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.
Keywords: (R)-Ketamine (or arketamine); (S)-Ketamine (or esketamine); Brain-gut-microbiota axis; Brain-spleen axis; Transforming growth factor.
Copyright © 2020 Elsevier Inc. All rights reserved.
Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective.Psychiatry Clin Neurosci. 2019 Oct;73(10):613-627. doi: 10.1111/pcn.12902. Epub 2019 Jul 11. Psychiatry Clin Neurosci. 2019. PMID: 31215725 Free PMC article. Review.
A historical review of antidepressant effects of ketamine and its enantiomers.Pharmacol Biochem Behav. 2020 Mar;190:172870. doi: 10.1016/j.pbb.2020.172870. Epub 2020 Feb 5. Pharmacol Biochem Behav. 2020. PMID: 32035078 Review.
Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine.Proc Natl Acad Sci U S A. 2019 Jan 2;116(1):297-302. doi: 10.1073/pnas.1814709116. Epub 2018 Dec 17. Proc Natl Acad Sci U S A. 2019. PMID: 30559184 Free PMC article.
An update on ketamine and its two enantiomers as rapid-acting antidepressants.Expert Rev Neurother. 2019 Jan;19(1):83-92. doi: 10.1080/14737175.2019.1554434. Epub 2018 Dec 4. Expert Rev Neurother. 2019. PMID: 30513009
AMPA Receptor Activation-Independent Antidepressant Actions of Ketamine Metabolite (S)-Norketamine.Biol Psychiatry. 2018 Oct 15;84(8):591-600. doi: 10.1016/j.biopsych.2018.05.007. Epub 2018 May 14. Biol Psychiatry. 2018. PMID: 29945718