{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T10:13:49Z","timestamp":1790158429563,"version":"4.1.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>Schizophrenia (SCZ) is a severe mental disorder where diagnosis remains subjective, and treatment efficacy is limited by high heterogeneity, particularly for negative and cognitive symptoms. There is an urgent need for objective molecular biomarkers, especially for early diagnosis and for identifying individuals at clinical high risk (CHR) for psychosis. This review analyzes blood proteomic studies in SCZ, CHR states, and related disorders (2019\u20132025), categorizing them into mass-spectrometry (MS)-based approaches (panoramic and targeted) and affinity-based methods (Olink, SOMAscan). It synthesizes findings from global discovery projects, targeted validation studies, critical risk prediction models, and large-scale Mendelian randomization analyses using UK Biobank data. The field is transitioning from cataloging differentially expressed proteins to identifying causal biomarkers with therapeutic potential (druggability). We propose a consolidated panel of high-priority protein markers, including the ITIH family, CRP, DNER, CTSS, and complement proteins. A critical gap remains in the incomplete coverage of these markers in commercial assays for targeted MS. The future lies in integrating validated proteomic panels with genetic data to enable personalized therapeutic strategies. However, significant hurdles related to reproducibility, cohort heterogeneity, and the lack of standardized validation protocols must be overcome before these biomarkers can be translated into routine clinical practice. Ongoing debates include the choice between MS-based and affinity-based platforms for clinical translation, the interpretation of complement and inflammatory markers as either core pathophysiological drivers or non-specific epiphenomena, and the predictive value of proteomic signatures for psychosis transition. Recent large-scale studies provide a crucial methodological framework, demonstrating the power of rigorous validation and the importance of harmonized, multi-cohort analyses for advancing the field toward clinical implementation.<\/jats:p>","DOI":"10.3389\/fmolb.2026.1882675","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T09:55:00Z","timestamp":1790157300000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Blood-based proteomics for schizophrenia: candidate biomarkers for risk assessment and precision psychiatry"],"prefix":"10.3389","volume":"13","author":[{"given":"Alexey S.","family":"Kononikhin","sequence":"first","affiliation":[{"name":"The Center for Bio- and Medical Technologies, Skolkovo Institute of Science and Technology","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna E.","family":"Bugrova","sequence":"additional","affiliation":[{"name":"The Center for Bio- and Medical Technologies, Skolkovo Institute of Science and Technology","place":["Moscow, Russia"]},{"name":"Emanuel Institute of Biochemical Physics, Russian Academy of Science","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arina S.","family":"Foliforova","sequence":"additional","affiliation":[{"name":"The Center for Bio- and Medical Technologies, Skolkovo Institute of Science and Technology","place":["Moscow, Russia"]},{"name":"Moscow Institute of Physics and Technology","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria I.","family":"Indeykina","sequence":"additional","affiliation":[{"name":"The Center for Bio- and Medical Technologies, Skolkovo Institute of Science and Technology","place":["Moscow, Russia"]},{"name":"Emanuel Institute of Biochemical Physics, Russian Academy of Science","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polina A.","family":"Strelnikova","sequence":"additional","affiliation":[{"name":"The Center for Bio- and Medical Technologies, Skolkovo Institute of Science and Technology","place":["Moscow, Russia"]},{"name":"Emanuel Institute of Biochemical Physics, Russian Academy of Science","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia V.","family":"Zakharova","sequence":"additional","affiliation":[{"name":"The Center for Bio- and Medical Technologies, Skolkovo Institute of Science and Technology","place":["Moscow, Russia"]},{"name":"Emanuel Institute of Biochemical Physics, Russian Academy of Science","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Y.","family":"Morozova","sequence":"additional","affiliation":[{"name":"Mental-Health Clinic No. 1 named after N.A. Alexeev","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George P.","family":"Kostyuk","sequence":"additional","affiliation":[{"name":"Mental-Health Clinic No. 1 named after N.A. Alexeev","place":["Moscow, Russia"]},{"name":"I.M. Sechenov First Moscow State Medical University (Sechenov University)","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeny N.","family":"Nikolaev","sequence":"additional","affiliation":[{"name":"The Center for Bio- and Medical Technologies, Skolkovo Institute of Science and Technology","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.schres.2020.04.010","article-title":"North American Prodrome Longitudinal Study (NAPLS 3): methods and baseline description","volume":"243","author":"Addington","year":"2020","journal-title":"Schizophr. