Schizophrenia risk increased by maternal inflammation

Schizophrenia is well recognized to have a neuroinflammatory component, and a study just published in the American Journal of Psychiatry links maternal inflammation during pregnancy as reflected in elevated CRP (C-reactive protein) levels with a markedly increased irisk of schizophrenia in offspring. The authors state:

"The objective of the present study was to investigate an association between early gestational C-reactive protein, an established inflammatory biomarker, prospectively assayed in maternal sera, and schizophrenia in a large, national birth cohort with an extensive serum biobank."

They examined the maternal sera of 777 schizophrenia cases for C-reactive protein in comparison to 777 matched control subjects. The correlation was striking:

"Increasing maternal C-reactive protein levels...were significantly associated with schizophrenia in offspring. This finding remained significant after adjusting for potential confounders, including maternal and parental history of psychiatric disorders, twin/singleton birth, urbanicity, province of birth, and maternal socioeconomic status."

A reviewer in Medscape Family Medicine notes:

"A growing body of epidemiologic and preclinical evidence suggests that infection and subsequent immune activation play a role in the etiology of schizophrenia, the researchers note."

Also noted in Medscape Family Medicine:

• "Overall, the median maternal C-reactive protein level for case patients was 2.47 mg/L. The median level for control individuals was 2.17 mg/L.
• The investigators found that for every 1 mg/L increase in maternal C-reactive protein, the risk for schizophrenia was increased by 28%.
• The investigators speculate that "maternal inflammation during pregnancy may 'prime' the brain to broadly increase the risk for the later development of different types of psychiatric syndromes."
• They note that their previous research in this same Finnish national birth cohort "demonstrated a significant increase in maternal C-reactive protein levels in pregnancies that gave rise to childhood autism."

Authors of an accompanying editorial note:

"Firstly, while the authors only assessed C-reactive protein, proinflammatory markers, such as interleukin 8 and tumor necrosis factor alpha, have been shown to have similar associations in other birth cohorts. This suggests that the risk is associated with a generally elevated inflammatory state. Secondly, the inflammation story does not appear to be specific to schizophrenia because elevated markers of inflammation are also found in association with depression, with posttraumatic stress disorder, and in many physical diseases Indeed, Brown and his research group have also reported elevated levels of maternal C-reactive protein in association with autism...The inflammatory system and the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response, are inextricably linked: cytokines can elicit a stress response through activation of the fetal HPA axis, and stressors can lead to HPA axis dysregulation and loss of normal glucocorticoid-associated anti-inflammatory tone. Cotter and Pariante previously proposed that many of the neuropathological features observed in schizophrenia are in keeping with nonspecific glucocorticoid-related brain changes. Autoimmunity may also underlie some of the elevation in inflammatory tone seen in people with schizophrenia, and a bidirectional association between schizophrenia and autoimmune disorders has been reported. The recent upsurge of interest in anti-N-methyl-d-aspartic acid receptor encephalitis as a differential diagnosis for schizophrenia demonstrates the importance of autoimmunity in psychosis."

The authors of the primary paper conclude:

"This finding provides the most robust evidence to date that maternal inflammation may play a significant role in schizophrenia, with possible implications for identifying preventive strategies and pathogenic mechanisms in schizophrenia and other neurodevelopmental disorders."

Infection and Autoimmunity

 Clinicians who undertake case management of autoimmunity that latent autoimmune conditions are often triggered by for which there are scores of examples. In this context it's edifying to consider another just-published study in BMJ (British Medical Journal) Open examining infection as a trigger for rheumatoid arthritis:

"We observed a marked increase in overall infections at the time of RA onset, and signs of a defective antibacterial defence mechanism, contrasting with fewer infections in the late RA stage...The model is supported by evidence indicating that monocytes and macrophages as well as other cytokine-producing cell types, are key players in RA, and by more recent reports of non-specific and sustained immunostimulation during RA development...It can be speculated that frequent early infections initiate a compensatory immune hyper-reactivity which reduces the infection load while stimulating the development of RA in predisposed individuals."

Clinical note: "...in predisposed individuals" is a critical point. Practitioners should be adept in comprehensively assessing the various potential underlying contributing causes that predispose to loss of immune tolerance.