Rationale & ObjectiveThe extent to which depression affects the progression of chronic kidney disease (CKD) and leads to adverse clinical outcomes remains inadequately understood. We examined the association of depressive symptoms (DS) and antidepressant medication use on clinical outcomes in 4,839 adults with non-dialysis CKD. Study DesignObservational cohort study. Setting & ParticipantsAdults with mild to moderate CKD who participated in the multicenter Chronic Renal Insufficiency Cohort Study (CRIC). ExposureThe Beck Depression Inventory (BDI) was used to quantify DS. Antidepressant use identified via medication bottles and prescription lists. Individual effects of DS and antidepressants were examined, along with categorization as follows: 1) BDI<11 and no antidepressant use, 2) BDI<11 with antidepressant use, 3) BDI≥11 and no antidepressant use, and 4) BDI≥11 with antidepressant use. OutcomesCKD progression, incident CVD composite, all-cause hospitalizations, and mortality. Analytic ApproachCox regression models were fitted for outcomes of CKD progression, incident CVD, and all-cause mortality, while hospitalizations utilized Poisson regression. ResultsAt baseline, 27.3% of participants had elevated DS, and 19.7% used antidepressants. Elevated DS at baseline were associated with significantly greater risk for an incident CVD event, hospitalization, and all-cause mortality, but not CKD progression, adjusted for antidepressants. Antidepressant use was associated with higher risk for all-cause mortality and hospitalizations, after adjusting for DS. Compared to participants without elevated DS and not using antidepressants, remaining groups (BDI<11 with antidepressants; BDI≥11 and no antidepressants; BDI≥11with antidepressants) showed higher risks of hospitalization and all-cause mortality. LimitationsInability to infer causality between depressive symptoms, antidepressants, and outcomes. Additionally, absence of non-pharmacological data, and required exploration of generalizability and alternative analytical approaches. ConclusionsElevated DS increased adverse outcome risk in non-dialysis CKD, unattenuated by antidepressants. Additionally, investigation into the utilization and counterproductivity of antidepressants in this population is warranted.