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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, \u03b3-aminobutyric acid-ergic interneuron inhibition, \u03b1-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.<\/jats:p>","DOI":"10.1177\/0269881120959644","type":"journal-article","created":{"date-parts":[[2020,11,6]],"date-time":"2020-11-06T21:05:51Z","timestamp":1604696751000},"page":"109-123","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":233,"title":["Ketamine: A tale of two enantiomers"],"prefix":"10.1177","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6398-5239","authenticated-orcid":false,"given":"Luke A","family":"Jelen","sequence":"first","affiliation":[{"name":"Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London, United Kingdom"},{"name":"South London and Maudsley NHS Foundation Trust, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan H","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London, United Kingdom"},{"name":"South London and Maudsley NHS Foundation Trust, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3051-0135","authenticated-orcid":false,"given":"James 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