In a proof-of-concept trial, researchers have obtained encouraging results for a medicine to treat premenstrual dysphoric disorder (PMDD)—a mood disorder affecting 3% to 5% of women of childbearing age.

Classic behavioral symptoms of PMDD include mood swings, irritability, depression, and anxiety in addition to physical symptoms associated with the disorder (bloating, swelling of the breasts, gastrointestinal problems).

PMDD is likely caused by fluctuations in sex hormones, especially progesterone. Symptoms usually manifest during the "late luteal" phase of the menstrual cycle, between ovulation and menstruation. When a new egg is not fertilized, levels of progesterone and other hormones that rise in preparation for possible pregnancy begin to fall rapidly. These ovarian hormone shifts correspond with the onset of PMDD symptoms, which affect quality of life and in some cases can be debilitating.

A research team based in Sweden and led by Inger Sundström-Poromaa, M.D., Ph.D., of Uppsala University, performed a randomized, double-blind clinical trial of a medicine called ulipristal acetate in a group of 95 women diagnosed with PMDD. Cynthia Neill Epperson, M.D., a 2005 BBRF Independent Investigator and 1997 and 1995 Young Investigator, who played an important role in developing brexanolone, a rapid-acting antidepressant approved in 2019 for use in postpartum depression, was part of the team. Their results were published in the American Journal of Psychiatry.

Ulipristal acetate, or UPA, was given at a dose (5mg/day) and regimen already approved for use in treating uterine fibroids by regulators in the European Union in 2009 and by the FDA in the U.S. the following year.

Forty-eight women received UPA in the trial and 47 received a placebo pill. The women ranged in age between 18 and 46 and had not been treated with psychotropic medications in the 3 months prior to their participation in the trial. The trial began in each participant on the first day of menses, and continued over three consecutive menstrual cycles.

UPA binds to and alters the function of two cellular receptors for progesterone. Among other places in the body, these are found in abundance in the amygdala and in other part of the brain involved in the processing of emotions: the hippocampus, the hypothalamus, the thalamus, and the frontal cortex. The drug's modulation of the receptors has the effect of inhibiting the synthesis and action of progesterone itself.

Each participant in the trial used a smartphone app to keep a daily log of mood and physical symptoms of PMDD, rating each on a scale ranging from "none" to "extreme." These self-reports generated a numerical score which was used to assess the comparative effects of UPA and placebo over three consecutive menstrual cycles.

While UPA showed no difference vs. placebo in moderating the physical symptoms of PMDD, women in the UPA group registered improvements in PMDD mood symptoms that the researchers found to be statistically significant. 85% of women in the UPA group experienced either a full remission (50%) or partial remission (35%) of mood symptoms by the end of three menstrual cycles. This compared with 52% of participants who experienced full (21%) or partial (31%) remission in the placebo group.

The impact of UPA was especially significant in moderating symptoms of depression, anger/irritability, interpersonal conflicts, and lack of energy, the researchers noted.

Side effects were rare, they said, the most common being headache and nausea (each experienced by about 8% of those who received UPA) and fatigue (about 6%). The researchers were careful to note that in both the EU and U.S., UPA has been under post-approval study since 2018 for its possible role in rarely reported cases of liver injury. While these studies are still in progress, continuous monitoring of liver function over the first 3 months of the drug's administration is now routinely performed in patients as a precaution.

The team also noted that while the mechanism of the drug is still not fully understood, up to 80% of those who have taken it for uterine fibroids have experienced anovulation—a lack of ovulation. Neither ovulation nor progesterone levels were measured in the current trial; however, amenorrhea, or the skipping of a menstrual period, was experienced by 27.5% of those in the current trial who received UPA.

The researchers say UPA is "a promising drug" for treatment of the mood symptoms of PMDD, and encourage larger trials to validate their results and to more closely study the drug's potential impact on the liver and on changes in the menstrual cycle. They also note that UPA's modulation of progesterone receptors provides an insight into the molecular mechanisms underlying PMDD, and opens the way to developing other compounds that have similar impact.