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Introduction: Previous studies have provided equivocal evidence of antidepressant use on subsequent cognitive impairment; this could be due to inconsistent modeling approaches. Our goals are methodological and clinical. We evaluate the impact of statistical modeling approaches on the associations between antidepressant use and risk of Mild Cognitive Impairment (MCI) in older adults with depression. Methods: 716 participants were enrolled. Our primary analysis employed a time-dependent Cox proportional hazards model. We also implemented two fixed-covariate proportional hazards models—one based on having ever used antidepressants during follow-up, and the other restricted to baseline use only. Results: Treating antidepressant use as a time-varying covariate, we found no significant association with incident MCI (HR = 0.92, 95% CI: 0.70, 1.20). In contrast, when antidepressant use was treated as a fixed covariate, we observed a significant association between having ever used antidepressants and lower risk of MCI (HR = 0.40, 95% CI: 0.28, 0.56). However, in the baseline-use only model, the association was non-significant (HR = 0.84, 95% CI: 0.60, 1.17). Discussion: Our results were dependent upon statistical models and suggest that antidepressant use should be modeled as a time-varying covariate. Using a robust time-dependent analysis, antidepressant use was not significantly associated with incident MCI among cognitively normal persons with depression. [ABSTRACT FROM AUTHOR]