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OBJECTIVE: The authors examined the effect of a 4-week course of estrogen therapy on depression in perimenopausal and postmenopausal women. METHOD: Twenty-two depressed women who were either perimenopausal (N=10) or postmenopausal (N=12) received open-label treatment with transdermal 17β-estradiol (100 μg/day) for 4 weeks. The Montgomery-Åsberg Depression Rating Scale and the Beck Depression Inventory were used to assess depressive symptoms, the Greene Climacteric Scale was used to assess menopause-related symptoms, and the Clinical Global Impression (CGI) was used to assess global clinical improvement in these women at baseline and after treatment. Remission of depression was defined as a score <10 on the Montgomery-Åsberg Depression Rating Scale and a score ≤2 on the CGI at week 4. RESULTS: Remission of depression was noted in eight of the 20 women who completed the study; two of these women were postmenopausal, and six were perimenopausal. Antidepressant response was not associated with severity or subtypes of depression at study entry or with concomitant improvement in menopause-related symptoms. CONCLUSIONS: Some perimenopausal women with depression may benefit from short-term use of estrogen therapy, and its role for postmenopausal depressed women warrants further investigation. Antidepressant benefit associated with estrogen therapy may be independent of improvement in physical symptoms.