Purpose <p>Understanding mechanism of action of effective agents for Premenstrual Dysphoric Disorder (PMDD) is necessary to advance care of these patients. It can be successfully treated with fluoxetine, but its efficacy with intermittent use is difficult to understand because of documented delays in the onset of antidepressant action of this drug.</p> Methods <p>Targeted review of the literature is used to examine the hypothesis that fluoxetine’s inhibiton of CYP3A4, which is needed to metabolize estrogen, underlies its utility when dosed intermittently.</p> Results <p>We propose that fluoxetine slows the degradation of estrogen the late luteal phase, thereby increasing its levels and reducing the PMDD symptoms that typically are associated with alterations in hormone concentrations. The hypothesis can be tested by using a potent CYP3A4 inhibitor that has no antidepressant action. Such agents include the antiviral drugs ritonavir and cobicistat which are potent CYP3A4 inhibitors and are currently being used to boost the levels of other antivirals in the treatment of human immunodeficiency virus (HIV). Prospective studies with women with PMDD in this population before and after initiation of CYP3A4 inhibiting anti-retrovirals would help clarify this question.</p> Conclusion <p>Confirmation of this mechanism may open the door to non-SRI treatments for women that do not tolerate SRI agents.</p>