Menopause can trigger depression in women, especially if they have had previous episodes of depression, depressive symptoms during pregnancy, or premenstrual syndrome (PMS), according to a recent study.

That study shows that administering estradiol, a form of estrogen, through skin patches can significantly reduce depressive symptoms for up to 24 weeks in perimenopausal women. This is the phase leading to menopause in which women transition from irregular menstruation to no menstruation, noted Claudio Soares, M.D., Ph.D., a research fellow in the department of psychiatry at the Center for Women’s Health at Massachusetts General Hospital in Boston.

Physical symptoms such as hot flashes and night sweats improved in up to 12 weeks, said Soares at APA’s annual meeting in Chicago in May.

Previous studies have shown that estrogen deficiency can cause or exacerbate psychological symptoms including depression. Research has also shown that replacing estrogen in women can improve mild depressive symptoms because the hormone increases the level of serotonin in the brain.

However, the study by Soares and his colleagues is the first to test whether estradiol improves major depression in perimenopausal women.

The researchers designed a controlled, randomized, 24-week study of 50 women in Sao Paulo, Brazil, who met the DSM-IV criteria for major depression, dysthymia, or depressive disorder not otherwise specified (NOS). From 1996 to 1998, half of the participants were given a relatively low dose of estradiol (100 micrograms), and the other half were given placebo for 12 weeks. All the participants had a four-week washout period and then an eight-week follow-up in which they received placebo.

The women were recruited from an outpatient menopause clinic and an outpatient psychiatric service in Sao Paulo. Researchers from the University of Sao Paulo, the University of Western Australia, and Harvard Medical School analyzed the data, said Soares.

The participants’ demographic data showed the following:

• The average age was 50 years.

• 44 percent were employed, 54 percent were married, and 38 percent were widowed or divorced.

• The average time of amenorrhea (no menstruation) was 151 days.

• 34 percent of the subjects had a history of depression during pregnancy.

Of those who had depressive disorders, 26 had major depression, 13 had a depressive disorder NOS, and 11 had dysthymia, said Soares.

The results showed that the women treated with estradiol had much better outcomes than the women who received placebo. There was a significant reduction in symptoms on the Montgomery-Asberg Depression Rating Scale (MADRS). The scores for the estradiol group dropped from 25 at baseline to 8 after 12 weeks. In contrast, the MADRS scores for the placebo group remained at 14 or higher throughout the trial, noted Soares. In addition, "70 percent of the women treated with estradiol reported a significant decrease in hot flashes at 12 weeks."

Moreover, the estradiol group sustained a significant decrease in their MADRS scores (a reduction of 12 points from baseline) at 24 weeks, he noted.

"Twenty-nine percent of the women treated with estradiol also met our criteria for remission of depression at 24 weeks, which was a score of fewer than 10 points on the MADRS," said Soares.

Hot flashes, night sweats, and joint pains were some of the physical symptoms that improved with estradiol on the Blatt-Kupperman Menopausal Index (BKMI), explained Soares. However, this improvement was not sustained at 24 weeks.

"Our preliminary results show that estradiol administered by a skin patch is an effective treatment for depression in perimenopausal women. There were similar rates of efficacy for the three types of depression [studied]," commented Soares.

He cautioned, however, that "the mechanism by which estradiol acts as an antidepressant in the brain remains unclear. We know that estrogen improves physical symptoms and increases serotonin, yet studies using SSRIs have shown mixed results in improving depression in perimenopausal women.

"My theory is that estrogen may affect more than one area of the brain involved in depression, such as the dopaminergic system, but more research is needed to determine that," said Soares.

His study had several limitations including small sample size, the recruitment of subjects from only specialty outpatient clinics, and brief exposure to estradiol treatment.

Soares said he plans to conduct a long-term study comparing the effects of estrogen with those of progesterone.

"The latter is used in long-term trials to protect women from developing endometrial cancer. Because our study was brief, we did not need to use progesterone," said Soares. However, "the pros and cons of combining progesterone with estrogen should be weighed carefully, because other research has shown that progesterone can increase a woman’s anxiety, mood disorder, and irritability, thus diminishing the positive effects of estrogen."

In the meantime, he suggested that clinicians try estradiol to treat perimenopausal women with mild depression.