe (December 19, 2019). Although (R)-ketamine has lower affinity for the N-methyl-d-aspartate receptor (NMDAR) vs. (S)-ketamine, (R)-ketamine has greater potency and longer-lasting antidepressant-like actions in animal models of depression. Importantly, (R)-ketamine has less detrimental side effects than does (R,S)-ketamine or (S)-ketamine in rodents, monkeys, and humans. A role for the brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) receptor in the antidepressant effects of ketamine and its two enantiomers has been suggested. A recent RNA-sequencing analysis suggested that the transforming growth factor β1 (TGF-β1) plays a role in the antidepressant effects of (R)-ketamine. A recent pilot study demonstrated that (R)-ketamine had rapid-acting and sustained antidepressant effects in treatment-resistant patients with depression. In this article, the author reviews the mechanisms of the antidepressant actions of the enantiomers of ketamine and its metabolites, (S)-norketamine and (2R,6R)-hydroxynorketamine (HNK) and discusses the role of the brain-gut-microbiota axis and brain-spleen axis in stress-related psychiatric disorders, such as depression.
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 89
- Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor Molecular Psychiatry May 7, 2021
- Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine Molecular Psychiatry November 24, 2021
- Arketamine, a new rapid-acting antidepressant: A historical review and future directions Neuropharmacology August 14, 2022
- EFFICACY AND SAFETY OF RACEMIC KETAMINE AND ESKETAMINE FOR DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS Expert Opinion on Drug Safety March 9, 2022
- Ketamine and its metabolites: Potential as novel treatments for depression. Neuropharmacology October 1, 2022
and 84 more in the library
Cites 50
- 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
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
and 45 more in the library