Inflammation in Schizophrenia: Pathogenetic Aspects and Therapeutic Considerations

Norbert Müller

Disclosures

Schizophr Bull. 2018;44(5):973-982. 

In This Article

The Possible Role of Infection in Schizophrenia

Animal models have provided evidence for the role of pre- and perinatal infections in the later development of schizophrenia.[66,67] For example, in animal models, offspring shows typical symptoms of schizophrenia, such as cognitive deterioration or startle reflex abnormalities, after prenatal exposure to viral agents.[68,69] Evidence is available also from studies in humans after prenatal or childhood exposure to different viruses,[70–73] respiratory infections,[74] genital or reproductive tract infections,[74,75] Toxoplasma gondii,[76] and other infections.[77–80] Although many studies have examined antibody titers against viruses in the sera of patients with schizophrenia, the results have been inconsistent.[81] The findings may have been unclear because studies did not control for confounding variables such as possible polyclonal immune activation or smoking and because antibody levels are affected by medication.[82] In one of our own studies, patients with schizophrenia had higher titers of various pathogens than healthy controls, a phenomenon that we termed the "infectious index."[83]

Several studies indicate that immune activation during pregnancy of the mother increases the offspring's risk for developing schizophrenia. For example, animal studies have shown that high IL-6 levels in utero cause schizophrenia-like symptoms in the offspring and that these symptoms can be reversed by anti-IL-6 antibodies.[84] Also, IL-6 levels in childhood predict the later risk for schizophrenia.[85]

Because of space limitations, the topic of a pro-inflammatory state in utero or early childhood as a risk factor for later development of schizophrenia cannot be discussed in detail here. An interesting example, however, is the pro-inflammatory cytokine IL-8, which has been studied in human pregnant mothers: offspring had a higher risk of developing schizophrenia if exposed prenatally to increased levels of IL-8.[86] Furthermore, people with schizophrenia showed decreased brain volume, ie, lower volumes of the right posterior cingulum and left entorhinal cortex and higher volumes of the ventricles, after prenatal exposure to higher maternal IL-8 levels (measured in assays from archived prenatal sera).[87]

Because schizophrenia is a disorder of late adolescence and early adulthood, the possible mechanism of the associations between early life infection and adult schizophrenia has to be addressed. Many studies show that early infection or immune activation influences several neurodevelopmental processes, including dopaminergic and glutamatergic neurotransmission in animal models.[46,88] In humans, studies on certain infections[89] and a cohort study of bacterial infections[74] are examples that underline this association. Increased levels of cytokines or C-reactive protein in childhood indicate an increased risk for schizophrenia.[90]

Infection in later life has also been linked to an increased risk for schizophrenia. For example, a large-scale, 30-year epidemiological register study in Denmark found that autoimmune disorders and severe infections requiring hospitalization increased the risk of schizophrenia and schizophrenia spectrum disorders, particularly in patients with both risk factors.[91] Interestingly, this study did not find evidence that infections of the parents, including intrauterine infections, were definite risk factors for the development of schizophrenia in the offspring.[91,92] However, despite the large scale of the study, the authors determined that the study did not have very high sensitivity, and the identified risk factors were therefore only the "tip of an iceberg."[92]

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