Neuroprotective Biomarker Modulation by Electroconvulsive Therapy in Schizophrenia: A Prospective Study of Alpha-Klotho, Neprilysin, USP9X

Abstract

Objective: To examine, in an exploratory pre-post design, changes in serum alpha-Klotho, neprilysin, and ubiquitinspecific protease 9X (USP9X) in schizophrenia patients receiving electroconvulsive therapy (ECT), and the associations between these biomarker changes and clinical and cognitive improvements.Methods: This single-arm prospective study included 34 schizophrenia patients receiving ECT; pharmacotherapy was maintained throughout.Serum samples obtained before the first and after the seventh ECT session were measured by sandwich enzyme-linked immunosorbent assay.Clinical assessments used the Positive and Negative Syndrome Scale (PANSS), Montreal Cognitive Assessment (MoCA), and Clinical Global Impression (CGI) scales.Pre-post comparisons used paired t tests with Benjamini-Hochberg false discovery rate (FDR) correction; associations were assessed by Spearman correlation.Results: Following ECT, PANSS total and CGI severity scores decreased and MoCA scores increased significantly (all p ＜ 0.001, FDR-corrected).Serum alpha-Klotho (p = 0.024), neprilysin (p = 0.022), and USP9X (p = 0.001) levels all increased significantly.The increases in alpha-Klotho and USP9X were positively correlated (r = 0.402, p = 0.018), and greater symptomatic improvement was associated with greater cognitive improvement (PANSS vs. MoCA r = -0.473,p = 0.005).Conclusion: In this exploratory single-arm pre-post study, ECT was associated with parallel improvements in psychotic symptoms, cognitive function, and serum levels of three biomarkers implicated in neuroprotective pathways.Biomarkerclinical correlations were modest after multiple-comparison correction; these hypothesis-generating findings warrant replication in larger, controlled studies.