Insulin resistance and the risk of incident depression: the role of age, glycemic status, and adiposity in a prospective cohort study

Background: Despite emerging evidence, the causal relationship between insulin resistance and depression remains controversial. This study aimed to investigate whether insulin resistance is associated with increased risk of incident depression and whether the association is affected by potential moderators. Methods: This multi-centered prospective cohort study analyzed health screening data from 233,452 Korean adults participating in the Kangbuk Samsung Health Study from 2011 to 2022. At baseline, all participants indicated no major psychiatric or neurologic disorders and had not used antidepressant or diabetes medications. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Incident depression was defined as having a Center for Epidemiologic Studies Depression Scale score of ≥16. Findings: Participants (age = 36.1 ± 8.6 years, 54.1% male) were followed up for 4.8 ± 2.9 years. During the 1,124,268 person-years of follow-up duration, 38,801 cases of incident depression were identified. Multivariate Cox proportional hazards analysis revealed a positive dose-dependent association between HOMA-IR level and the risk of incident depression (hazard ratio [HR] for highest vs. lowest quartile = 1.15, 95% confidence interval [CI] = 1.11–1.19). This association was particularly strong in younger adults under 40 years and in individuals with euglycemia, overweight, and low muscle-to-fat ratio. Interpretation: Insulin resistance may be a modifiable risk factor for depression, underscoring the importance of early screening and management of insulin resistance to potentially reduce the burden of depression, especially among at-risk subgroups. Funding: None.