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.
Treatment-resistant depression (TRD) affects about 20-30% of people with major depressive disorder. Esketamine nasal spray was approved for TRD in 2019, but its mechanisms of action remain unclear. This protocol describes the ReDREAM project, an observational, prospective study that will use metabolomics to identify metabolic biosignatures associated with response to esketamine. Sixty people with TRD from three Italian clinical sites will receive esketamine nasal spray twice weekly for four weeks (induction phase), then once weekly for four more weeks (maintenance phase). The study will test correlations between baseline metabolic profile and depressive symptom improvement at weeks 4 and 8, and explore metabolic differences between responders and non-responders. Hypothesized involvement includes energy metabolism, amino acid metabolism, urea cycle, and nitric oxide synthesis.