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.
Highlights
There are significant limitations to current widely prescribed antidepressant treatments
Administration of the ketamine metabolite (2R,6R)-HNK resulted in redistribution of Gαs from lipid rafts and an increase cyclic adenosine monophosphate (cAMP) production. These findings suggest the translocation of Gαs from lipid rafts is a reliable hallmark of antidepressant action; further research is needed to examine to what degree this mechanism contributes to the antidepressant effect of the individual enantiomers of ketamine
In a recent study, infusion of a selective 5-HT1A receptor agonist into the medial prefrontal cortex (mPFC) produced ketamine-like rapid synaptic and antidepressant-like behavioural responses in a rodent model that were blocked by co-infusion of an amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptor antagonist (Fukumoto et al, 2020)
Summary
There are significant limitations to current widely prescribed antidepressant treatments. In a recent study, infusion of a selective 5-HT1A receptor agonist into the mPFC produced ketamine-like rapid synaptic and antidepressant-like behavioural responses in a rodent model that were blocked by co-infusion of an AMPA receptor antagonist (Fukumoto et al, 2020) Taken together, it appears another route via which (R,S)-ketamine may cause its antidepressant effects is through 5-HT1A receptor activation in the mPFC, by AMPA receptor-dependent 5-HT release, with downstream convergence on signalling mechanisms. Additional research findings indicate that dopamine D1 receptor activity in the mPFC are necessary for the rapid antidepressant actions of (R,S)-ketamine using optogenetic stimulation in a mouse model (Hare et al, 2019) Another potential convergence from a signal transduction perspective may involve NMDA and D1 receptor-dependent induction of mTORC/ERK and inactivation of eEF2 kinase resulting in increased protein synthesis (David et al, 2020). Further work with rigorous trial design and parallel mechanistic studies are required to understand the function of the ketamine-opioid receptor interaction and subsequent signalling cascades in the antidepressant effect of each of ketamine and its individual enantiomers
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