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Alprazolam Works, Progesterone Doesn't, for PMS

Progesterone has long been advocated as a treatment for premenstrual syndrome (PMS) despite a lack of scientific support. The negative results from many clinical trials have been attributed to problems with the vaginal suppository route of administration. Alprazolam is also used to treat PMS, although results from controlled clinical trials have been mixed. Both of these agents are more attractive than antidepressants because they are required during the luteal phase only. This flexible-dose randomized study compared the efficacy of oral micronized progesterone (mean dose, 1760 mg), alprazolam (mean dose, 1.5 mg), and placebo in 170 women with diary-confirmed PMS mood symptoms and a three-cycle baseline measurement.

Patients received their assigned treatment during the two-week luteal phase of their menstrual cycle (day 18 of one menstrual cycle to day 2 of the next) followed by a two-day taper. Eighty-one percent of patients completed the study with no differences in dropout rates among the three groups.

During the first cycle, all three treatments were associated with a 20% drop in symptom severity. During the second and third cycles, alprazolam separated from the other two agents achieving a 43% reduction in symptom severity with no withdrawal effects. Of note, progesterone improved physical symptoms such as bloating and breast tenderness despite its lack of efficacy in reducing core mood symptoms. Fatigue and sedation were the most common side effects for both active treatments. Progesterone was associated with more dizziness, headaches, and confusion. Patients in all three groups with the most severe symptoms had the poorest response.

Comment: These results reinforce previous studies indicating that progesterone is not an effective treatment for PMS. The significant effect of alprazolam may have been evident because the sample size was larger than that in previous negative studies. Alprazolam may be an attractive treatment for many patients because it is only required for part of the month. However, the possible long-term effects of this intermittent regimen have not been explored. Studies are needed to compare alprazolam directly with selective serotonin reuptake inhibitors (SSRIs) and examine whether intermittant SSRI treatment is effective for PMS (see JW for Psychiatry, vol. 1, p. 43).

— P Roy-Byrne

Published in Journal Watch Psychiatry August 1, 1995

Citation(s):

Freeman EW et al. A double-blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome. JAMA 1995 Jul 274 51-57.

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