Women and depression: An underrated problem

Clinical depression is a common disorder, but its burden on health and productivity in the United States and throughout the world has long been underestimated. In an established market economy, such as that of the United States, unipolar major depression (MD) is the second-leading cause of disease burden, surpassed only by ischemic heart disease. Worldwide, it is the No. 1cause of disability among persons aged five and older, and up to 15% of individuals suffering from the severe forms of depression eventually commit suicide, signifying the high morbidity and mortality associated with this disorder. It is also important to note that depression exerts its biggest toll on women.

MD affects more than 19 million Americans annually, and while depression occurs across all education, racial, ethnic, and economic groups, women appear to bear the brunt of it. Extensive epidemiological data have shown that women are at least twice as likely as men to experience a major depressive episode at least once during their lifetime. According to a 2002 news release from the Agency for Healthcare Research & Quality (AHRQ), depression was the second-leading cause of hospitalization for young women in 2000. Data showed that approximately 205,000 women between the ages of 18 and 44 were hospitalized in association with the treatment of depression.

Biological and psychosocial factors both contribute to the higher risk in women, requiring a multidimensional approach to treatment. "Pharmacists should be aware of the mood disorders in women that occur during their life cycle, since recognition and treatment are essential to reduce morbidity and improve the functioning of women in our society," said Martie Fankhauser, M.S., clinical associate professor at the College of Pharmacy, University of Arizona, Tucson. Pharmacists can improve the detection and treatment of MD by providing patient education about the disorder and appropriate treatment, as well as referring women with depressive symptoms for evaluation.

Biological factors

MD is a multifactorial disorder and may be influenced by any number of risk factors, including age, socioeconomic status, childhood history of sexual abuse, and recent stressful life events. The exact reason for the disparity between genders is not completely understood, but there are numerous theories as to why women experience higher rates.

There is significant and increasing evidence that biological factors contribute to the etiology of depression. One hypothesis attributes the higher prevalence of MD to the frequent shifts in female reproductive hormone levels. Women often have an earlier onset of depression, such as menstrually related mood disorders that begin at puberty, said Fankhauser. "They are also vulnerable to depression during their reproductive years."

Premenstrual dysphoric disorder, for example, is a severe subtype of premenstrual syndrome and is associated with a serotonin deficiency state. "Perimenopause is associated with a reduction of 17-beta estradiol production as well as drastic fluctuations in hormones that cause a wide range of symptoms, including depression, mood swings, irritability, decreased and disrupted sleep, memory impairment, decreased energy levels, low libido, muscle pains, hot flashes, and irregular menses," Fankhauser explained.

The high incidence of depression during both pregnancy and postpartum also lend further credence to a hormonal influence. A study of 3,472 pregnant women, conducted by researchers from the Depression Center at the University of Michigan, Ann Arbor, found that as many as one in five pregnant women may be experiencing symptoms of depression.

People tend to associate depression with the postpartum period and not with pregnancy, said Sheila Marcus, M.D., lead author of the study and a clinical assistant professor of psychiatry at the University of Michigan Medical School. In fact, doctors used to consider pregnancy a kind of reprieve from the risk of depression, but research no longer supports this view. Alterations in a pregnant woman's hormone levels may affect the levels of mood-regulating neurotransmitters, resulting in symptoms indicative of depression. Studies have shown that women who are depressed during pregnancy may be more likely to experience full-blown postpartum depression. According to Marcus, women with a history of depression are also at a high risk for a recurrence of symptoms during pregnancy.

"It is important to note," said Patrick R. Finley Pharm.D., BCPP, "that depression is comparable between boys and girls, and it's only when girls reach menarche that the incidence goes up. It remains twice as high throughout the reproductive years, but then drops off when women reach menopause."

Symptoms also seem to follow a certain continuum, according to Finley, who is an associate clinical professor at the University of California at San Francisco. "Women who have severe premenstrual syndrome (PMS) symptoms—more emotional than physical—are more likely to have depression during and after pregnancy and during perimenopause."

Some data suggest that genetics may also account for the higher rates of depression among women. There is evidence of familial tendencies toward depression, but it is unclear how much is attributable to genes compared with a shared environment. Researchers from the University of Pittsburgh Medical Center, Pittsburgh, have made some progress in identifying the first susceptibility gene for clinical depression, uncovering significant evidence that links unipolar mood disorders to a specific region of chromosome 2q33-35 in women.

Psychosocial factors & incidence

Other factors may also contribute to the high incidence of depression in women. Stressful life events, such as the death of a spouse, divorce, or loss of a job, can modulate neurotransmitter activity, leading to depression onset. But even though stress can cause depression in both sexes, severe stress is three times more likely to cause MD in women. Traumatic events, such as partner violence, and childhood and adult sexual abuse, have also been linked to higher rates of depression in women.

Comorbid anxiety disorders, such as generalized anxiety disorder, panic disorder, and posttraumatic stress disorder are more common in women, said Frankhauser, and 75% of cases of depression may have a precipitating life event. Women will also often experience a seasonal pattern of depression with a worsening of mood in winter months.

Economic and social inequalities have also been cited as possible factors. "Even though it's changing, women may still feel bound by traditional roles," Finley pointed out. "They may not have the same career advancement as men, receive the same pay, or feel they have the same opportunities."

Treatment

MD is primarily treated with antidepressants alone or in combination with some form of psychotherapy. The selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and agents such as bupropion and venlafaxine are all used as therapeutic agents. The SSRIs, which are among the most prescribed medications in the United States, appear to be better tolerated than the older tricyclics, and have become the first-line treatment for MD in women.

Women clearly respond better to SSRIs than do men, and not only do they respond better but also they tolerate them better, said Finley. "This indicates a hormonal component not only to depression but to the response to antidepressants." However, this benefit is seen only in pre-menopausal women.When women reach menopause, the response rate to SSRIs becomes relatively equal in men and women.

There are several novel compounds being investigated to treat depression, said Christian J. Tetter, Pharm.D., BCPP, an assistant professor of pharmacy at Northeastern University School of Pharmacy. "One is the corticotropin-releasing factor antagonist, and the other is the substance P antagonist." The corticotropin-releasing hormone is the primary regulator of the hypothalamic-pituitary-adrenal (HPA) axis and an activator of the sympathoadrenal (SA) and systemic sympathetic (SS) systems, said Teter. A number of mental disorders, including MD, have been associated with disruptions in the HPA and SA/SS systems. Substance P belongs to the neurokinin class of neuropeptides and interacts with the NK1 receptor, which regulates affective behavior and pain perception.

"These are the two most novel approaches in the pipeline, but they are nowhere near approval," said Teter. "There is also duloxetine (Eli Lilly), a new serotonin/norepinephrine inhibitor similar to venlafaxine." The final approval of duloxetine may be delayed, however, due to a recent suicide by one of the study participants.

One new agent that is already out on the market is escitalopram, an SSRI. "Escitalopram is the active isomer of citalopram and is more potent at blocking the reuptake pumps of serotonin compared with other SSRIs," said Fankhauser. "It also has fewer drug interactions, has good tolerability, and minimal adverse effects, so it is becoming a popular choice for women."

Roxanne Nelson

THE AUTHOR  is a Seattle-based medical writer.

 

Roxanne Nelson. Women and depression: An underrated problem. Drug Topics May 2, 2004;148:14s.