BACKGROUND: Existing research on menopause and Bipolar Disorder indicates a general exacerbation in depressive symptoms but lacks clear distinctions between menopausal stages, despite their specific hormonal and symptomatic profiles. This study assesses how postmenopause versus the reproductive phase impacts the progression and antidepressant responsiveness of bipolar depression in women with Bipolar I Disorder. METHODS: This prospective cohort study included 364 women with moderate to severe depressive episodes. Participants were classified into postmenopausal and reproductive groups based on the Stages of Reproductive Aging Workshop + 10 criteria. Over four weeks, all participants received a personalized treatment, with depressive symptoms assessed weekly. RESULTS: Similar depression severity was observed between groups at the outset of the study. However, women in postmenopause experienced worse treatment responses and lower remission rates, despite the application of more complex treatment strategies. Notably, the impact of postmenopause on treatment outcomes, despite a small effect size, proved independent of age and comorbidities. CONCLUSIONS: This exploratory research is the first to specifically assess the impact of postmenopause on bipolar depression, revealing its independent and negative influence on treatment outcomes. The small outcomes differences observed between groups, achieved through the use of more complex treatment strategies, suggest that developing tailored therapeutic protocols could significantly improve the clinical management of these patients.