Ketamine: A tale of two enantiomers

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.

Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?

“…In addition, preclinical studies assessing locomotor activity, prepulse inhibition and conditioned place preference, have suggested that (R)-ketamine would be a safer antidepressant than (R,S)-or (S)-ketamine (Chang et al, 2019). The mechanisms involved in the antidepressant action of (R)-ketamine have been reviewed recently (Hashimoto, 2020;Jelen et al, 2021); these authors outlined, among others, the role of transforming growth factor β (TGF-β), ERK activation, tropomyosin kinase B signaling, mTORC1, the beneficial role on alterations in the gut microbiota, and spleen, concluding that (R)-ketamine has fewer harmful side effects than (R,S)-ketamine or (S)-ketamine in rodents, monkeys, and humans. Interestingly, Leal et al (2020), in a pilot study in TRD patients observed that (R)ketamine (arketamine) might produce a fast (60 min) and sustained antidepressant effect (7 days).…”

Depression as a Failed Anxiety: The Continuum of Precision-Weighting Dysregulation in Affective Disorders

“…Perhaps most germane evidence can be gleaned from ketamine studies, since ketamine is the only known medication with an acute antidepressant effect (Jelen et al, 2020). In addition to its anti-depressant effect, ketamine has an acute anxiolytic effect (Glue et al, 2018).…”

“…In addition to its anti-depressant effect, ketamine has an acute anxiolytic effect (Glue et al, 2018). Among several suggested mechanisms of action, one of the better documented is ketamine's inhibition of NMDA receptors on cortical GABAergic interneurons, which leads to a surge of glutamatergic activity in the pyramidal neurons (Jelen et al, 2020). High pyramidal activity can be interpreted as activation of prediction error processing (Bastos et al, 2012), which may indicate increased precision of PEs/decreased precision of priors, as stipulated by the model (Figure 1Dw).…”

Analgesic and Antidepressant Effects of the Clinical Glutamate Modulators Acetyl-L-Carnitine and Ketamine

“…Other NMDA antagonists (i.e., MK801 and memantine) do not have the same anesthetic, analgesic, and antidepressant effects of KET, leaving open the question of its mechanisms of action ( Kelland et al, 1993 ; Gould et al, 2019 ; Robu and Lavand’homme, 2019 ). Besides the glutamate system, KET interacts with several other neurotransmitter systems ( Jelen et al, 2020 ). For example, the administration of the insulin growth factor small-interfering RNA blocks KET antidepressant effects in the mouse learned helplessness model of depression ( Grieco et al, 2016 ).…”