Jelen, Luke A, Young, Allan H and Stone, James M (2021) Ketamine: a tale of two enantiomers. Journal of Psychopharmacology, 35 (2). pp. 109-123. ISSN 0269-8811

PDF - Published Version Available under License Creative Commons Attribution. Download (1MB)

Abstract

The discovery of the rapid antidepressant effects of the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate receptor antagonist, is arguably the most important breakthrough in depression research in the last 50 years. Ketamine remains an off-label treatment for treatment-resistant depression with factors that limit widespread use including its dissociative effects and abuse potential. Ketamine is a racemic mixture, composed of equal amounts of (S)-ketamine and (R)-ketamine. An (S)-ketamine nasal spray has been developed and approved for use in treatment-resistant depression in the United States and Europe; however, some concerns regarding efficacy and side effects remain. Although (R)-ketamine is a less potent N-Methyl-D-Aspartate receptor antagonist than (S)-ketamine, increasing preclinical evidence suggests (R)-ketamine may have more potent and longer lasting antidepressant effects than (S)-ketamine, alongside fewer side effects. Furthermore, a recent pilot trial of (R)-ketamine has demonstrated rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research is ongoing to determine the specific cellular and molecular mechanisms underlying the antidepressant actions of ketamine and its component enantiomers in an effort to develop future rapid-acting antidepressants that lack undesirable effects. Here, we briefly review findings regarding the antidepressant effects of ketamine and its enantiomers before considering underlying mechanisms including N-Methyl-D-Aspartate receptor antagonism, γ-aminobutyric acid-ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor activation, brain-derived neurotrophic factor and tropomyosin kinase B signalling, mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase signalling, inhibition of glycogen synthase kinase-3 and inhibition of lateral habenula bursting, alongside potential roles of the monoaminergic and opioid receptor systems.

Item Type:	Article
Keywords:	(R)-ketamine, (S)-ketamine, 5-HT, AMPA receptor, BDNF, ERK, GSK-3, Ketamine, NMDA receptor, TrkB, depression, dopamine, mTORC1, opioid receptor
Schools and Departments:	Brighton and Sussex Medical School > Neuroscience
SWORD Depositor:	Mx Elements Account
Depositing User:	Mx Elements Account
Date Deposited:	09 Sep 2021 09:59
Last Modified:	09 Sep 2021 10:00
URI:	http://sro.sussex.ac.uk/id/eprint/101597

View download statistics for this item

📧 Request an update