Elevated C-Reactive Protein Associated With Late- and Very-Late-Onset Schizophrenia in the General Population: A Prospective Study

Abstract

Background: Individuals with autoimmune diseases and severe infections have persistent or acutely elevated inflammatory biomarkers and increased risk of schizophrenia. We tested the hypothesis that baseline elevated plasma levels of the inflammatory biomarker, C-reactive protein (CRP), associate with increased risk of late-and very-lateonset schizophrenia in the general population, and if such an association possibly is causal. Method: We analyzed data from 78 810 men and women, aged 20-100 years, from 2 large population studies. Endpoints were hospitalization with schizophrenia and schizophrenia and schizophrenialike psychosis combined. We performed prospective and cross-sectional analyses adjusted for potential confounders with up to 20 years of follow-up. Furthermore, we used genetic variants influencing plasma CRP levels to perform a Mendelian randomization study. Results: Age-and gender-adjusted hazard ratios vs individuals in the first quartile of CRP were 1.7 (95% CI: 0.3-8.9) for second quartile, 2.1 (0.4-10) for third quartile, and 11 (2.8-40) for fourth quartile individuals. The corresponding hazard ratio for fourth quartile individuals after multifactorial adjustment was 5.9 (1.4-24). Furthermore, individuals with vs without schizophrenia had 63% increased plasma levels of CRP (P = 1 × 10 −4 ). Finally, when CRP was on a continuous scale, a doubling in CRP yielded an age-and gender-adjusted observational OR of 1.5 (1.3-1.8) and a corresponding causal OR of 1.4 (0.5-4.3) (observed vs causal: P = .89). Conclusion: Baseline elevated plasma CRP is associated with a 6-to 11-fold increased risk of late-and very-late-onset schizophrenia in the general population. We cannot exclude that this is a causal association. These are novel findings.

C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications

“…Of those, 76 were excluded on the basis of the title and the abstract, leaving 48 studies for further evaluation. Twenty-six studies fulfiled our inclusion criteria, 19 for the between-group meta-analysis of SZ versus control, 14,[17][18][19]21,24,25,[27][28][29][30][31][33][34][35][36]38,39,41 6 for the withingroup meta-analysis of CRP changes after initiation of antipsychotics 20,21,23,27,32,37 and 3 for the within-group metaanalysis of CRP changes with substitution of the type of the antipsychotic. 22,26,40 Some studies provided more than one pairwise comparison, as whenever possible we extracted data according to medication status.…”

“…3 Moreover, several cross-sectional studies and an early meta-analysis found increased inflammatory biomarkers, mostly cytokines, in the plasma and the serum of subjects with SZ. 11 Some inflammatory cytokines, 14 in particular interleukin 6 (IL-6) and interleukin 1β (IL-1β), have also been suggested to represent state markers for acute exacerbations of psychosis. 11 Taken together, these findings suggest that immune dysregulation may indeed be involved in the pathogenesis of SZ, and that SZ is a systemic disease with an inflammatory component (at least in patient subgroups) that could at least in part be responsible for common risk pathways in SZ and obesity.…”

“…These indicate a state of low-grade inflammation, which is frequently associated with obesity and metabolic syndrome, and predicts an increased risk of depression 13 and cardiovascular diseasescommon comorbidities in persons with SZ. 14 CRP is mainly produced by hepatocytes and is directly modulated by IL-6 and IL-1β, both of which appear to be increased particularly during exacerbations of psychotic status. 11,15,16 This raises the possibility that CRP, in addition to inflammatory cytokines, may play a role in the inflammatory hypothesis of SZ and therefore be involved in its pathophysiology in a similar manner.…”

“…14, Furthermore, the results are constrained by diverging methodological characteristics among the different reports, such as small sample sizes and presence of systemic clinical diseases (for instance, diabetes and atherosclerosis). It is also controversial whether CRP is increased in SZ per se or whether it is merely a marker of the associated systemic inflammation commonly found in this disorder, due to increased prevalence of obesity and metabolic syndrome, among others.…”

Late-Onset Psychosis; Is It Real?

“…A recent prospective study demonstrated the association of C-reactive protein (CRP) measured on average of 7-8 years before hospitalization with schizophrenia or schizophrenia-like psychosis, with a 6-11-fold increased risk of late-and very-lateonset schizophrenia in the general population. 75 CRP is one of the most commonly used inflammation markers. The biological mechanism linking CRP and schizophrenia is not fully understood.…”