Joint associations of comorbidity burden and polypharmacy with depressive symptoms, and joint effects of comorbidity burden, polypharmacy, and depressive symptoms on all-cause mortality among US adults aged 45 years and older: a dual cross-sectional and cohort study

Abstract

Although comorbidity burden and polypharmacy are increasingly prevalent among middle-aged and older adults and may contribute to depressive symptoms, evidence on their joint associations remains scarce. Furthermore, the combined impact of comorbidity burden, polypharmacy, and depressive symptoms on all-cause mortality has not been well characterized. This study aimed to evaluate the joint associations of comorbidity burden and polypharmacy with depressive symptoms, and the joint associations of comorbidity burden, polypharmacy, and depressive symptoms with all-cause mortality among adults aged ≥ 45 years. This dual cross-sectional and cohort study used data from the NHANES 2005–2018, with follow-up until December 31, 2019. Comorbidity burden was quantified using the Charlson Comorbidity Index (low: 0–1; high: ≥ 2), and polypharmacy was defined as the concurrent use of ≥ 5 prescription medications. Depressive symptoms were defined as a Patient Health Questionnaire-9 score of ≥ 10. Weighted logistic regression was used for cross-sectional analyses, and weighted Cox proportional hazards models were applied for mortality analyses. Restricted cubic splines and subgroup analyses were performed. High comorbidity burden and polypharmacy were associated with depressive symptoms. High comorbidity burden with polypharmacy showed higher odds compared with the unexposed group (OR = 3.21, 2.34–4.39) and high comorbidity burden without polypharmacy (OR = 1.53, 1.09–2.15), but no difference compared with low comorbidity burden with polypharmacy (OR = 1.13, 0.76–1.67). High comorbidity burden, polypharmacy, and depressive symptoms were associated with higher mortality. High comorbidity burden with polypharmacy or depressive symptoms showed higher mortality risk than unexposed or single-exposure patterns. Polypharmacy with depressive symptoms showed higher risk compared with the unexposed group (HR = 2.56, 1.87–3.51) and non-polypharmacy with depressive symptoms (HR = 1.46, 1.01–2.12), but no difference compared with polypharmacy without depressive symptoms (HR = 1.25, 0.92–1.70). Among adults aged ≥ 45 years, high comorbidity burden and polypharmacy were associated with depressive symptoms, and the coexistence of comorbidity burden, polypharmacy, and depressive symptoms was associated with increased all-cause mortality risk. These findings underscore the importance of early recognition and integrated management of multimorbidity, medication burden, and depressive symptoms, particularly among middle-aged adults.