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"eadx2678","DOI":"10.1126\/science.adx2678","article-title":"A human pan-disease blood atlas of the circulating proteome","volume":"390","author":"\u00c1lvez","year":"2025","journal-title":"Science"},{"key":"B10","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1001\/jamapsychiatry.2025.0033","article-title":"Circulating blood-based proteins in psychopathology and cognition: a Mendelian randomization Study","volume":"82","author":"Bhattacharyya","year":"2025","journal-title":"JAMA Psychiatry"},{"key":"B3","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1093\/schbul\/sbad184","article-title":"Proteomic biomarkers for the prediction of transition to psychosis in individuals at clinical high risk: a multi-cohort model development Study","volume":"50","author":"Byrne","year":"2024","journal-title":"Schizophr. Bull."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1038\/s41380-021-01339-z","article-title":"Multi-omics of human plasma reveals molecular features of dysregulated inflammation and accelerated aging in schizophrenia","volume":"27","author":"Campeau","year":"2022","journal-title":"Mol. Psychiatry"},{"key":"B5","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1074\/mcp.M113.036095","article-title":"Targeted peptide measurements in biology and medicine: best practices for mass spectrometry-based assay development using a fit-for-purpose approach","volume":"13","author":"Carr","year":"2014","journal-title":"Mol. Cell Proteomics"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1093\/schbul\/sby058","article-title":"Global epidemiology and burden of schizophrenia: findings from the global burden of disease Study 2016","volume":"44","author":"Charlson","year":"2018","journal-title":"Schizophr. Bull."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41398-025-03738-0","article-title":"Circulating inflammatory proteins associated with risks of schizophrenia, bipolar disorder, and major depressive disorder: a Mendelian randomization study","volume":"16","author":"Chen","year":"2025","journal-title":"Transl. Psychiatry"},{"key":"B8","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.biopsych.2019.10.015","article-title":"The genetics of the mood disorder spectrum: genome-wide association analyses of more than 185,000 cases and 439,000 controls","volume":"88","author":"Coleman","year":"2020","journal-title":"Biol. Psychiatry"},{"key":"B9","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/s41398-018-0219-2","article-title":"Proteomics for blood biomarker exploration of severe mental illness: pitfalls of the past and potential for the future","volume":"8","author":"Comes","year":"2018","journal-title":"Transl. Psychiatry"},{"key":"B11","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1111\/gbb.12016","article-title":"Neuropsychological effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253","volume":"12","author":"Donohoe","year":"2013","journal-title":"Genes Brain Behav."},{"key":"B12","doi-asserted-by":"publisher","first-page":"809071","DOI":"10.3389\/fpsyt.2022.809071","article-title":"Proteomic analysis of plasma markers in patients maintained on antipsychotics: comparison to patients off antipsychotics and normal controls","volume":"13","author":"Engelke","year":"2022","journal-title":"Front. Psychiatry"},{"key":"B13","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/j.bbi.2023.04.020","article-title":"Immunological protein profiling of first-episode psychosis patients identifies CSF and blood biomarkers correlating with disease severity","volume":"111","author":"Eren","year":"2023","journal-title":"Brain Behav. Immun."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.1038\/nn.4399","article-title":"Gene expression elucidates functional impact of polygenic risk for schizophrenia","volume":"19","author":"Fromer","year":"2016","journal-title":"Nat. Neurosci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"3634","DOI":"10.1039\/c9an01893j","article-title":"Determination of the concentration range for 267 proteins from 21 lots of commercial human plasma using highly multiplexed multiple reaction monitoring mass spectrometry","volume":"145","author":"Gaither","year":"2020","journal-title":"Analyst"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e10427","DOI":"10.15252\/emmm.201910427","article-title":"Plasma proteome profiling to detect and avoid sample-related biases in biomarker