{"id":"doi:10.1016/j.bcp.2020.113935","kind":"review","title":"Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine","authors":["Hashimoto K"],"author_count":1,"year":2020,"published":"2020-03-26","venue":"Biochemical pharmacology","cited_by":181,"doi":"10.1016/j.bcp.2020.113935","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/j.bcp.2020.113935","archive_url":"https://space-kitty.com/papers/doi:10.1016/j.bcp.2020.113935","updated":null,"pmid":"32224141","pmcid":null,"openalex_id":null,"pdf_url":null,"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.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":false,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine\" by Hashimoto K, https://doi.org/10.1016/j.bcp.2020.113935, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"psychiatric-therapeutics","name":"Novel Psychiatric Therapeutics","domain_slug":"neuroscience"}],"cited_in_dossiers":[]}