Ole Köhler-Forsberg1,2,3, Liselotte Petersen4,5, Christiane Gasse4, Preben B Mortensen4,5,6, Soren Dalsgaard4,7, Robert H Yolken8, Ole Mors1,2,5, Michael E Benros3,4. 1. Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. 2. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. 3. Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark. 4. The National Centre for Register-based Research, Aarhus University, Aarhus, Denmark. 5. The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark. 6. Centre for Integrated Register-based Research at Aarhus University (CIRRAU), Aarhus, Denmark. 7. Department of Child and Adolescent Psychiatry, Hospital of Telemark, Kragerø, Norway. 8. Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Abstract
Importance: 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. Objective: 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. Exposures: 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. Results: 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.
Importance: 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. Objective: 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. Exposures: 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. Results: 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.
Authors: Michael E Benros; Berit L Waltoft; Merete Nordentoft; Søren D Ostergaard; William W Eaton; Jesper Krogh; Preben B Mortensen Journal: JAMA Psychiatry Date: 2013-08 Impact factor: 21.596
Authors: Aswin Sekar; Allison R Bialas; Heather de Rivera; Avery Davis; Timothy R Hammond; Nolan Kamitaki; Katherine Tooley; Jessy Presumey; Matthew Baum; Vanessa Van Doren; Giulio Genovese; Samuel A Rose; Robert E Handsaker; Mark J Daly; Michael C Carroll; Beth Stevens; Steven A McCarroll Journal: Nature Date: 2016-01-27 Impact factor: 49.962
Authors: Lauren Breithaupt; Ole Köhler-Forsberg; Janne Tidselbak Larsen; Michael E Benros; Laura Marie Thornton; Cynthia M Bulik; Liselotte Petersen Journal: JAMA Psychiatry Date: 2019-08-01 Impact factor: 21.596
Authors: Younga H Lee; Sara Cherkerzian; Larry J Seidman; George D Papandonatos; David A Savitz; Ming T Tsuang; Jill M Goldstein; Stephen L Buka Journal: Am J Psychiatry Date: 2019-10-04 Impact factor: 18.112
Authors: M E Glover; J L Cohen; J R Singer; M N Sabbagh; J R Rainville; M T Hyland; C D Morrow; C T Weaver; G E Hodes; Ilan A Kerman; S M Clinton Journal: Neuroscience Date: 2021-02-01 Impact factor: 3.590