Childhood Infections May Trigger Mental Illness

Megan Brooks

December 05, 2018

A large Danish population-based study provides strong evidence of an association between childhood infection, antibiotic treatment, and subsequent neuropsychiatric disorders.

Investigators found that the risk of developing a mental disorder increased by more than 80% after hospitalization for severe infection. The use of anti-infectives, specifically antibiotics, to treat the infection was associated with about a 40% increased risk for a subsequent mental disorder.

"Our findings linking infections with mental disorders in the developing brain, despite several limitations that make causal links impossible, add more knowledge to this growing field showing that there exists an intimate connection between the body and the brain," first author Ole Kohler-Forsberg, MD, from the Psychosis Research Unit, Aarhus University Hospital, Denmark, told Medscape Medical News.

The study was published online December 5 in JAMA Psychiatry.

Harbinger of Mental Illness?

Some prior research has also linked infections with the development of mental disorders.

"However, no study has had the opportunity to investigate this association between all treated infections (covering hospitalizations and treatment with anti-infective agents) with the development of any treated mental disorder within such a large cohort of 1.1 million children and adolescents who were followed since birth," Kohler-Forsberg noted.

The cohort included all individuals up to age 18 years born in Denmark from 1995 to 2012. The participants were followed until a mean age of 9.7 years. During follow-up, 42,462 (3.9%) were hospitalized for any mental disorder, and 56,847 (5.2%) filled a prescription for psychotropic medication.

Infections requiring hospitalization were strongly associated with subsequent increased risk of being diagnosed with any mental disorder (hazard rate ratio [HRR], 1.84; 95% confidence interval [CI], 1.69 - 1.99) and with filling a prescription for psychotropic medication (HRR, 1.42; 95% CI, 1.37 - 1.46).

Infection treated with an antibiotic was associated with a 41% increased risk for mental disorders (HRR, 1.41; 95% CI, 1.35 - 1.46) and a 22% increased risk for use of psychotropic medication (HRR, 1.22; 95% CI, 1.17 - 1.27).

Schizophrenia spectrum disorders, obsessive-compulsive disorder, personality and behavior disorders, mental retardation, autism spectrum disorder, attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, and tic disorders were associated with the highest risks following a severe infection.

The risk for a mental disorder after a severe infection increased with the number of infections and with the temporal proximity of the last infection. The biggest increase in risk was observed 0 to 3 months after infection. Results of the primary analyses were supported by analyses that included different reference groups and siblings.

"It therefore appears that infections and the inflammatory reaction that follows afterwards can affect the brain and be part of the process of developing severe mental disorders. This can, however, also be explained by other causes, such as some people having a genetically higher risk of suffering more infections and mental disorders," Kohler-Forsberg told Medscape Medical News.

"Future studies need to investigate in more detail whether and how specific infectious agents or the amount of infections can lead to mental disorders. A better understanding of the role of infections and antimicrobial therapy in the pathogenesis of mental disorders might lead to new methods for the prevention and treatment of these devastating disorders," said Kohler-Forsberg.

Compelling Results, Pressing Questions

Authors of an accompanying editorial note that the study provides "compelling epidemiologic evidence that severe infections, as well as exposure to anti-infective agents, are linked to the onset of neuropsychiatric illnesses in children."

Viviane Labrie, PhD, and Lena Brundin, MD, PhD, from the Center for Neurodegenerative Sciences, Van Andel Research Institute, Grand Rapids, Michigan, also say the results of the study leave a number of "pressing questions.

"Since the study controlled for important confounders and validated the findings in a sibling cohort, the results may reflect a causative biological mechanism," they write, but "what could this mechanism be? More importantly, could we reduce the incidence of debilitating childhood neuropsychiatric disorders by targeting infection?"

"These results bring a sense of urgency to detailing the underlying mechanisms of this association, in particular because of the possibility that these severe and occasionally permanent neuropsychiatric conditions might be rapidly recognized and treated by pharmacological compounds already in clinical use," Labrie and Brundin conclude.

The study was funded by the Lundbeck Foundation and the Independent Research Fund Denmark. The authors have disclosed no relevant financial relationships. Dr Brundin has received funding from the Michael J. Fox Foundation, the Department of Veterans Affairs, and the National Institutes of Health. Dr Labrie has received funding from the Department of Defense and the Alzheimer's Society of Canada.

JAMA Psychiatry. Published online December 5, 2018. Full text, Editorial

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