Exorcising the Noonday Demon: Esketamine and Other Novel Approaches for Addressing Treatment-Resistant Depression

Abstract

Esketamine is a newly approved glutamatergic antidepressant that acts through a novel pathway not addressed by most drugs adhering to the monoamine hypothesis. This study aims to utilize the literature to connect the many different theories about the mechanism of the pathophysiology of depression into a single chart that marks where common antidepressants begin effecting change in the pathways in question. This will serve as a point of comparison between entry points of monoaminergic antidepressants and glutamatergic antidepressants. There is also potential for different interpretations of the mechanism of action of ketamine because while esketamine was the enantiomer approved by the FDA, there is evidence supporting a metabolite of the R-enantiomer (2R,6R-hydroxynorketamine) as the epitome of therapeutic efficacy for ketamine through its interaction with the AMPA receptor. By evaluating the mechanistic implications of the literature, we can then propose recommendations for drug discoverers to develop faster-acting antidepressants. Ideally, antidepressants that are as effective and fast-acting as esketamine won't just be used for TRD, but will be a first line treatment once the side effects and recreational abuse potential of future drugs like esketamine are reduced.