COVID-19 and Risk for Mental Disorders Among Adults in Denmark

Abstract

Importance: Psychiatric outcomes after COVID-19 have been of high concern during the pandemic; however, studies on a nationwide level are lacking.

Objective: To estimate the risk of mental disorders and use of psychotropic medication among individuals with COVID-19 compared with individuals not tested, individuals with SARS-CoV-2-negative test results, and those hospitalized for non-COVID-19 infections.

Design, setting, and participants: This nationwide cohort study used Danish registries to identify all individuals who were alive, 18 years or older, and residing in Denmark between January 1 and March 1, 2020 (N = 4 152 792), excluding individuals with a mental disorder history (n = 616 546), with follow-up until December 31, 2021.

Exposures: Results of SARS-CoV-2 polymerase chain reaction (PCR) testing (negative, positive, and never tested) and COVID-19 hospitalization.

Main outcomes and measures: Risk of new-onset mental disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F00-F99) and redeemed psychotropic medication (Anatomical Therapeutic Chemical classification codes N05-N06) was estimated through survival analysis using a Cox proportional hazards model, with a hierarchical time-varying exposure, reporting hazard rate ratios (HRR) with 95% CIs. All outcomes were adjusted for age, sex, parental history of mental illness, Charlson Comorbidity Index, educational level, income, and job status.

Results: A total of 526 749 individuals had positive test results for SARS-CoV-2 (50.2% men; mean [SD] age, 41.18 [17.06] years), while 3 124 933 had negative test results (50.6% women; mean [SD] age, 49.36 [19.00] years), and 501 110 had no tests performed (54.6% men; mean [SD] age, 60.71 [19.78] years). Follow-up time was 1.83 years for 93.4% of the population. The risk of mental disorders was increased in individuals with positive (HRR, 1.24 [95% CI, 1.17-1.31]) and negative (HRR, 1.42 [95% CI, 1.38-1.46]) test results for SARS-CoV-2 compared with those never tested. Compared with individuals with negative test results, the risk of new-onset mental disorders in SARS-CoV-2-positive individuals was lower in the group aged 18 to 29 years (HRR, 0.75 [95% CI, 0.69-0.81]), whereas individuals 70 years or older had an increased risk (HRR, 1.25 [95% CI, 1.05-1.50]). A similar pattern was seen regarding psychotropic medication use, with a decreased risk in the group aged 18 to 29 years (HRR, 0.81 [95% CI, 0.76-0.85]) and elevated risk in those 70 years or older (HRR, 1.57 [95% CI, 1.45-1.70]). The risk for new-onset mental disorders was substantially elevated in hospitalized patients with COVID-19 compared with the general population (HRR, 2.54 [95% CI, 2.06-3.14]); however, no significant difference in risk was seen when compared with hospitalization for non-COVID-19 respiratory tract infections (HRR, 1.03 [95% CI, 0.82-1.29]).

Conclusion and relevance: In this Danish nationwide cohort study, overall risk of new-onset mental disorders in SARS-CoV-2-positive individuals did not exceed the risk among individuals with negative test results (except for those aged ≥70 years). However, when hospitalized, patients with COVID-19 had markedly increased risk compared with the general population, but comparable to risk among patients hospitalized for non-COVID-19 infections. Future studies should include even longer follow-up time and preferentially include immunological biomarkers to further investigate the impact of infection severity on postinfectious mental disorder sequelae.

Figure 1.. Schematic Presentation of Study Design and Structure of Data Analysis

SARS-CoV-2 polymerase chain reaction testing of study population during the COVID-19 pandemic and how each individual contributes to observation time in potentially 3 different exposure groups are shown. Exposure is time-varying and hierarchical (ie, status can change from not tested to negative or positive and from negative to positive but not vice versa). Individual numbers 1st, 2nd, 3rd, etc, illustrate examples of each individual in the study contributing observation time to different groups of exposure.

Figure 2.. Risk of New-Onset Mental Disorder and Psychotropic Medication Use Among Individuals Tested for SARS-CoV-2 and Patients Hospitalized for COVID-19 or Other Respiratory Tract Infections

Includes any and specific incident mental disorders defined as International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F00 to F99 among individuals undergoing SARS-CoV-2 testing (A); any redeemed newly prescribed psychotropic medication defined as Anatomical Therapeutic Chemical classification codes N05 to N06 among individuals undergoing SARS-CoV-2 testing (B); and patients hospitalized for COVID-19 or other non–COVID-19 respiratory tract infections (C). Error bars indicate 95% CIs. Individuals with a prior hospitalization for a respiratory tract infection between 2010 and March 2020 were excluded prior to analysis to ensure that the hospital contact for other respiratory tract infections was new onset and not a recurrent condition. All analyses were adjusted for age, sex, parental history of mental illness, Charlson Comorbidity Index, educational level, income, and work status. HRR indicates hazard rate ratio. ^aThe lower limit of the 95% CI was smaller than 1.00 (P = .05).

Figure 3.. Risk of New-Onset Mental Disorder and Psychotropic Medication Use Among Individuals Tested for SARS-CoV-2 and Patients Hospitalized for COVID-19 Stratified in Age Groups

Includes any incident mental disorder defined as International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F00 to F99 in individuals undergoing SARS-CoV-2 testing (A); any redeemed newly prescribed psychotropic medication defined as Anatomical Therapeutic Chemical classification codes N05 to N06 in individuals undergoing SARS-CoV-2 testing (B); and patients hospitalized for COVID-19 or other non–COVID-19 respiratory tract infections (C). Error bars indicate 95% CIs. Individuals with a prior hospitalization for a respiratory tract infection between 2010 and March 2020 were excluded prior to analysis to ensure that the hospital contact for other respiratory tract infections was new onset and not a recurrent condition. All analyses were adjusted for age, sex, parental history of mental illness, Charlson Comorbidity Index, educational level, income, and work status. HRR indicates hazard rate ratio.

Figure 4.. Risk of New-Onset Mental Disorders After Hospitalization for COVID-19 or Non–COVID-19 Infections

Any incident mental disorder is defined as International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F00 to F99. Due to Danish General Data Protection Regulation rules applied to the use of the nationwide registers, outcome results from groups with fewer than 5 individuals are prohibited to be displayed to ensure data privacy; thus, risk was not calculated in the group with influenza. Error bars indicate 95% CIs. Individuals with a prior hospitalization for a respiratory tract infection between 2010 and March 2020 were excluded prior to analysis to ensure that the hospital contact for other respiratory tract infections was new onset and not a recurrent condition. All analyses were adjusted for age, sex, parental history of mental illness, Charlson Comorbidity Index, educational level, income, and work status. HRR indicates hazard rate ratio. ^aNo statistical difference between COVID-19 and all other non–COVID-19 infections.