Inflammation in Adolescence and Schizophrenia Risk in Adulthood By Brian Miller, MD, PhD, MPH 2016 Psychiatric Times
RESEARCH UPDATE The investigation of immune system abnormalities in schizophrenia, though ongoing for decades, has more recently become a popular area of research. There is evidence that patients with schizophrenia have increased inflammation in the blood, cerebrospinal fluid, and central nervous system, including elevated C-reactive protein (CRP) levels. 1 CRP is an acute-phase protein that is produced by hepatocytes and is useful in the diagnosis and monitoring of many acute and chronic inflammatory conditions. Lenetstan/Shutterstock
It is difficult to ascertain the direction of association between inflammation and schizophrenia from cross-sectional data. Few previous longitudinal studies of inflammatory markers and subsequent psychotic illness have been performed to investigate whether inflammation is a cause or consequence of illness. However, a recent cohort study found that higher blood interleukin-6 levels at age 9 were associated with a 2- fold increased risk of psychotic-like experiences and psychotic disorder at age 18. 2
Metcalf and colleagues 3 reported on a longitudinal study of blood CRP levels assessed at age 15 to 16 and hospitalization for schizophrenia and related psychotic disorders until age 27 in the 1986 Northern Finland Birth Cohort (NFBC 1986). The NFBC 1986 is a general population-based longitudinal birth cohort study that included all pregnant women from the 2 northernmost provinces of Finland and 9432 lives births between July 1985 and June 1986. GongTo/Shutterstock
The present study was based on 6362 participants who had fasting blood CRP levels measured during a physical assessment at age 15 to 16. Cases of schizophrenia and other non-affective psychosis were identified using several nationwide registers in Finland. IllustrationForest/Shutterstock
Martan/Shutterstock Participants were trichotomized into schizophrenia, nonschizophrenia non-affective psychosis, and no psychosis groups. CRP was analyzed as both a continuous and categorical (<1 mg/l = low; 1-3 mg/l = medium; >3 mg/l = high) variable using logistic regression, controlling for age, sex, body mass index, maternal education, smoking, and alcohol use.
Non-affective psychosis was diagnosed in 88 of the 6362 participants by age 27 (1.4%), including 22 cases of schizophrenia. Mean CRP levels at age 15 to 16 were significantly higher in the schizophrenia group compared with the other 2 groups. There was a 1.2-fold increased odds of schizophrenia at age 27 for each standard deviation increase in CRP level at age 15 to 16. Similarly, high CRP levels were associated with a 4.3-fold increased odds of schizophrenia compared with low CRP levels. There were no significant associations between CRP, sex, and age of onset of illness in schizophrenia. By contrast, blood CRP levels were not associated with significant increased risk of non-affective psychoses (including schizophrenia). MichaelJung/Shutterstock
WavebreakMedia/Shutterstock The study authors concluded that there was a significant longitudinal association between higher blood CRP levels in adolescence and subsequent schizophrenia by age 27, after controlling for important potential confounding factors. Although findings warrant replication in larger samples, the association suggests that inflammation plays a role in the pathogenesis of schizophrenia.
IMPORTANT STUDY LIMITATIONS 1. about one-third of known cases of psychosis in the cohort did not have data on blood CRP levels in adolescence and 2. data on history of infections around the time of blood CRP levels were not available Lenetstan/Shutterstock
THE BOTTOM LINE This study provides evidence that inflammatory pathways represent a novel potential target for prevention and therapeutics in schizophrenia. Lenetstan/Shutterstock
About the author Dr. Miller is Associate Professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, GA, and Schizophrenia Section Editor for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.
REFERENCES 1. Miller BJ, Goldsmith DR. Towards a schizophrenia immunophenotype: progress, potential mechansisms, and future directions. Neuropsychopharmacology Rev. 2016 Oct 19. doi: 10.1038/npp.2016.211. [Epub ahead of print] 2. Khandaker GM, Pearson RM, Zammit S, et al. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry. 2014;71:1121-1128. 3. Metcalf SA, Jones PB, Nordstrom T, et al. Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: a prospective birth cohort study. Brain Behav Immun. 2016 Sep 10. pii: S0889-1591(16)30417-2. doi: 10.1016/j.bbi.2016.09.008. [Epub ahead of print]