Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine

Biochem Pharmacol. 2020 Jul;177:113935. doi: 10.1016/j.bcp.2020.113935. Epub 2020 Mar 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / chemistry*
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use
  • Brain / metabolism
  • Brain-Derived Neurotrophic Factor / metabolism
  • Depression / drug therapy
  • Depression / metabolism
  • Gastrointestinal Microbiome / drug effects
  • Humans
  • Ketamine / analogs & derivatives*
  • Ketamine / chemistry
  • Ketamine / pharmacology
  • Ketamine / therapeutic use
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Spleen / metabolism


  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Receptors, N-Methyl-D-Aspartate
  • Esketamine
  • Ketamine
  • BDNF protein, human
  • norketamine