The Restoration of Energy Pathways Indicates the Efficacy of Ketamine Treatment in Depression: A Metabolomic Analysis.

Ketamine improves depressive symptoms in major depressive disorder by altering energy metabolism, including changes in adenosine triphosphate, adenosine diphosphate (ADP), and pyruvate. The shift in ADP levels strongly correlated with reductions in depression severity scores. Lower baseline levels of free triiodothyronine (FT3) predicted a better response to ketamine, suggesting FT3 may serve as a biological marker for treatment efficacy. These findings come from a study of 40 patients in a discovery cohort and 24 in a validation cohort, using metabolomic analysis of serum samples.

Study at a glance

Abstract

Despite the clinical benefits of ketamine in treating major depressive disorder (MDD), some patients exhibit drug resistance, and the intricate mechanisms underlying this await comprehensive explication. We used metabolomics to find biomarkers for ketamine efficacy and uncover its mechanisms of action. The study included 40 MDD patients treated with ketamine in the discovery cohort and 24 patients in the validation cohort. Serum samples from the discovery cohort receiving ketamine were analyzed using ultra performance liquid chromatography-mass spectrometry to study metabolomic changes and identify potential biomarkers. Metabolic alterations were evaluated pre- and post-ketamine treatment. Spearman correlation was applied to examine the relationship between metabolite alterations and depressive symptom changes. In addition, potential biomarkers, particularly thyroxine, were investigated through quantitative measurements in the validation cohort. We found that energy metabolite changes (adenosine triphosphate, adenosine diphosphate [ADP], pyruvate) were different in responders versus non-responders. The magnitude of the ADP shift was strongly correlated with the rate of reduction in Montgomery-Asberg Depression Rating Scale (MADRS) scores (Rho = 0.48, pFDR = 0.018). Additionally, baseline free triiodothyronine (FT3) levels are inversely associated with the rate of MADRS reduction (Rho = -0.645, p = 0.017). Ketamine ameliorates depressive symptoms by modulating metabolic pathways linked to energy metabolism. Low baseline FT3 levels appear to predict a positive response in MDD patients, suggesting FT3 has potential as a biological marker for clinical ketamine treatment. ChiCTR-OOC-17012239.