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

Ketamine, developed as an anesthetic in the 1960s, is also abused recreationally for its dissociative effects. It shows strong antidepressant effects in treatment-resistant depression. The racemic mixture contains (R)-ketamine and (S)-ketamine; (S)-ketamine nasal spray was approved by the US FDA in 2019 and in Europe later that year. Although (R)-ketamine has lower affinity for the NMDAR, it produces more potent and longer-lasting antidepressant-like effects in animal models with fewer side effects than (R,S)-ketamine or (S)-ketamine. BDNF and TrkB receptor involvement is suggested, and RNA-sequencing points to TGF-β1 in (R)-ketamine's effects. A pilot study showed rapid, sustained antidepressant effects of (R)-ketamine in treatment-resistant patients. This review covers mechanisms of ketamine enantiomers and metabolites and discusses the brain-gut-microbiota and brain-spleen axes in stress-related disorders.

Study at a glance

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.