Köhler-Forsberg O, Petersen L, Gasse C, Mortensen PB, Dalsgaard S, Yolken RH, Mors O, Benros ME. A Nationwide Study in Denmark of the Association Between Treated Infections and the Subsequent Risk of Treated Mental Disorders in Children and Adolescents. JAMA Psychiatry. 2018 Dec 5. doi:10.1001/jamapsychiatry.2018.3428. [Epub ahead of print]
Infections have been associated with increased risks for mental disorders, such as schizophrenia and depression. However, the association between all infections requiring treatment and the wide range of mental disorders is unknown to date.
To investigate the association between all treated infections since birth and the subsequent risk of development of any treated mental disorder during childhood and adolescence.
DESIGN, SETTING, AND PARTICIPANTS:
Population-based cohort study using Danish nationwide registers. Participants were all individuals born in Denmark between January 1, 1995, and June 30, 2012 (N = 1 098 930). Dates of analysis were November 2017 to February 2018.
All treated infections were identified in a time-varying manner from birth until June 30, 2013, including severe infections requiring hospitalizations and less severe infection treated with anti-infective agents in the primary care sector.
MAIN OUTCOMES AND MEASURES:
This study identified all mental disorders diagnosed in a hospital setting and any redeemed prescription for psychotropic medication. Cox proportional hazards regression was performed reporting hazard rate ratios (HRRs), including 95% CIs, adjusted for age, sex, somatic comorbidity, parental education, and parental mental disorders.
A total of 1 098 930 individuals (51.3% male) were followed up for 9 620 807.7 person-years until a mean (SD) age of 9.76 (4.91) years. Infections requiring hospitalizations were associated with subsequent increased risk of having a diagnosis of any mental disorder (n = 42 462) by an HRR of 1.84 (95% CI, 1.69-1.99) and with increased risk of redeeming a prescription for psychotropic medication (n = 56 847) by an HRR of 1.42 (95% CI, 1.37-1.46). Infection treated with anti-infective agents was associated with increased risk of having a diagnosis of any mental disorder (HRR, 1.40; 95% CI, 1.29-1.51) and with increased risk of redeeming a prescription for psychotropic medication (HRR, 1.22; 95% CI, 1.18-1.26). Antibiotic use was associated with particularly increased risk estimates. The risk of mental disorders after infections increased in a dose-response association and with the temporal proximity of the last infection. In particular, schizophrenia spectrum disorders, obsessive-compulsive disorder, personality and behavior disorders, mental retardation, autistic spectrum disorder, attention-deficit/hyperactivity disorder, oppositional defiant disorder and conduct disorder, and tic disorders were associated with the highest risks after infections.
CONCLUSIONS AND RELEVANCE:
Although the results cannot prove causality, these findings provide evidence for the involvement of infections and the immune system in the etiology of a wide range of mental disorders in children and adolescents.
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…
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…
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.