The Infection-Psychosis Connection

Severe infections (requiring hospitalization) are associated with an increased risk of mental disorders.¹ By contrast, most infections in childhood are treated on an outpatient basis. Some studies have found that less severe infections are associated with risk of schizophrenia and depression.²

Kohler-Forsberg and colleagues³ investigated associations between all types of treated infections and the risk of any treated mental disorder. The authors performed a nationwide register-based cohort study of the entire Danish population (~5.5 million people). They identified all persons born in Denmark between 1995 and 2012.

All redeemed prescriptions for anti-infective agents were identified from the Danish National Prescription Registry. Persons who redeemed no prescriptions, or only prescriptions for penicillin G or topical antibiotics, during the study period served as a control group.
 

Data on all inpatient and outpatient psychiatric contacts for a first diagnosis of a mental disorder (F20-99) were obtained from the Danish Psychiatric Central Research Register. Organic mental disorders and those due to psychoactive substance use were excluded. Associations with any mental disorder and specific diagnostic categories (eg, schizophrenia-spectrum disorders and affective disorders) were included.

The first redeemed prescription for psychotropic medication was also identified using the Danish National Prescription Registry. Subjects were followed from birth until June 30, 2013. Data were analyzed using Cox Proportional Hazards models, adjusting for age, sex, physical comorbidity, parental education, and parental mental disorder.

The primary analyses compared 1) persons with versus without hospitalization for infection, and 2) persons with ≥1 versus 0 redeemed anti-infective prescription. For both analyses, the authors investigated, 1) risk of hospitalization for any mental disorder, and 2) risk of redeeming a prescription for psychotropic medication. The authors identified 1,098,930 persons (51% male, mean age 10) for inclusion. A total of 42,462 persons (3.9%) had a hospitalization for mental disorder, and 56,847 (5.2%) redeemed a psychotropic medication prescription.

Hospitalization for infection was associated with a significant 1.84-fold increased risk of hospitalization for any mental disorder and a 1.42-fold increased risk for redeeming a psychotropic medication prescription. Risk of psychiatric hospitalization (Hazard Ratio [HRR]=1.34) and psychotropic medication treatment (HRR=1.20) were significant increased for subjects with treated infections that did not require hospitalization.

The risk of mental disorders increased in a dose-response fashion based on the number of treated infections and different infective agents. Hospitalization for infection was associated with a significant 1.80-fold increased risk, and infection treated with an anti-infective agent was associated with a non-significant 1.14-fold increased risk of schizophrenia-spectrum disorders. Risk estimates remained significant but were attenuated in sibling analyses.

The authors concluded that infections were associated with increased risk of any mental disorder in a dose-dependent fashion. Potential mechanisms for these associations include direct CNS influences of infections, alterations in the gut microbiome, and increased genetic susceptibility to infections. Although results cannot prove causality, they 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.

Dr Miller is Associate Professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, GA, and Schizophrenia Section Editor and Editorial Board Member for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.