COVID-19 and risk of first-time major depressive disorder in patients without history of psychiatric disorders

Several studies have shown that patients who survived hospitalization with COVID-19 are at higher risk of psychiatric illness including major depressive disorder (MDD) compared to COVID− controls. However, few prior studies excluded patients with prior psychiatric illness from their analyses, and therefore the post-COVID risk of new-onset MDD among those without psychiatric vulnerabilities remains unclear. This observational study analyzed patients with at least one COVID-19 test, no history of prior psychiatric diagnosis, and at least one follow-up visit 30 days post-COVID-19 test from February 2020 to August 2024. Risk of new-onset MDD was assessed using Fine-Gray subdistribution hazards models, accounting for all-cause mortality as a competing risk. Demographic variables, pre-existing comorbidities, insurance, Zone Improvement Plan (ZIP) code-linked median household income, and the presence of unmet social needs were adjusted for using multivariate regression and inverse probability weighting (IPW). The possibility of unmeasured residual confounding was investigated using an array approach, to assess the extent of confounder variable prevalence imbalance and effect size necessary to fully explain the observed effect estimate. 8,836 COVID+ hospitalized, 22,253 COVID + non-hospitalized, and 82,482 COVID− patients were included in the analysis. Compared to COVID− patients, COVID + non-hospitalized patients were at similar risk of new-onset MDD, while COVID+ hospitalized patients were at higher risk (multivariate adjusted hazard ratio [HR] = 1.15 [1.05, 1.27], IPW-adjusted HR = 1.17 [1.03, 1.33]). This association was robust to sensitivity analyses addressing potential residual confounding. Risk of new-onset MDD was particularly highest among females, younger patients, Hispanics, those with type-2 diabetes, asthma, tobacco use, those on Medicare, Medicaid, those living in low-income ZIP codes, and those with unmet social needs. Among patients with no prior history of psychiatric illness, hospitalization for COVID-19 is an independent risk factor for new-onset clinician-diagnosed MDD. Addressing clinical risk factors for MDD and social determinants of health will be essential to mitigating the long-term mental health consequences.