Multiple studies support the efficacy of serotonin reuptake inhibitors (SRIs) for the treatment of premenstrual dysphoric disorder (PMDD).  In the initial studies, treatment was administered daily throughout the entire menstrual cycle.  Researchers observed that for the treatment of PMDD, SRIs seemed to work more rapidly, taking effect within a few days of treatment initiation (as opposed to the 2-4 weeks needed for the treatment of major depression).  Subsequent studies demonstrated that many women benefit from SRI treatment when dosing is limited to the luteal phase (the last two weeks) of the menstrual cycle.  There is also  some evidence to suggest that SRI treatment may be beneficial when initiated at the time of symptom onset through the onset of menses.

There has been only one double-blind, placebo-controlled randomized clinical trial  assessing  the efficacy of symptom-onset dosing with an SRI.  In this study, 252 women with PMDD started treatment — sertraline 50-100 mg or placebo — at symptom onset and continued until the first few days of menses for 6 menstrual cycles.

As compared to women who received placebo, symptom improvement was better for women with sertraline when measured using the Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C) and Daily Record of Severity of Problems (DRSP). This difference was most prominent on the DRSP Anger/Irritability subscale. However, when the Premenstrual Tension Scale (PMTS) scale was used to assess the severity of PMDD symptoms, there was no difference between the placebo and treatment groups.

Treatment was well tolerated.  Dropout rates did not differ between groups, the rates of adverse events were generally similar, and there was no evidence of withdrawal symptoms after stopping sertraline treatment each month.

The efficacy signal in this study was not as large as observed in PMDD trials of SSRIs using continuous and luteal-phase dosing.  Based on these findings, it would be possible to conclude that symptom-onset dosing is ineffective or less effective than other dosing schedules;however, the authors point to several other explanations for their findings.  Because the analysis  included symptomatic days before the onset of treatment in the luteal phase of each month, the overall effect of treatment was diminished.   The researchers also questioned whether frequent contacts of all participants with the research staff may have had a therapeutic benefit.

The Take-Home Message

OK, so symptom-onset dosing may or may not work.  How can we use these data to inform our clinical decisions?

From a clinical standpoint, one might argue that it is best to start treatment with an SRI daily throughout the entire menstrual cycle.  This is the dosing regimen that is most likely to succeed.  After adjusting the dose and assessing tolerability, it may be possible to reduce the number of days of treatment.  This is where it is important to individually tailor the approach according to each patient’s pattern of symptoms.  Some women have two weeks of premenstrual symptoms; for those women we would recommend initiating SRI treatment at day 14 and stopping after the onset of menses.  But if a woman has only 4-5 days of symptoms,, she might be able to start at day 21 or later.  Because retrospective reporting of PMDD symptoms is notoriously unreliable, daily charting of symptoms is indispensable in terms of to monitoring the effects of any treatment changes.

Ruta Nonacs, MD PhD

Yonkers KA, Kornstein SG, Gueorguieva R, et al.  Symptom-Onset Dosing of Sertraline for the Treatment of Premenstrual Dysphoric Disorder: A Randomized Clinical Trial.  JAMA Psychiatry. 2015; 72(10):1037-44.