Metabolomic signatures of electroconvulsive therapy in schizophrenia: Mitochondrial energy metabolism and inflammation as therapeutic targets

IF 7.5 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity Pub Date : 2026-03-01 Epub Date: 2025-12-20 DOI:10.1016/j.bbi.2025.106235

Yan Li , Guangfa Wang , Xinyu Fang , Yuru Ling , Chao Zhou , Jin Fang , Renliang Cai , Yunshan Hu , Chaoran Wu , Shaotong Zhang , Ayesha Zafar Iqbal , Yu Wang , Kuan-Pin Su , Xiangrong Zhang

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引用次数: 0

Abstract

Background

Electroconvulsive therapy (ECT) demonstrates efficacy in treatment-resistant schizophrenia, yet the underlying metabolic mechanisms remain poorly understood. This study employed comprehensive metabolomics to elucidate the therapeutic mechanisms of ECT and identify predictive biomarkers.

Methods

We conducted untargeted metabolomics analyses (GC–MS/LC-MS) on plasma samples from 78 schizophrenia patients (pre- and post-ECT) and 76 healthy controls, followed by targeted metabolomics validation in an independent schizophrenia cohort (n = 66). Advanced bioinformatics, including WGCNA and SVM-RFE, identified treatment-responsive metabolites.

Results

Schizophrenia patients exhibited 542 differentially expressed metabolites compared to controls (420 downregulated, 122 upregulated), predominantly lipids involved in energy metabolism pathways. Post-ECT, 200 metabolites changed significantly (153 upregulated, 47 downregulated), primarily affecting glycolysis, ketone body metabolism, and inflammatory pathways. WGCNA revealed metabolites in the turquoise module (n = 1329) strongly correlated with symptom severity. SVM-RFE identified 10 baseline metabolites distinguishing ECT responders from non-responders (AUC = 0.724). Targeted validation confirmed 6 metabolites, with 4 showing consistent elevation in responders: N-phenylanthranilic acid, Hydroxy-alpha-sanshool and Linoelaidic acid, and Piperine. Crucially, only responders demonstrated significant post-ECT increases in Hydroxy-alpha-sanshool and Piperine, both TRPV1/TRPA1 channel agonists implicated in neuroprotection and inflammation modulation.

Conclusions

This first comprehensive metabolomic investigation of ECT in schizophrenia reveals energy metabolism dysregulation as a core pathophysiological mechanism. ECT’s therapeutic effects involve metabolic reprogramming and inflammation resolution, with Hydroxy-alpha-sanshool and Piperine emerging as potential predictive and therapeutic candidates. These findings advance precision psychiatry approaches and provide mechanistic insights for developing novel schizophrenia treatments targeting mitochondrial-inflammatory networks.

查看原文本刊更多论文

精神分裂症电休克治疗的代谢组学特征：线粒体能量代谢和炎症作为治疗靶点。

背景：电痉挛疗法（ECT）在治疗难治性精神分裂症中显示出疗效，但其潜在的代谢机制仍然知之甚少。本研究采用综合代谢组学来阐明ECT的治疗机制并确定预测性生物标志物。方法：我们对78名精神分裂症患者（ect前和ect后）和76名健康对照的血浆样本进行了非靶向代谢组学分析（GC-MS/LC-MS），然后在一个独立的精神分裂症队列中进行了靶向代谢组学验证（n = 66）。先进的生物信息学，包括WGCNA和SVM-RFE，鉴定了治疗反应性代谢物。结果：与对照组相比，精神分裂症患者表现出542种代谢物的差异表达（420种下调，122种上调），主要是参与能量代谢途径的脂质。ect后，200种代谢物发生显著变化（153种上调，47种下调），主要影响糖酵解、酮体代谢和炎症途径。WGCNA显示绿松石模块代谢物（n = 1329）与症状严重程度密切相关。SVM-RFE鉴定出10种区分ECT应答者和无应答者的基线代谢物（AUC = 0.724）。靶向验证确认了6种代谢物，其中4种显示反应者一致升高：n -苯基氨基苯甲酸，羟基- α -三酚和亚麻酸，以及胡椒碱。至关重要的是，只有应答者在ect后表现出羟基- α -三酚和胡椒碱的显著增加，这两种TRPV1/TRPA1通道激动剂都与神经保护和炎症调节有关。结论：该研究首次对精神分裂症患者的ECT进行了全面的代谢组学研究，揭示了能量代谢失调是其核心病理生理机制。ECT的治疗效果包括代谢重编程和炎症消退，羟基- α -三酚和胡椒碱成为潜在的预测和治疗候选者。这些发现推进了精确的精神病学方法，并为开发针对线粒体炎症网络的新型精神分裂症治疗提供了机制见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain, Behavior, and Immunity 医学-免疫学

CiteScore

29.60

自引率

2.00%

发文量

290

审稿时长

28 days

期刊介绍： Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.