Ketamine: A tale of two enantiomers

This review (2020) summarizes the clinical findings of ketamine as a treatment for depression, and discusses the differences between (S)-ketamine and (R)-ketamine.

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.”

Authors: Luke A. Jelen, Allan H. Young & James M. Stone

Notes

The two entinomers (together called a racemic mixture) or handedness of ketamine are S and R ketamine, or esketamine and arketamine. Esketamine has a three to fourfold greater binding affinity for the NMDA receptor, this is also why we think it’s more potent than arketamine as a anaesthetic/analgesic (numb sensations/pain relieving). This has, however, not been found in recent studies on the dissociative (psychedelic) effects of ketamine.

Esketamine has been studied for use in the treatment of depression and a nasal spray (Spravato) has been approved for use by the FDA (and EMA) in combination with using existing or new antidepressant medication (SSRIs typically).

Arketamine may have better long-term outcomes whilst having fewer acute side-effects. A very promising study by Leal and colleagues (2020) is mentioned where 57% of patients were in remission at the 7-day mark (open-label, n=7).

The activity at the AMPA receptors is probably not what leads to the antidepressant effects of ketamine. The mGlu2 receptors and AMPA receptor activation do probably play a role here. As well as the inhibition of the GABAergic system.

Esketamine’s antidepressant effects may even not work via AMPA receptor activation and brain-derived neurotrophic factor (BDNF), TrkB and mTORC, are mentioned as pathways.

The AMPA receptor activation has a role in the antidepressant effects of ketamine, but the specific pathways need to be better studied. Downstream from these effects, ketamine also influences BDNF-TrkB, mTORC1 and ERK signaling.  

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