ABSTRACT The complement system is a set of immune proteins involved in first-line defense against pathogens and removal of waste materials. Recent evidence has implicated the complement

cascade in diseases involving the central nervous system, including schizophrenia. Here, we provide an up-to-date narrative review and critique of the literature on the relationship between

schizophrenia and complement gene polymorphisms, gene expression, protein concentration, and pathway activity. A literature search identified 23 new studies since the first review on this

topic in 2008. Overall complement pathway activity appears to be elevated in schizophrenia. Recent studies have identified complement component 4 (C4) and _CUB and Sushi Multiple Domains 1_

analysis through MAGMA which supported the role of Human Leukocyte Antigen class (HLA) III genes and, to a lesser extent, _CSMD1_ in schizophrenia; however, the HLA-schizophrenia association

was likely driven by the C4 gene. Lastly, we identified several limitations of the literature on the complement system and schizophrenia, including: small sample sizes, inconsistent

methodologies, limited measurements of neural concentrations of complement proteins, little exploration of the link between complement and schizophrenia phenotype, and lack of studies

exploring schizophrenia treatment response. Overall, recent findings highlight complement components-in particular, C4 and _CSMD1_—as potential novel drug targets in schizophrenia. Given the

growing availability of complement-targeted therapies, future clinical studies evaluating their efficacy in schizophrenia hold the potential to accelerate treatment advances. Access through

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CONTENT BEING VIEWED BY OTHERS COMPLEMENT COMPONENT C4 LEVELS IN THE CEREBROSPINAL FLUID AND PLASMA OF PATIENTS WITH SCHIZOPHRENIA Article 22 September 2020 INCREASED ACTIVATION PRODUCT OF

COMPLEMENT 4 PROTEIN IN PLASMA OF INDIVIDUALS WITH SCHIZOPHRENIA Article Open access 22 September 2021 DYSREGULATION OF COMPLEMENT AND COAGULATION PATHWAYS: EMERGING MECHANISMS IN THE

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references ACKNOWLEDGEMENTS This study was funded by the Ontario Ministry of Research, Innovation, and Science and University of Toronto’s Faculty of Medicine. We would also like to thank 

Larry and Judy Tanenbaum for their generous donations to the Centre for Addiction and Mental Health.  AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Tanenbaum Centre for Pharmacogenetics,

Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada Julia J. Woo, Jennie G. Pouget, Clement C. Zai 

& James L. Kennedy Authors * Julia J. Woo View author publications You can also search for this author inPubMed Google Scholar * Jennie G. Pouget View author publications You can also

search for this author inPubMed Google Scholar * Clement C. Zai View author publications You can also search for this author inPubMed Google Scholar * James L. Kennedy View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to James L. Kennedy. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare

that they have no conflict of interest. ADDITIONAL INFORMATION PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional

affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TABLE 1 SUPPLEMENTARY TABLE 2 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Woo, J.J., Pouget,

J.G., Zai, C.C. _et al._ The complement system in schizophrenia: where are we now and what’s next?. _Mol Psychiatry_ 25, 114–130 (2020). https://doi.org/10.1038/s41380-019-0479-0 Download

citation * Received: 14 June 2018 * Revised: 06 February 2019 * Accepted: 11 February 2019 * Published: 22 August 2019 * Issue Date: January 2020 * DOI:

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