Association of Serum Interleukin 6 and C-Reactive Protein in Childhood With Depression and Psychosis in Young Adult Life

Abstract

IMPORTANCE Longitudinal studies have linked the systemic inflammatory markers interleukin 6 (IL-6) and C-reactive protein (CRP) with the risk of developing heart disease and diabetes mellitus, which are common comorbidities for depression and psychosis. Recent meta-analyses of cross-sectional studies have reported increased serum levels of these inflammatory markers in depression, first-episode psychosis, and acute psychotic relapse; however, the direction of the association has been unclear. OBJECTIVE To test the hypothesis that higher serum levels of IL-6 and CRP in childhood would increase future risks for depression and psychosis. DESIGN, SETTING, AND PARTICIPANTS The Avon Longitudinal Study of Parents and Children (ALSPAC)is a prospective general population birth cohort study based in Avon County, England. We have studied a subsample of approximately 4500 individuals from the cohort with data on childhood IL-6 and CRP levels and later psychiatric assessments. MEASUREMENT OF EXPOSURE Levels of IL-6 and CRP were measured in nonfasting blood samples obtained in participants at age 9 years. MAIN OUTCOMES AND MEASURES Participants were assessed at age 18 years. Depression was measured using the Clinical Interview Schedule–Revised (CIS-R) and Mood and Feelings Questionnaire (MFQ), thus allowing internal replication; psychotic experiences (PEs) and psychotic disorder were measured by a semistructured interview. RESULTS After adjusting for sex, age, body mass index, ethnicity, social class, past psychological and behavioral problems, and maternal postpartum depression, participants in the top third of IL-6 values compared with the bottom third at age 9 years were more likely to be depressed (CIS-R) at age 18 years (adjusted odds ratio [OR], 1.55; 95% CI, 1.13-2.14). Results using the MFQ were similar. Risks of PEs and of psychotic disorder at age 18 years were also increased with higher IL-6 levels at baseline (adjusted OR, 1.81; 95% CI, 1.01-3.28; and adjusted OR, 2.40; 95% CI, 0.88-6.22, respectively). Higher IL-6 levels in childhood were associated with subsequent risks of depression and PEs in a dose-dependent manner. CONCLUSIONS AND RELEVANCE Higher levels of the systemic inflammatory marker IL-6 in childhood are associated with an increased risk of developing depression and psychosis in young adulthood. Inflammatory pathways may provide important new intervention and prevention targets for these disorders. Inflammation might explain the high comorbidity between heart disease, diabetes mellitus, depression, and schizophrenia.

Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study

“…The finding of an association between IL-6 and features of hypomania echoes the results from a previous study from the ALSPAC cohort that reported an association between childhood IL-6 and depressive and psychotic symptoms at the age of 18 years (Khandaker et al 2014a). Combined, this body of work suggests that aberrant immune response in childhood might influence the risk of a range of major mental disorders.…”

“…An enzyme-linked immunosorbant assay (ELISA) (R&D systems, UK) was used to measure IL-6. These methods have been reported elsewhere (Khandaker et al 2014a). All interand intra-assay coefficients of variation for IL-6 and CRP were less than 5%.…”

“…We also ran an additional model adjusting for International Classification of Diseases (ICD)-10 diagnosis of depression at the age of 18 years made via the Clinical Interview Schedule-Revised (CIS-R) (Lewis et al 1992). This was to check that any association was not purely driven by the previously reported relationship between inflammatory markers and depression symptoms in this cohort (Khandaker et al 2014a). …”

“…However, there is a paucity of longitudinal research investigating whether alterations in inflammatory markers occur as a precursor to mental disorders. Data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK general population birth cohort, recently showed that higher serum levels of interleukin-6 (IL-6) in childhood is associated with depression and psychosis in young adult life (Khandaker et al 2014a).…”

Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages

“…Autoimmune and inflammatory diseases are commonly associated with mood disorders and several lines of evidence indicate inflammation may give rise to or exacerbate them 1, 2. Studies of animals exposed to proinflammatory challenges, ranging from LPS administration to social defeat, reveal that activation of the peripheral innate immune system causes a depression‐like syndrome of illness behavior: social withdrawal, reduced mobility/energy, sleep disturbance, weight loss, and anhedonia 3, 4, 5.…”