Surface protein dynamics of neuron-derived extracellular vesicles track electroconvulsive therapy response in schizophrenia

Electroconvulsive therapy (ECT) is effective for treatment-resistant schizophrenia (SCZ), but its neurobiological mechanism remains unclear. We profiled plasma extracellular vesicles (EVs) and L1CAM⁺ EVs in schizophrenia patients and controls before and after ECT to identify EV signatures of ECT response. In a discovery cohort (30 SCZ, 15 controls), we used single-EV proximity barcoding assays to profile EV surface proteins at baseline and after 6 ECT sessions. A validation cohort (50 SCZ, 50 controls) was analyzed by EV-Array, and protein changes were correlated with clinical response (PANSS). Baseline total EV (tEV) counts were higher in patients than controls, and after ECT, tEV counts and neuronal L1CAM⁺ EV levels declined, especially in responders. Single-EV profiling revealed widespread dysregulation of immune and neurovascular proteins in patients, which partially normalized after ECT. In the validation cohort, baseline tEV surface protein markers were elevated in patients versus controls; after ECT, tEV surface proteins ADAM10, ESAM, and AIF1 decreased. Among responders, ADAM10 on neuronal EVs decreased more than in non-responders, and a strong positive ADAM10-L1CAM correlation at baseline was lost after treatment. These findings suggest that schizophrenia is characterized by altered EV abundance and surface proteomes, and that ECT selectively restructures EV quantity, subpopulation architecture, and protein landscapes, particularly within neurovascular and inflammatory pathways, and is associated with changes in ADAM10 and L1CAM on EVs. EV surface proteins emerge as promising biomarkers of ECT response and potential targets for precision interventions.