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

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.