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Objectives To examine the associations between depressive symptoms, antidepressant use, and duration of use with incident frailty 3 years later in nonfrail women aged 65 and older. Design Secondary analysis of the Women's Health Initiative Observational Study ( WHI- OS), a prospective cohort study. Setting WHI- OS was conducted in 40 U. S. clinical centers. Participants Women aged 65 to 79, not frail at baseline. Measurements Antidepressant use was assessed through medication container inspection at baseline. Four groups were created according to baseline use and Burnam depression screen (range 0-1, 0.06 cutoff): antidepressant nonusers without depressive symptoms (reference group), antidepressant nonusers with depressive symptoms, antidepressant users without depressive symptoms, and antidepressant users with depressive symptoms. Frailty components included slowness or weakness, exhaustion, low physical activity, and unintended weight loss, ascertained through self-report and physical measurements at baseline and Year 3. Results Of 27,652 women at baseline, 1,350 (4.9%) were antidepressant users and 1,794 (6.5%) were categorized as depressed. At Year 3, 4,125 (14.9%) were frail. All groups had a greater risk of incident frailty than the reference group. Odds ratios ( ORs) ranged from 1.73 (95% confidence interval ( CI) = 1.41-2.12) in antidepressant users who were not depressed to 3.63 in antidepressant users who were depressed (95% CI = 2.37-5.55). All durations of use were associated with incident frailty (<1 year OR = 1.95, 95% CI = 1.41-2.68; 1-3 years OR = 1.99, 95% CI = 1.45-2.74; >3 years OR = 1.60, 95% CI = 1.20-2.14). Conclusion In older adult women, depressive symptoms and antidepressant use were associated with frailty after 3 years of follow-up. [ABSTRACT FROM AUTHOR]