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OBJECTIVE: The authors investigated the role of acute serotonergic modulation in the efficacy of selective serotonin reuptake inhibitors (SSRIs) in women with premenstrual dysphoric disorder. METHOD: Patients with premenstrual dysphoric disorder (whose symptoms had remitted during treatment with fluoxetine) and a group of unmedicated healthy comparison women received the serotonin receptor antagonist metergoline as part of a double-blind, placebo-controlled crossover study. RESULTS: The patients with premenstrual dysphoric disorder experienced a return of symptoms 24 hours after treatment with metergoline but not diphenhydramine (active placebo). The comparison women experienced no changes in mood. CONCLUSIONS: These data support the role of altered serotonergic transmission in the efficacy of SSRI treatment for premenstrual dysphoric disorder.