Colorado State University Research Uncovers New Opportunities to Treat Depression

A Colorado State University researcher’s work to discover hormonal links between gender and depression may unlock new opportunities to treat the disease. Robert Handa, a professor in the College of Veterinary Medicine and Biomedical Sciences, is working to better understand the role estrogen receptors in the brain may play in men and women who suffer from depression.

Depression is two to two-and-a-half times more prevalent in women than men, according to Handa and other well-known research in the field. In addition, anxiety disorders, which can occur alone or with other diseases, are up to 10 times more common in women than men. Handa’s research points to the influence of estrogen as a clue for the disparity in depression and anxiety between the sexes.

"If researchers are better able to understand the role of estrogen receptors, perhaps types of these receptors can be selectively targeted with drugs. Our research points to the possibility that selectively targeting one type of estrogen receptor can effectively treat depression and anxiety in addition to reducing unwanted side effects of some types of medication," Handa said. "This would provide physicians with more treatment options to help patients who suffer the often debilitating effects of depression and the complications of side effects from prescription treatments."

Handa couples clues gained from both depression research and estrogen replacement therapy in women. Estrogen plays a major role in changing how genes are expressed, which can influence behaviors. One clue of estrogen’s role is the increased rate of depression in menopausal women who are experiencing a decline in estrogen circulating in their systems.

"We believe that the prevalence of depression in adult women relates in part to changes in estrogen and other hormones," Handa said. "Estrogen replacement therapy was recently a popular strategy employed by doctors to treat symptoms of menopause, including mood disorders, depression and anxiety. But recent studies show that the pros of estrogen replacement therapy don’t outweigh the negative side effects, so doctors have, for the most part, quit prescribing this therapy. Unfortunately, that leaves a large gap in their ability to treat the psychological effects of losing estrogen."

For example, women receiving estrogen replacement therapy felt reduced anxiety and less depression, but also had a higher incidence of breast cancer.

However, estrogen does not always have the same effect on young adult women who are not near the age of menopause, depending on individual history.

"The way in which estrogen changes behaviors and coping skills can cause some women to become depressed, but not all women," said Handa. "There are increasing clues that problems in fetal development can make some people more prone to become depressed."

While estrogen is typically thought of as a female hormone, it is also found in males. In fact, testosterone can be converted to estrogen and other compounds that can bind with estrogen receptors in the male brain, influencing behavior and coping ability.

The brain contains two forms of estrogen receptors – a beta receptor and an alpha receptor. Handa explains receptors as locks and estrogen as a key. Once estrogen fits into either receptor, it "unlocks" the receptor to allow it to control expression of a gene.

Hormone replacement therapy typically uses estrogens that bind to both the alpha and beta estrogen receptor to treat mood and cognitive changes that occur at menopause.

However, Handa’s research into depression has found that drugs that bind to only beta estrogen receptors resulted in reduced anxiety without some of the negative side affects typical of estrogen. He also found that drugs that bind to the alpha estrogen receptor actually increase anxiety.

"We also suspect that the fetal female brain may be more susceptible than the fetal male brain to specific stressors, such as an expectant mother’s emotional or physical stress or alcohol abuse during pregnancy, that make these offspring more susceptible to onset of depression in adulthood," Handa said.

Handa points out that this also ties to another important difference between the sexes: Adult male and female brains use different strategies to cope with stressors, and stress affects brain function of the two sexes differently. The combination of these factors may well have much to do with the onset of bouts of depression and its increased prevalence in females.

Many patents with depression have difficulty finding the right treatment and may struggle with inadequate medications for their depression for years, said Handa. In addition, current depression and anxiety medications often have undesirable side effects.

Handa’s findings, to date, are restricted to studying the behavior of rats in his laboratory and have not been tested on humans with depression or anxiety. Rats and mice demonstrate depressive and anxiety-like behavior similar to the behavior humans exhibit when depressed and anxious.

"Using a rat model, we can further understand the impact of beta estrogen receptors and their potential as a pharmaceutical target," Handa said. "Eventually, new drugs and approaches from this research can be tested in human clinical trials."