studies","volume":"11","author":"Geyer","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/978-1-4939-7057-5_1","article-title":"Direct assessment of plasma\/serum sample quality for proteomics biomarker investigation","volume":"1619","author":"Greco","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1038\/s41586-025-09820-3","article-title":"Mapping the genetic landscape across 14 psychiatric disorders","volume":"649","author":"Grotzinger","year":"2025","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/s41380-021-01197-9","article-title":"Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis","volume":"27","author":"Heurich","year":"2022","journal-title":"Mol. Psychiatry"},{"key":"B20","doi-asserted-by":"publisher","first-page":"4085","DOI":"10.1021\/acs.jproteome.9b00503","article-title":"Mass spectrometry-based plasma proteomics: considerations from sample collection to achieving translational data","volume":"18","author":"Ignjatovic","year":"2019","journal-title":"J. Proteome Res."},{"key":"B21","unstructured":"Global health data exchange (GHDx)"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2139","DOI":"10.1038\/s41598-023-29117-7","article-title":"Consolidation of metabolomic, proteomic, and GWAS data in connective model of schizophrenia","volume":"13","author":"Kopylov","year":"2023","journal-title":"Sci. Rep."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1038\/s41588-019-0512-x","article-title":"Comparative genetic architectures of schizophrenia in East Asian and European populations","volume":"51","author":"Lam","year":"2019","journal-title":"Nat. Genet."},{"key":"B24","doi-asserted-by":"publisher","first-page":"S27","DOI":"10.1016\/j.biopsych.2017.02.077","article-title":"Increased C3 and C4 proteins in serum of FEP and UHR patients: implications for inflammatory subtyping in SCZ","volume":"81","author":"Laskaris","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"B25","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1146\/annurev-clinpsy-032813-153657","article-title":"Excess early mortality in schizophrenia","volume":"10","author":"Laursen","year":"2014","journal-title":"Annu. Rev. Clin. Psychol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.gene.2013.04.014","article-title":"Pathway analysis of a genome-wide association study in schizophrenia","volume":"525","author":"Lee","year":"2013","journal-title":"Gene"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1630","DOI":"10.1021\/acs.jproteome.2c00575","article-title":"Quantification of 782 plasma peptides by multiplexed targeted proteomics","volume":"22","author":"Lesur","year":"2023","journal-title":"J. Proteome Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11427-025-2990-0","article-title":"Schizophrenia: from mechanism to therapy","volume":"69","author":"Lu","year":"2026","journal-title":"Sci. China Life Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/s41537-025-00633-x","article-title":"Cardiovascular protein profiling in patients with first-episode psychosis","volume":"11","author":"Malmqvist","year":"2025","journal-title":"Schizophr"},{"key":"B30","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1001\/jamapsychiatry.2020.2459","article-title":"Development of proteomic prediction models for transition to psychotic disorder in the clinical high-risk state and psychotic experiences in adolescence","volume":"78","author":"Mongan","year":"2020","journal-title":"JAMA Psychiatry"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1554","DOI":"10.1038\/mp.2017.151","article-title":"The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis","volume":"22","author":"Nimgaonkar","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.1093\/schbul\/sbx166","article-title":"Can we reduce the duration of untreated psychosis? A systematic review and meta-analysis of controlled interventional studies","volume":"44","author":"Oliver","year":"2018","journal-title":"Schizophr. Bull."},{"key":"B33","doi-asserted-by":"crossref","first-page":"5","DOI":"10.17116\/jnevro20201200625","article-title":"Shizofreniya i drugie psikho ticheskie rasstroistva v MKB\u221211 i DSM\u22125: razvitie kontseptsii i sovremennoe sostoyanie","volume":"120","author":"Pavlichenko","year":"2020","journal-title":"Zh Nevrol. Psikhiatr Im. S S Korsakova"},{"key":"B34","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/s41537-025-00610-4","article-title":"Body fluid biomarkers and psychosis risk in the accelerating medicines partnership\u00ae schizophrenia program: design considerations","volume":"11","author":"Perkins","year":"2025","journal-title":"Schizophrenia"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1483933","DOI":"10.3389\/fmolb.2024.1483933","article-title":"Extended range proteomic analysis of blood plasma from schizophrenia patients","volume":"11","author":"Petrovskiy","year":"2024","journal-title":"Front. Mol. Biosci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"4917","DOI":"10.3390\/ijms23094917","article-title":"Systematic review and meta-analysis of mass spectrometry proteomics applied to human peripheral fluids to assess potential biomarkers of schizophrenia","volume":"23","author":"Rodrigues","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.psc.2015.09.006","article-title":"Bipolar disorder and inflammation","volume":"39","author":"Rosenblat","year":"2016","journal-title":"Psychiatr. Clin. North Am."