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

IF 4.8 1区医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2025-03-09 DOI:10.1111/cns.70324

Zerui You, Xiaofeng Lan, Chengyu Wang, Haiying Liu, Weicheng Li, Siming Mai, Haiyan Liu, Fan Zhang, Guanxi Liu, Xiaoyu Chen, Yanxiang Ye, Yanling Zhou, Yuping Ning

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Abstract

Aims

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.

Methods

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.

Results

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, p_FDR = 0.018). Additionally, baseline free triiodothyronine (FT3) levels are inversely associated with the rate of MADRS reduction (Rho = −0.645, p = 0.017).

Conclusions

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.

Trial Registration: ChiCTR-OOC-17012239

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.