17. MOLECULAR STAGING OF SCHIZOPHRENIA AND BIPOLAR DISORDER USING CEREBROSPINAL FLUID PROTEOMICS

Abstract

Background Schizophrenia (SCZ) and bipolar disorder (BD) share considerable genetic risk andoverlap in clinical presentation, yet the nature and extent of their molecular convergence, particularly in relation to illness progression, remains insufficiently defined. Cerebrospinal fluid(CSF) proteomics offers a minimally invasive approach to characterizing brain biology in vivo andoffers potential for biomarker discovery Methods We analyzed CSF from 400 individuals (160 with SCZ-spectrum disorders, 139 withBD, and 101 controls) across four Swedish cohorts using Olink Proximity Extension Assay targeting 1,152 proteins. A subset (n=186) underwent repeated CSF sampling after a median of6.5 years. We examined differential protein abundance across diagnostic categories, illness stages, and longitudinal change in relation to manic or psychotic episodes Results We identified 139 proteins with differential abundance across SCZ and BD subgroupsimplicating synaptic and neurodevelopmental pathways, as well as immune, metabolism, and cell_x0002_structural functions—some of which map to genes prioritized in BD and SCZ risk loci. Effect sizeswere strongly correlated between SCZ and BD subgroups, indicating shared molecular pathology,with larger fold changes in SCZ, particularly in more chronic and treatment-resistant stages. Proteomic alterations in first-episode psychosis later diagnosed with SCZ resembled chronic SCZ.Longitudinal analyses linked changes in immune and synaptic proteins to relapse over the 6.5year follow-up Discussion These findings suggest a progressive and shared molecular pathology across theBD–SCZ spectrum, with early proteomic changes detectable at illness onset in SCZ. If confirmedby longitudinal studies, CSF proteomics could provide a basis for biomarker-informed stagingframeworks to guide diagnosis, prognosis, and treatment development in severe mental illness