Evidence from preclinical and clinical metabolomics studies on the antidepressant effects of ketamine and esketamine.

Ketamine and esketamine are known to relieve depression, but how they work at the molecular level remains unclear. This mini-review summarizes studies using metabolomics to examine metabolic changes after low-dose ketamine or esketamine in animals and humans. Both types of studies show alterations in pathways related to energy production (tricarboxylic acid cycle, glycolysis, pentose phosphate pathway), lipid and amino acid metabolism, the kynurenine pathway, and the urea cycle. These findings suggest the drugs influence mitochondrial function, energy metabolism, membrane maintenance, and cell signaling. Metabolomics may help uncover markers of treatment response and guide personalized depression care, though more research is needed to distinguish effects of the racemic drug from its enantiomers.

Study at a glance

Abstract

The antidepressant effects of ketamine and esketamine are well-documented. Nonetheless, most of the underlying molecular mechanisms have to be uncovered yet. In the last decade, metabolomics has emerged as a useful means to investigate the metabolic phenotype associated with depression as well as changes induced by antidepressant treatments. This mini-review aims at summarizing the main findings from preclinical and clinical studies that used metabolomics to investigate the metabolic effects of subanesthetic, antidepressant doses of ketamine and esketamine and their relationship with clinical response. Both animal and human studies report alterations in several metabolic pathways - including the tricarboxylic acid cycle, glycolysis, the pentose phosphate pathway, lipid metabolism, amino acid metabolism, the kynurenine pathway, and the urea cycle - following the administration of ketamine or its enantiomers. Although more research is needed to clarify commonalities and differences in molecular mechanisms of action between the racemic compound and its enantiomers, these findings comprehensively support an influence of ketamine and esketamine on mitochondrial and cellular energy production, membrane homeostasis, neurotransmission, and signaling. Metabolomics may thus represent a promising strategy to clarify molecular mechanisms underlying treatment-resistant depression and related markers of clinical response to ketamine and esketamine. This body of preclinical and clinical evidence, if further substantiated, has the potential to guide clinicians towards personalized approaches, contributing to new paradigms in the clinical management of depression.