The causes of clinical depression and anxiety are complex — a weave of social, biological, and genetic factors.

At the heart of it all, there’s this: Women have twice the risk of depression as men do.

“This is true across all countries, all cultures, all income levels, across all levels of success — women have higher rates of depression,” says Myrna M. Weissman, PhD, an epidemiologist and psychiatry professor at Columbia University School of Medicine in New York.

“Before puberty, rates of depression are about equal between boys and girls,” she tells WebMD. “At puberty, the rates skyrocket in girls. There are men who suffer from depression, but not anything near the rate in women.”

In 1999, Surgeon General David Satcher, MD, noted these same rates in his report on mental health. Although women have more opportunities than ever before, they still fight a bigger battle against depression, anxiety, and other mental health problems.

Under the Skull

Using sophisticated brain imaging, researchers have found that men’s and women’s brains are indeed built differently.

In one study, a group of researchers found that men’s brains synthesize more of the mood-lifting brain chemical serotonin than women’s brains do — 52% more.

Men and women also respond to antidepressant medications differently. Some antidepressant drugs work better for men while others may prove to be more beneficial for women.

For women, antidepressant drugs that affect serotonin, like Prozac, Paxil, and Zoloft, work better, reports Susan G. Kornstein, MD, head of the outpatient psychiatry clinic at the Virginia Commonwealth University.

Serotonin found primarily in a brain region called the amygdala, where emotions are processed, explains Stephan Hamann, PhD, a psychology researcher at Emory University in Atlanta.

This is the “fight-or-flight” center of the brain, the region that registers anxiety, fear, joy, stress, even lust, he says.

Emotional Secrets of the Amygdala

The amygdala is an almond-shaped area of the brain that controls emotion. In adulthood, the size of a man’s amygdala doesn’t differ much from a woman’s. However, recent studies have found that when men and women look at photographs, they register the memory on opposite sides of the amygdala.

In studies involving spouses, women could recall memories – first date, last vacation, a recent argument — more quickly than men did. Women’s memories were also more emotionally intense and vivid than men’s memories, Hamann adds.

“Women may be more predisposed to experience events more intensely, more vividly,” he tells WebMD. That ability has a downside: “Women have greater propensity to rumination; going over the same negative events amplifies its negative consequences.”

Animal studies show similar patterns, he says. “The emotional arousal that leads to stress responses and stress hormones affects basic memory machinery in male and female rats differently.”

Evolution at Work

As our species evolved, this emotional sensitivity helped females in protecting themselves and their young. On the other hand, “males want to remember where better hunting grounds are,” says Hamann.

This makes sense, in terms of how stress affects today’s women. “Emotional responses are hardwired in women; we’re more sensitive to losses of attachment,” Weissman tells WebMD. “That’s what depression is about — loss of attachment. The breakup of a relationship, divorce, separation, or death is a major precipitating event for depression.”

Estrogen seems to indirectly set the stage for depression after a stressful event by triggering an intense hormonal response to stress. Research has shown that estrogen increases and prolongs the body’s production of cortisol, a stress hormone. Cortisol is thought to play a key role in depression.

One large study of twins showed that — if there is a family history of depression — an episode of major stress like divorce could double a woman’s risk of developing depression, says Kenneth S. Kendler, MD, a psychiatrist and geneticist at the Medical College of Virginia.

Also, panic attacks (related to depression and anxiety) are more frequent in women over age 50. This is especially true if they had five or more stressful events in one year or if they suffered from depression, reports Jordan W. Smoller, MD, ScD, a psychiatric researcher with Massachusetts General Hospital in Boston.

Genes at Play

Genetics are another critical part of depression. Researchers like to use heart disease risk as an analogy: For people with family history, an unhealthy lifestyle will increase the risk dramatically. If you don’t have family history, your body can tolerate more abuse.

Researchers like George Zubenko, MD, PhD, are investigating sex-specific “susceptibility” genes that increase risk for clinical depression.

“There is an enormous amount of literature supporting the fact that major depressive disorder is about twice as high in women as in men,” says Zubenko, who is a professor of psychiatry at the University of Pittsburgh Medical School.

His evidence:

• Twin studies demonstrate that genetic factors typically account for 40% to 70% of the risk for developing depression.
• Family studies have shown a twofold increased risk among first-degree relatives.
• Adoption studies have also confirmed an important role for genetic risk factors in the development of depression.

Zubenko’s study involved 81 families with recurrent, early-onset (before age 25) major depression. He found that nearly one-half of first-degree relatives suffered from one or more mood disorders – six times the risk of the general population.

He also identified 19 genetic regions that were linked to recurrent, early-onset depression. Sixteen regions were linked to only one sex, and only three were linked to depression in both sexes.

There appear to be more genes that preferentially affect women’s risk. The effects of “sex-specific” risk genes may diminish after age 35 to 40, when sex hormone levels begin to fall, he says.

“The number of genes that appear to affect risk in one sex or the other preferentially affect risk in one gender but not both,” Zubenko tells WebMD. “And the majority of those sex-specific genes affect women.”

The genes that influence risk of depression appear to work together to increase risk – and typically affect a spectrum of depressive disorders as well as alcoholism, he says.

Liberated From What?

Some researchers are convinced, however, that when women’s roles in society improved, their odds of depression decreased.

While genetics may play some role, women’s self-confidence and self-esteem are at the heart of depression, says Ronald C. Kessler, PhD, professor of health care policy at Harvard Medical School and author of several major depression studies.

In the 1950s and 1960s, studies showed that women had three times the rate of clinical depression as men. Since then, that number has steadily decreased — today’s women have 1.7 times the rate of depression, he tells WebMD.

“As gender roles in society have grown similar, we’ve seen the gap decrease,” says Kessler, who is heading a nationwide study of gender-related depression patterns in adolescents. “That’s not to say that 1.7 times risk isn’t genetic.”

“The gender difference in depression tends to emerge in mid-puberty,” he says. “Many people think that it’s linked to the menstrual cycle. But there are a lot of things that happen at puberty, including breast budding and girls getting attention from older boys.”

One large nationwide study showed that girls’ rates of clinical depression increased when they graduated from elementary school to middle school or high school – regardless what their age was, says Kessler.

“It had nothing to do with puberty or hormones. When young girls went to school with older boys, that’s when their self-esteem took a nosedive.”

Published March 22, 2004.