Inflammatory and Immune System Components Could Contribute to Psychosis

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Psychological disorders such as schizophrenia and bipolar disorder are categorized as severe mental disorders, having large costs to both the individual and society.

The pathogenic process of psychosis is complex, involving many biological and environmental factors across one’s lifetime. Importantly, early identification and intervention are linked with improved symptomatic and functional outcomes. A key aspect of ongoing research is the identification of risk factors for development of psychosis in high-risk individuals. Trying to predict risk is difficult when relying on clinical symptoms alone, with only around 20–35% of high-risk individuals developing psychosis at the age of 3. Therefore, there is a pressing need to identify early biomarkers of psychosis risk, that can be translated clinically.

In our body’s immune system, there are two major pathways our cells take to get rid of pathogenic substances when our bodies get infected. These two pathways are called the complement pathway and the coagulation pathway. Recently, baseline blood biomarkers, mainly the components of the complement and coagulation pathways, have been found to discriminate between high-risk individuals who do and do not go on to develop a first psychotic episode. This suggests that dysfunction of these systems could play a key role in early detection and may provide insight into the early pathophysiology of psychosis. Therefore, suggesting that inflammation and immune activation (which trigger these 2 pathways) are implicated in psychotic disorders such as schizophrenia, bipolar disorder, and other major mental disorders.

The paper in question focuses on the roles the complement and coagulation pathways play in our normal physiology, before focusing on how their dysregulation may cause pathology. The researchers integrate new findings into an adjustment of the dominant “two-hit” hypothesis, where early genetic and/or environmental factors disrupt the developing central nervous system (the “first-hit”) and increase the vulnerability of the individual to subsequent, late environmental disruptions (the “second-hit”). This new proposed theory integrates complement and coagulation dysregulation, that leads to immune activation, and subsequently contributing to the development of a psychotic disorder. Finally, the researchers of this paper considered the potential implications of treatment of psychotic disorders and proposed directions for future research.

The complement and coagulation pathways are vital to our body’s defense against pathogen infection and injury. The complement system is a main component of the innate (primary) immune defense. It is composed of plasma and proteins bound to cells, which are activated through three distinct pathways: the classical, lectin, and alternative pathways, which meet at the level of C3 (a type of immune system protein) activation leading to formation of a membrane-attack complex that causes bacterial cell lysis leading to bacterial cell death. Innate immune defense mechanisms can trigger coagulation to limit the invasiveness of the pathogens, as well as respond to injury through fibrin formation by intrinsic (contact activation) or extrinsic (tissue factor) pathway activation. This is then regulated by plasminogen activation-mediated fibrinolysis. Increased evidence of molecular crosstalk between coagulation and inflammation (as shown by image 1 below) suggests that coagulation activation can increase inflammation, which in turn amplifies coagulation.

Image 1: Diagram showing crosstalk between coagulation and inflammation

Literature supporting the significant contribution of (neuro)inflammation in the pathogenic occurrence of psychotic disorders has started to find its way into this discourse. Many studies demonstrate changes in plasma protein levels, years before the onset of psychotic experiences or psychotic disorder. For instance, there is evidence of increased levels of IL-6 (a proinflammatory protein) in schizophrenia patients. Further, other proinflammatory proteins were increased in high-risk individuals who later developed psychosis compared to those who did not; linking inflammatory proteins to complement and coagulation protein expression.

Per the results of this paper, there is now compelling evidence for a key role of complement and coagulation changes in psychosis spectrum disorders. It has also been proposed that these changes lead to increased risk for psychosis. These pathways may provide objective biomarkers of psychosis, and enable identification of therapeutic targets for early and more effective intervention strategies and treatment.

Original Paper:
Heurich, M., Föcking, M., Mongan, D. et al. Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis. Molecular Psychiatry (2021). doi.org/10.1038/s41380-021-01197-9

Original Link: https://www.nature.com/articles/s41380-021-01197-9

Image 1: https://www.researchgate.net/publication/257135500_Atypical_Hemolytic-Uremic_Syndrome_The_Interplay_Between_Complements_and_the_Coagulation_System/figures?lo=1&utm_source=bing&utm_medium=organic

Featured Image: Photo by Karolina Grabowska from Pexels

Edited by Malavika.

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