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Ketamine: A Tale of Two Enantiomers

Research output: Contribution to journalArticle

Original languageEnglish
JournalJournal of Psychopharmacology
Accepted/In press10 Aug 2020

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Abstract

The discovery of the rapid antidepressant effects of the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate (NMDA) 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 (TRD) 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 TRD in the United States and Europe, however, some concerns regarding efficacy and side-effects remain. Although (R)-ketamine is a less potent NMDA 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 TRD. 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 NMDA receptor antagonism, γ-aminobutyric acid (GABA)ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor activation, brain-derived neurotrophic factor (BDNF) and tropomyosin kinase B (TrkB) signalling, mammalian target of rapamycin complex 1 (mTORC1) and extracellular signal-regulated kinase (ERK) signalling, inhibition of glycogen synthase kinase-3 (GSK-3) and inhibition of lateral habenula bursting, alongside potential roles of the monoaminergic and opioid receptor systems.

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