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Association of Serum Interleukin 6 and C-Reactive Protein in Childhood With Depression and Psychosis in Young Adult Life: A Population-Based Longitudinal Study

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Khandaker, Golam M., Pearson, Rebecca M., Zammit, Stanley, Lewis, Glyn, Jones, Peter B.·2014·JAMA Psychiatry
DOI 10.1001/jamapsychiatry.2014.1332PMC PMC4561502
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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.

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  • Fludrocortisone accelerates the onset of action of standard antidepressants in one randomized controlled trial.

    “Fludrocortisone, a mineralocorticoid receptor agonist, has been shown to accelerate the onset of action of standard antidepressants in one randomized controlled trial 79”

    From Major depressive disorder (2016) · cites this paper as [79]

    The Discussion (page unavailable) mentions randomized trials of celecoxib as an adjunct to standard treatment, not fludrocortisone. Searches for fludrocortisone, mineralocorticoid agonists, and accelerated antidepressant onset found no passage addressing the attributed trial. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

  • About one-third of depressed patients show a low-grade inflammatory state (CRP > 3.0 mg/L).

    “Indeed, about a third of all depressed patients seem to express CRP levels > 3.0 mg/L [86,119,120].”

    From C-Reactive protein as a biomarker for major depressive disorder? (2022) · cites this paper as [120]

  • Increased circulating cytokines are detected in depression and anxiety.

    “The idea that stress itself induces endocrine mediators like IL6, which is traditionally associated with inflammation, has since been supported by the detection of increased circulating cytokines in depression and anxiety (Felger and Lotrich, 2013; Khandaker et al., 2014), and by the association of IL6 polymorphisms in individuals with depression (Zhang et al., 2016).”

    From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Khandaker et al., 2014

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Research works printed but not linked: 1

  1. [32]World Health Organization SCAN: Schedules for Clinical Assessment in Neuropsychiatry, Version 2.0 1994 Psychiatric Publishers International/American Psychiatric Press Inc Geneva, Switzerland

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Authors
Khandaker, G. M., Pearson, R. M., Zammit, S., Lewis, G., & Jones, P. B.
Affiliations
  • National Health Service (GB)
  • University of Bristol (GB)
Corresponding author
Khandaker, Golam M.
ORCID
Venue
JAMA Psychiatry
Publisher
American Medical Association (AMA)
Published
2014-10-01
Volume
71
Issue
10
Pages
1121
ISSN
2168-622X (ISSN-L)
DOI
10.1001/jamapsychiatry.2014.1332
PMC
PMC4561502
OpenAlex
W2134549690
Cited by
846
References
45
Citations by year
2026: 85 · 2025: 66 · 2024: 75 · 2023: 81 · 2022: 72 · 2021: 102 · 2020: 100 · 2019: 70 · 2018: 52 · 2017: 57 · 2016: 48 · 2015: 35 · 2014: 3
FWCI
14.58
Type
journal article
Language
en
Open access
Locations
  • JAMA Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Explore Bristol Research (submittedVersion)
Funders
  • Wellcome Trust (088869/Z/09/Z, 095844/Z/11/Z, 102215, 092731, 095844, 084268/Z/07/Z)
  • National Institute for Health and Care Research (RP-PG-0606-1335)
  • Medical Research Council (MR/L010305/1, MC_PC_15018)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
interleukin-6, C-reactive protein, depression, psychosis, psychotic experiences, inflammatory markers, early adulthood, Avon Longitudinal Study of Parents and Children, dose-response relationship, postpartum depression, psychiatric comorbidity, cardiovascular comorbidity, diabetes comorbidity, first-episode psychosis, psychotic relapse
MeSH terms
Adolescent, C-Reactive Protein, Child, Depression, England, Female, Humans, Interview, Psychological, Male, Prospective Studies, Psychiatric Status Rating Scales, Psychotic Disorders, Risk Factors, Biomarkers, Interleukin-6

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