Autoimmune Diseases and Severe Infections as Risk Factors for Schizophrenia: A 30-Year Population-Based Register Study
Abstract
OBJECTIVE: Autoimmune diseases have been associated with an increased risk of schizophrenia. It has been suggested that brain-reactive autoantibodies are part of the mechanisms behind this association. Furthermore, an increased permeability of the blood-brain barrier has been observed during periods of infection and inflammation. The authors therefore investigated whether autoimmune diseases combined with exposures to severe infections may increase the risk of schizophrenia METHOD: Nationwide population-based registers in Denmark were linked, and the data were analyzed in a cohort study using survival analysis. All analyses were adjusted for calendar year, age, and sex. Incidence rate ratios and accompanying 95% confidence intervals (CIs) as measures of relative risk were used. RESULTS: A prior autoimmune disease increased the risk of schizophrenia by 29% (incidence rate ratio=1.29; 95% CI=1.18-1.41). Any history of hospitalization with infection increased the risk of schizophrenia by 60% (incidence rate ratio=1.60; 95% CI=1.56-1.64). When the two risk factors were combined, the risk of schizophrenia was increased even further (incidence rate ratio=2.25; 95% CI=2.04-2.46). The risk of schizophrenia was increased in a dose-response relationship, where three or more infections and an autoimmune disease were associated with an incidence rate ratio of 3.40 (95% CI=2.91-3.94). The results remained significant after adjusting for substance use disorders and family history of psychiatric disorders. Hospital contact with infection occurred in nearly 24% of individuals prior to a schizophrenia diagnosis. CONCLUSIONS: Autoimmune disease and the number of infections requiring hospitalization are risk factors for schizophrenia. The increased risk is compatible with an immunological hypothesis in subgroups of schizophrenia patients.
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Serious infections increase the risk of subsequently developing schizophrenia, and genetic risk factors for schizophrenia increase microglial phagocytosis of synapses, leading to the idea that schizophrenia is triggered by excessive microglial phagocytosis of synapses during adolescence, and one potential cause of this is increased endotoxin.
“Serious infections increase the risk of subsequently developing schizophrenia [110], and genetic risk factors for schizophrenia increase microglial phagocytosis of synapses [111], leading to the idea that schizophrenia is triggered by excessive microglial phagocytosis of synapses during adolescence [111], and one potential cause of this is increased endotoxin.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [110]
It is well established that physical and mental distresses can trigger psychotic behavior in (genetically) vulnerable patients.
“It is well established that physical and mental distresses can trigger psychotic behavior in (genetically) vulnerable patients [117].”
From Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation (2019) · cites this paper as [117]
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- Authors
- Benros, M. E., Nielsen, P. R., Nordentoft, M., Eaton, W. W., Dalton, S. O., & Mortensen, P. B.
- Affiliations
- University of Copenhagen (DK)
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2011-12
- Volume
- 168
- Issue
- 12
- Pages
- 1303-1310
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- OpenAlex
- W2102181001
- Cited by
- 582
- References
- 34
- Citations by year
- 2026: 21 · 2025: 43 · 2024: 51 · 2023: 37 · 2022: 50 · 2021: 44 · 2020: 50 · 2019: 46 · 2018: 29 · 2017: 43 · 2016: 41 · 2015: 45 · 2014: 35 · 2013: 34 · 2012: 11
- FWCI
- 17.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Institute of Mental Health (MH 53188, R01MH053188)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Neurology › Autoimmune Neurological Disorders and Treatments
- Keywords
- schizophrenia, autoimmune disease, serious infections, hospitalization, risk factors, blood-brain barrier permeability, inflammation, dose-response relationship
- MeSH terms
- Adolescent, Adult, Autoimmune Diseases, Denmark, Female, Humans, Infections, Male, Middle Aged, Registries, Risk, Risk Factors, Schizophrenia, Cohort Studies, Incidence
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