Minor Proteins Involved in Neuronal Functions in Serum of Patients With Major Mental Disorders According to Proteomic Analysis

Background: Schizophrenia (SCZ) and bipolar disorder (BD) share common clinical features, complicating the identification of specific peripheral biomarkers. The objective of this study was to identify biomarkers that specifically characterize different clinical forms of BD and SCZ. Methods: A comparative proteomic analysis of serum samples from patients with SCZ and BD, as well as healthy controls, was performed using untargeted mass spectrometry to identify differentially expressed proteins. In an expanded cohort, accounting for clinical heterogeneity, the levels of six minor proteins (N-methyl-D-aspartate receptor 1 (NMDAR1), ankyrin 3 (ANK3), ankyrin repeat domain-containing protein 12 (ANKRD12), low-density lipoprotein receptor-related protein 2 (LRP2), dermcidin (DCD), and anti-NMDAR antibodies) were quantified using enzyme-linked immunosorbent assay (ELISA) and targeted mass spectrometry (for NMDAR1). Results: Comparative serum proteomic analysis identified 440 unique proteins in healthy controls versus 221 in patients with SCZ, and 474 unique proteins in healthy controls versus 55 in patients with BD. Quantitative analysis revealed the following findings: (1) a significant increase in NMDAR1 protein levels in patients with BD experiencing a current depressive episode (BD-cDE); (2) decreased ANK3 levels in patients with BD-cDE and SCZ; (3) increased ANKRD12 protein levels in patients with SCZ characterized by predominant negative symptoms and in patients with BD-cDE; (4) decreased DCD levels in patients with SCZ in remission compared with those in the acute phase of the disease; and (5) significantly increased LRP2 levels in both BD and SCZ. Elevated anti-NMDAR antibody levels were more frequently observed in patients with BD, although absolute antibody levels were also increased in patients with acute-phase SCZ. Conclusions: These findings suggest a common mechanism of synaptopathy involving destabilization of the ANK3-NMDAR scaffold, accompanied by a compensatory neuroprotective response in both BD and SCZ. The identified alterations in the serum protein profile may serve as potential biomarkers for the differential diagnosis of these disorders as part of multimarker diagnostic panels.