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Peripheral complement proteins in schizophrenia: A systematic review and meta-analysis of serological studies.

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posted on 2021-03-12, 16:32 authored by David MonganDavid Mongan, Sophie Sabherwal, Subash Raj Susai, Melanie FockingMelanie Focking, Mary CannonMary Cannon, David CotterDavid Cotter

Background: There is renewed focus on the complement system in the pathogenesis of schizophrenia. In addition to providing aetiological insights, consistently dysregulated complement proteins in serum or plasma may have clinical utility as biomarkers.

Methods: We performed a systematic literature review searching PubMed, Embase and PsycINFO for studies measuring complement system activity or complement protein concentrations in serum or plasma from patients with schizophrenia compared to controls. Random-effects meta-analyses were performed to calculate pooled effect estimates (Hedges' g standardised mean difference [SMD]) for complement proteins whose concentrations were measured in three or more studies. The review was pre-registered on the PROSPERO database (CRD42018109012).

Results: Database searching identified 1146 records. Fifty-eight full-text articles were assessed for eligibility and 24 studies included. Seven studies measured complement system activity. Activity of the classical pathway did not differ between cases and controls in four of six studies, and conflicting results were noted in two studies of alternative pathway activity. Twenty studies quantified complement protein concentrations of which complement components 3 (C3) and 4 (C4) were measured in more than three studies. Meta-analyses showed no evidence of significant differences between cases and controls for 11 studies of C3 (SMD 0.04, 95% confidence interval [CI] -0.29-0.36) and 10 studies of C4 (SMD 0.10, 95% CI -0.21-0.41).

Conclusions: Serological studies provide mixed evidence regarding dysregulation of the complement system in schizophrenia. Larger studies of a longitudinal nature, focusing on early phenotypes, could provide further insights regarding the potential role of the complement system in psychotic disorders.


Health Research Board (Grant Number 203930/B/16/Z)

European Research Council Consolidator Award (iHEAR 724809).

Wellcome Trust

Health Service Executive National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland



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Published Citation

Mongan D, Sabherwal S, Susai SR, Föcking M, Cannon M, Cotter DR. Peripheral complement proteins in schizophrenia: A systematic review and meta-analysis of serological studies. Schizophrenia Research.. 2020;222:58-72.

Publication Date

24 May 2020

PubMed ID



  • Psychiatry
  • Beaumont Hospital

Research Area

  • Neurological and Psychiatric Disorders
  • Immunity, Infection and Inflammation




  • Published Version (Version of Record)

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