Premenstrual dysphoric disorder (PMDD) affects 3-8% of reproductive age women. The disorder is a complex of mood, behavioral, and physical symptoms that disrupt family, social, and occupational functioning during each menstrual cycle. 70% of women with PMDD respond to treatment with serotonin reuptake inhibitors (SRIs); the onset of response is unusually rapid, occurring within a few days. Restricting SRI use to 2 weeks prior to menses appears to provide a similar degree of symptom relief as continuous daily dosing throughout the menstrual cycle. However, many women have symptoms for <1 week, and there has been inadequate examination of whether a briefer (< 2 week) period of SRI treatment is effective. Such an approach would reduce medication exposure, financial cost, and side effect burden for women with PMDD; symptom-onset dosing would be more convenient and the participatory nature of the approach may enhance compliance. While some practitioners already prescribe symptom-onset treatment, it has not been tested in an adequately powered, placebo-controlled study increasing the risk of under-treating patients if this modality is not effective. Moreover, abruptly stopping SRIs may be associated with discontinuation symptoms and this risk has not been adequately evaluated. The primary specific aims of this application are to: 1) assess whether the SRI sertraline is more effective than placebo at ameliorating symptoms of PMDD when capsules are taken from the point premenstrual symptoms begin through the onset of menses (i.e., "symptom-onset dosing"); and 2) evaluate whether stopping pills at the onset of menses or shortly thereafter is associated with SRI discontinuation symptoms. Secondary analyses will explore whether symptom severity, impairing physical symptoms and suicidality moderate treatment response. 300 women will be enrolled across 3 sites: Yale School of Medicine, Weill Medical College of Cornell University, and Virginia Commonwealth University. Following 2 months of prospective screening assessment, subjects who meet criteria for PMDD will be randomized to symptom-onset treatment with either sertraline or placebo for 6 months. Independent blinded evaluators will observe and confirm scoring on subjective measures of outcome. The findings of this study, designed to reflect real-life implementation (i.e., symptom onset), will assist in developing practical treatment guidelines for women with PMDD. [unreadable] [unreadable] [unreadable] [unreadable]