Royal College of Surgeons in Ireland
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Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis

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journal contribution
posted on 2021-07-06, 10:53 authored by Meike Heurich, Melanie FockingMelanie Focking, David MonganDavid Mongan, Gerard Cagney, David CotterDavid Cotter
Early identification and treatment significantly improve clinical outcomes of psychotic disorders. Recent studies identified protein components of the complement and coagulation systems as key pathways implicated in psychosis. These specific protein alterations are integral to the inflammatory response and can begin years before the onset of clinical symptoms of psychotic disorder. Critically, they have recently been shown to predict the transition from clinical high risk to first-episode psychosis, enabling stratification of individuals who are most likely to transition to psychotic disorder from those who are not. This reinforces the concept that the psychosis spectrum is likely a central nervous system manifestation of systemic changes and highlights the need to investigate plasma proteins as diagnostic or prognostic biomarkers and pathophysiological mediators. In this review, we integrate evidence of alterations in proteins belonging to the complement and coagulation protein systems, including the coagulation, anticoagulation, and fibrinolytic pathways and their dysregulation in psychosis, into a consolidated mechanism that could be integral to the progression and manifestation of psychosis. We consolidate the findings of altered blood proteins relevant for progression to psychotic disorders, using data from longitudinal studies of the general population in addition to clinical high-risk (CHR) individuals transitioning to psychotic disorder. These are compared to markers identified from first-episode psychosis and schizophrenia as well as other psychosis spectrum disorders. We propose the novel hypothesis that altered complement and coagulation plasma levels enhance their pathways’ activating capacities, while low levels observed in key regulatory components contribute to excessive activation observed in patients. This hypothesis will require future testing through a range of experimental paradigms, and if upheld, complement and coagulation pathways or specific proteins could be useful diagnostic or prognostic tools and targets for early intervention and preventive strategies.


Irish Health Research Board, ILP POR-2019-005 and HRB ILP POR-2017-039

Wellcome Trust, 220438Z/20/Z and 102215/2/13/2

Irish Clinical Academic Training (ICAT) Programme

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

Health Service Executive National Doctors Training and Planning

Health and Social Care, Research and Development Division, Northern Ireland

UK Medical Research Council

The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project is funded by grant agreement HEALTH-F2-2010-241909 (Project EU-GEI) from the European Community’s Seventh Framework Programme.



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Published Citation

Heurich, M., Föcking, M., Mongan, D., Cagney G., Cotter D.R.. Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis. Mol Psychiatry 2021.

Publication Date

5 July 2021


  • Psychiatry

Research Area

  • Neurological and Psychiatric Disorders
  • Immunity, Infection and Inflammation


Springer Science and Business Media LLC


  • Published Version (Version of Record)