},{"key":"B38","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1038\/nature16549","article-title":"Schizophrenia risk from complex variation of complement component 4","volume":"530","author":"Sekar","year":"2016","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2376","DOI":"10.1021\/acs.jproteome.4c00040","article-title":"Protein profiles and novel molecular biomarkers of schizophrenia based on 4D-DIA proteomics","volume":"23","author":"Shen","year":"2024","journal-title":"J. Proteome Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1021\/acs.jproteome.3c00580","article-title":"Evaluation of a nondepleted plasma multiprotein-based model for discriminating psychiatric disorders using multiple reaction monitoring-mass spectrometry: proof-of-concept study","volume":"23","author":"Shin","year":"2024","journal-title":"J. Proteome Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1186\/s12864-019-5848-1","article-title":"The difference in serum proteomes in schizophrenia and bipolar disorder","volume":"20","author":"Smirnova","year":"2019","journal-title":"BMC Genomics"},{"key":"B42","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/s41537-024-00440-w","article-title":"Association study of the complement component C4 gene and suicide risk in schizophrenia","volume":"10","author":"Sokolowski","year":"2024","journal-title":"Schizophrenia"},{"key":"B43","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3390\/ijms27010015","article-title":"Plasma protein panel for assessing the risk of alzheimer's disease by MRM-MS analysis: the study of two independent clinical cohorts","volume":"27","author":"Strelnikova","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.schres.2023.11.015","article-title":"The schizophrenia syndrome, circa 2024: what we know and how that informs its nature","volume":"264","author":"Tandon","year":"2024","journal-title":"Schizophr. Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1001\/jamapsychiatry.2022.4350","article-title":"Lipid alteration signature in the blood plasma of individuals with schizophrenia, depression, and bipolar disorder","volume":"80","author":"Tkachev","year":"2023","journal-title":"JAMA Psychiatry"},{"key":"B46","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1038\/s41398-025-03323-5","article-title":"Investigating the association of the plasma lipidomic profile with cognitive performance and genetic risk in the PsyCourse study","volume":"15","author":"Oraki Kohshour","year":"2025","journal-title":"Transl. Psychiatry"},{"key":"B47","doi-asserted-by":"publisher","first-page":"18008","DOI":"10.1038\/nrdp.2018.8","article-title":"Bipolar disorders","volume":"4","author":"Vieta","year":"2018","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B48","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1038\/s41380-019-0479-0","article-title":"The complement system in schizophrenia: where are we now and what's next?","volume":"25","author":"Woo","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"B49","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/s41398-020-00902-6","article-title":"Multi-trait analysis for genome-wide association study of five psychiatric disorders","volume":"10","author":"Wu","year":"2020","journal-title":"Transl. Psychiatry"},{"key":"B50","doi-asserted-by":"publisher","first-page":"111396","DOI":"10.1016\/j.pnpbp.2025.111396","article-title":"Identifying novel protein biomarkers with cross-psychiatric disorders effects and potential intervention targets: evidence from proteomic-mendelian randomization","volume":"139","author":"Zhang","year":"2025","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"B51","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/s41398-021-01583-5","article-title":"Increased activation product of complement 4 protein in plasma of individuals with schizophrenia","volume":"11","author":"Kalinowski","year":"2021","journal-title":"Transl. Psychiatry"}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1882675\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T09:55:06Z","timestamp":1790157306000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1882675\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":51,"alternative-id":["10.3389\/fmolb.2026.1882675"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2026.1882675","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]},"article-number":"1882675"}}