Psychiatric comorbidities and the mortality paradox in sickle cell disease: A national inpatient analysis

Abstract Background: Sickle cell disease (SCD) is a genetic hemoglobinopathy which causes recurrent hospitalization. Psychiatric comorbidities including major depressive disorder (MDD), anxiety, alcohol use, and substance use disorders are common but understudied in this population. Their impact on hospitalization outcomes remains unclear. In this study we examined the associations between psychiatric comorbidities and in-hospital mortality, length of stay (LOS), and hospital costs in a national inpatient cohort. Methods: We analyzed 105,938 SCD hospitalizations from the 2020–2022 National Inpatient Sample using ICD-10 codes. Psychiatric comorbidities (MDD, anxiety, alcohol use and substance use disorders) were identified from diagnosis fields. Outcomes included in-hospital mortality (primary), LOS, and inflation-adjusted total costs (secondary). Multivariable models, logistic (mortality), negative binomial (LOS), and gamma (cost), were adjusted for demographics, socioeconomic status, hospital characteristics, comorbidity burden (Elixhauser index), and admission year. Model diagnostics were performed to assess fit and multicollinearity. Results: Among the cohort, 11.4% had MDD, 10.9% anxiety, 1.5% alcohol use disorder, and 10.9% substance use disorder. MDD (OR 0.60, 95% CI 0.47–0.78, p<0.001) and substance use disorder (OR 0.61, 95% CI 0.47–0.79, p<0.001) were associated with significantly lower in-hospital mortality. Anxiety and alcohol use disorder were not associated with mortality. MDD and anxiety were linked to increased LOS (IRRs 1.11 and 1.14, respectively, p<0.001). Anxiety was associated with higher costs (CR 1.09), while alcohol and substance use disorders were linked to reduced costs (CRs 0.85 and 0.87, respectively). Higher Elixhauser scores, older age, and male sex predicted worse outcomes. Model diagnostics confirmed adequate fit and no major multicollinearity. Conclusions: Psychiatric comorbidities significantly impact hospitalization outcomes in SCD. MDD and substance use disorders were paradoxically associated with lower in-hospital mortality. This is possibly due to earlier admission, more frequent healthcare contact, or engagement with psychosocial services. However, MDD and anxiety increased LOS and costs, indicating higher resource utilization. These findings support integrating mental health screening and care into inpatient SCD management to improve outcomes and optimize resource use.