Discontinuing Hormone Therapy May Increase Risk of Depression in Some Women

The natural changes in hormones that characterize the transition into menopause can lead to varying degrees of hot flashes, sleep problems, and more in women. For some, this period—known as perimenopause—can also mark the onset or the return of depression.

Previous studies show hormone therapy can offer women some relief from menopausal symptoms. But, as the findings of the well-known Women’s Health Initiative revealed, long-term use can carry major health risks, including increased risk of breast cancer, stroke, and more. As a result, the Food and Drug Administration advises that women who use hormone therapy to treat menopausal symptoms should take the smallest dose for the shortest amount of time possible.

A study published in JAMA Psychiatry now finds that discontinuing estrogen therapy may lead to an increase in symptoms of depression in postmenopausal women who experienced depression during perimenopause.

National Institute of Mental Health

For the study, Peter Schmidt, M.D., chief of the Section on Behavioral Endocrinology at the National Institute of Mental Health, and colleagues recruited 121 postmenopausal women between the ages of 45 and 65. Participants included women who reported a history of major or minor depression at midlife in association with menstrual cycle irregularity (perimenopausal depression) and experienced the remission of symptoms following hormone therapy, and those who had no history of depression and were receiving or had previously received hormone therapy.

For three weeks, all participants received transdermal estradiol therapy (100 μg/d) while their mood symptoms were monitored. The women were then randomly assigned to receive either estradiol (at the same dose given during the open-label period) or placebo skin patches for an additional three weeks.

During weekly clinic visits, the study participants were screened for depression, using, among other measures, the Center for Epidemiologic Studies-Depression Scale and the Hamilton Depression Rating Scale. Participants were also asked to document the presence and severity of vasomotor symptoms daily.

Within three weeks, the women with past perimenopausal depression (PMD) who were withdrawn from estradiol therapy reported more depressive symptoms compared with women with past PMD who continued on estradiol therapy and women with no history of PMD. These differences were seen despite similarities between the groups in reports of hot flashes and plasma hormone levels after estradiol withdrawal.

“The same hormonal event triggered depressive symptoms in one group, but not in others,” Schmidt told Psychiatric News. “This is the first direct evidence that a change in estrogen in some women can trigger depressive illness.”

“Now, the million dollar question is what is it about women with past perimenopausal depression that makes them respond differently to estrogen?” Schmidt continued. Understanding the answer to this question could offer new insights into the biology of depression and alternative treatments for the disease, he said.

Nada Stotland, M.D., a professor of psychiatry and obstetrics and gynecology at Rush Medical College and a past president of APA, told Psychiatric News that she did not believe the results would change the way psychiatrists treat women who present with depression in midlife.

“We have treatments for women who are depressed,” Stotland said. “It is important to take a history to rule out psychosocial causes of depression. If this is done and there is strong evidence that a patient is very sensitive to hormone change, you can try estrogen therapy, but the side effects of estrogen are more concerning than those of antidepressants.”

While the Women’s Health Initiative raised concerns over the safety of hormone therapy during postmenopause, Mary Morrison, M.D., a professor of psychiatry and behavioral science at Temple University School of Medicine, who was not involved with the study, told Psychiatric News that there are several factors that may lead postmenopausal women to try estrogen therapy over antidepressants, including, among others, the view that estrogen is a more natural choice and has a proven record of mitigating other symptoms of menopause.

“Both antidepressants and estradiol can have side effects. After three to five years on a hormone, patients must ask themselves, ‘Am I starting to accrue increased health risk because of being on hormone therapy?’” Schmidt said. “Our study suggests that one of the risks that must be considered when withdrawing from the hormone is whether there was a history of any depressive symptoms during perimenopause,” he said.

“What’s important about the findings of our paper is the fact we show that estradiol withdrawal has a direct effect on mood destabilization. And only a subgroup of women is adversely affected—making the biology of risk an important focus for understanding how ovarian hormones regulate mood in some women,” Schmidt said.

The study by Schmidt and colleagues was supported by the Intramural Research Program of the National Institute of Mental Health and the National Institutes of Health. Novartis Pharmaceuticals supplied the estradiol skin patches and matched placebos. ■