Risk of New-onset Mood Disorders following Coronavirus Disease 2019: A Large-scale Retrospective Cohort Study Across Severity and Variants

Abstract Background: The coronavirus disease 2019 (COVID-19) pandemic has been linked to an increase in long-term psychiatric complications, including mood disorders, with previous research suggesting systemic inflammation, neuroinvasion, and psychosocial factors as potential causes. This study aimed to assess whether individuals diagnosed with COVID-19 exhibit a higher rate of new-onset mood disorders compared to those with other acute respiratory infections, and to determine differences based on infection severity and dominant viral variants. Materials and Methods: This large-scale retrospective cohort study utilized the TriNetX United States (US) Collaborative Network, analyzing anonymized electronic health records from approximately 130 million patients across 72 US healthcare organizations (HCOs). The analysis included 1,276,339 propensity score-matched COVID-19 patients and an equal number of control patients diagnosed with other acute respiratory infections. Cohorts were stratified by treatment setting (outpatient, hospitalized, intensive care unit (ICU)) and period of infection to reflect dominant viral variants (wild-type, Alpha, Delta, Omicron). Results: Findings revealed that within 180 days post-diagnosis, 1.73% of COVID-19 patients developed a new-onset mood disorder, significantly higher than 1.33% in the control group. This risk escalated with infection severity, reaching 1.48% for outpatients, 3.60% for hospitalized (non-ICU) patients, and 4.24% for ICU patients. Furthermore, while earlier variants showed lower or comparable risks, the Omicron-dominant phase exhibited the highest risk in the COVID-19 group (2.0%) compared to controls (1.3%). Conclusions: These results demonstrate a significant elevation in the risk of new-onset mood disorders following COVID-19 infection, influenced by disease severity and circulating variant. Future research should explore inflammatory biomarkers, mechanisms, and interventions to address long-term psychiatric effects of COVID-19.