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Perimenopause is often a time of social, emotional, and physical change. Various factors contribute to the development of mood disorders during this time. There is a known association among women with previous history of major depressive disorder or bipolar disorder and relapse during the menopausal transition. First-onset mood disorders during this time have been less studied. A literature review in PsycInfo Ovid of records pertaining to first-onset mood disorders during perimenopause showed that this multifactorial process involves hormonal fluctuations, with estrogen being a key player. In addition, vasomotor symptoms, previous negative life events, and socioeconomic status were found to contribute to first-onset mood disorders during perimenopause. Treatment options include established medication regimens for psychiatric conditions; however, hormone therapy also has proven beneficial for this patient population. Further research, particularly on bipolar disorder, is needed to develop a clear association between perimenopause and first-onset mood disorders.