Elsevier

Biological Psychiatry

Volume 73, Issue 10, 15 May 2013, Pages 951-966
Biological Psychiatry

Review
Inflammatory Cytokines and Neurological and Neurocognitive Alterations in the Course of Schizophrenia

https://doi.org/10.1016/j.biopsych.2013.01.001Get rights and content

A growing body of evidence suggests that immune alterations, especially those related to inflammation, are associated with increased risk of schizophrenia and schizophrenia-related brain alterations. Much of this work has focused on the prenatal period, because infections during pregnancy have been repeatedly (albeit inconsistently) linked to risk of schizophrenia. Given that most infections do not cross the placenta, cytokines associated with inflammation (proinflammatory cytokines) have been targeted as potential mediators of the damaging effects of infection on the fetal brain in prenatal studies. Moreover, additional evidence from both human and animal studies suggests links between increased levels of proinflammatory cytokines, immune-related genes, and schizophrenia as well as brain alterations associated with the disorder. Additional support for the role of altered immune factors in the etiology of schizophrenia comes from neuroimaging studies, which have linked proinflammatory cytokine gene polymorphisms with some of the structural and functional abnormalities repeatedly found in schizophrenia. These findings are reviewed and discussed with a life course perspective, examining the contribution of inflammation from the fetal period to disorder presentation. Unexplored areas and future directions, such as the interplay between inflammation, genes, and individual-level environmental factors (e.g., stress, sleep, and nutrition), are also discussed.

Section snippets

Overview of Link Between Schizophrenia and Infection

The first associations between schizophrenia and infection were found in ecologic studies (8). Although findings have been mixed, winter to spring births (a period of heightened infections) and pregnancy during influenza epidemics have been associated with risk for schizophrenia among offspring (3). However, ecologic studies are limited by their presumption of infection based on events that occur for an entire population without direct confirmation of exposure (3).

Nevertheless, the association

Cytokines

With the exception of parasitic infections, like toxoplasmosis gondii, most infections do not seem to cross the placenta; thus, damaging effects to the fetus are likely operating through maternal, fetal, and/or placental responses to infection 26, 27. Among these responses to infections, prime candidates have been cytokines associated with inflammation (termed proinflammatory cytokines), some of which seem to cross the placenta 28, 29. Cytokines are soluble polypeptide signaling proteins that

Immunological and Inflammatory Cytokine Alterations in Schizophrenia

Research on the influence of early life exposure to infection and inflammation on immune functioning across the lifespan is highly relevant, given repeated studies that have found immunological abnormalities in schizophrenia populations (66). Furthermore, schizophrenia has been associated with inflammation and increased levels of cytokines, IL-2 receptors, IL-1 receptor agonists (IL-1RA), and acute phase reactants such as IL-1β and IL-6 in plasma 67, 68. Potvin et al. (31) published a recent

Schizophrenia and Neuroinflammation

Neuroinflammation is characterized by activation of microglia cells, which are the resident macrophages of the brain and primary reservoirs of proinflammatory cytokines 93, 94. Findings on neuroinflammation in schizophrenia have been mixed, with some postmortem studies finding increases in activated microglia cells in the brains of schizophrenia patients 95, 96, 97, whereas others fail to find differences 98, 99, 100, 101. Active neuroinflammation can be assessed with a PET tracer, (R)-N-11

Remarks

Most studies on inflammation and schizophrenia have examined proinflammatory cytokines in the prenatal period and after schizophrenia onset, leaving the premorbid period unexamined. Understanding inflammation and immune abnormalities during the premorbid and prodromal periods of schizophrenia will play a crucial role in determining whether inflammation contributes to the neurodevelopmental course of schizophrenia. Currently, there are two primary theories with regard to how early immune insults

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