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DEPRESSION ACROSS THE FEMALE LIFESPAN
Depression is very common in women, who have twice the rate of depression as do men.  A striking one of five women will have at least one episode of depression in their lifetimes. Clinical depression is a brain disorder characterized by disruption of the coordination of central nervous system circuits for control of mood, thought, sleep, appetite, and behavior. It results from influence of multiple genes acting together with environmental factors, such as stressful life events. The definition of major depression is at least five of the following symptoms, for two weeks, most of the day nearly every day, and one must be mood or interest:
- Depressed mood
- Diminished interest/pleasure
- Weight loss/ gain unrelated to dieting
- Insomnia/ hypersomnia
- Psychomotor agitation/ retardation
- Fatigue or loss of energy
- Feelings of worthlessness/guilt
- Diminished ability to concentrate
- Recurrent thoughts of death
Contributing to the higher rate of depression in women are the hormonal fluctuations that occur during reproductive milestones, such as the first menstrual period (menarche), before menstrual cycles, during pregnancy, postpartum and the perimenopause. The normal (but substantial) fluctuation in hormones increases the risk for physiological destabilization and depression in women with elevated central nervous system sensitivity. Depressive syndromes occur during the dramatic reproductive events of women's lives and affect function and health.
Many types of treatments are efficacious for major depression in women: short-term psychotherapy, antidepressant medications, bright light therapy, regular exercise, repetitive transcranial stimulation; however, achievement of full remission is the goal and only about half of women treated with any modality have a full remission of symptoms. Additional research to improve treatment outcomes is urgently needed, and, according to epidemiologic studies, the vast majority of depressed women are neither identified nor treated in America.
Depression during the Menarche
Epidemiologic studies consistently show that the rate of depression in children is the same until puberty, when the risk for depression in females increases to two times that of males. Additionally, early menarche (before 11.5 years; the average age of first menstruation is 12.5 years) is associated with a higher risk for depression in adolescence. More than half of the girls who develop depression report having an anxiety disorder prior to the onset of depression, and depressive symptoms in 7th grade predict symptom levels throughout secondary school. The onset of use of drugs and alcohol typically follows an episode of depression in girls. Tragically, suicide is the third leading cause of death among 15-24 year olds. However, very little research has been done to explore the contributions to depression development in menarchal girls or preventive or interventional therapies for menarchal depression. This is unfortunate, since these episodes are predictors of subsequent disease across women's lives.
Premenstrual dysphoric disorder (PMDD)
The majority of women are aware of mild symptoms related to their menstrual cycles, but they are not always associated with functional impairment. However, about 5% of women have premenstrual dysphoric disorder, which is characterized by symptoms of depression, with a particularly prominent symptom being irritability that is uncharacteristic of the woman.
PMDD is a regularly occurring cyclical depressive disorder that occurs only during the 1-2 weeks before the menstrual cycle, with emotional lability and marked irritability plus the symptoms of depression noted above. During the remainder of the month, the woman is essentially asymptomatic.  PMDD must be differentiated from major depression with premenstrual exacerbation, in which symptoms are present all month but worsen premenstrually. The average age of onset is 26 years, and symptoms increase across time until menopause without treatment.
The primary treatments for PMDD are serotonergic antidepressant medications, which can be given only during the symptomatic premenstrual days, in contrast to major depression, for which the medication must be given daily. Non-serotonergic medications are also effective. Few data are available for novel therapies that impact serotonergic function, such as morning light therapy or nutritional augmentation.
Depression during Pregnancy and After Birth
The prevalence of major depressive disorder during pregnancy is 12.7%, particularly unfortunate during the time when women and families hope to welcome the new baby.
Recent research has demonstrated that the quality of the intrauterine environment has a major impact not only on fetal but on life-long health. Depression during pregnancy increases risk to the woman and her fetus. The physiological dysregulation of depression is a suboptimal milieu for pregnancy. Maternal prenatal stress is significantly associated with low infant birth weight and preterm birth in humans. The symptoms of depression impact appetite and nutrition, attention to self and infant safety, prenatal care compliance, increase alcohol and drug use, decrease in personal and family resources.
Treatment of depression during pregnancy is my main area of research, which includes studying the outcomes of untreated and treated depression in women, and developing interventions to improve the health of both the mother and the infant. I have recently been on advisory committees for both the FDA and the CDC on safe use of medication during pregnancy.
Postpartum Depression
This condition is another example of the profound effect of reproductive events on psychopathology. With a striking prevalence of 21.9% the year following birth, depression is a frequent complication of childbearing. However, recognition and treatment rates are even lower in pregnant and postpartum women (14%) than in the general population (26%). Low treatment rates are juxtaposed against mounting evidence that postpartum depression increases the risk for multiple adverse outcomes for women and their offspring.  Maternal depression interferes with child development and increases the rates of insecure attachment and poor cognitive performance. Suicide accounts for about 20% of postpartum deaths and is the second most common cause of death in postpartum women.
Childbearing is an opportune time for intervention because women have contact with health care professionals, access to health insurance, and are motivated toward positive behaviors to invest in their offspring's welfare. Identification of PPD through universal screening has been recommended (and is mandated in several states). The most frequently used PPD screening tool is the Edinburgh Postnatal Depression Scale (EPDS).
Antidepressants and psychotherapy are first-line treatments for PPD. I have published several papers on the exposure of infants to antidepressant through breastmilk, which has shown very low, usually nondetectable, levels of antidepressants in the infant. Novel treatments for PPD, such as bright light therapy and estradiol skin patch, are part of my research to move this field forward. Strategies to differentiate women with Bipolar from Unipolar Disorders are urgently needed since the treatment differs, with antidepressants increasing the risk for unstable mood in bipolar women.
Perimenopausal Depression
This conditions characterized by a syndrome of somatic and psychological symptoms that are associated with a reduction in circulating levels of the female sex steroids. Epidemiologic studies have shown that the hormonal instability that occurs in the five years prior to cessation of menstrual cycles is one of high risk for depression in women.
There is a complex relationship between gonadal hormones and depression. For example, depression is not the result of a hormone deficiency, and hormone levels do not distinguish women with and without depression. However, several investigators have found that estradiol delivered through a skin patch is effective for perimenopausal depression. Estradiol has many effects in the brain that are similar to antidepressants. The mood enhancing effects of estradiol occur independent of the presence of hot flashes. Antidepressants and psychotherapy first line treatments for perimenopausal depression, and transdermal estradiol (E2) is a second line treatment supported by small randomized clinical trials. Additionally, fat deposits impact the absorption through skin of estradiol, and minimal data are available about how this impacts dose especially in overweight women.
In closing, women with vulnerability to depression during hormonal changes are vulnerable to others; for example, women with premenstrual dysphoric disorder are vulnerable to postpartum and perimenopausal depression. With a life cycle approach that considers women within at their life phase, preparation for wellness during future reproductive events is possible and is an intriguing area of research.
Author: Katherine L. Wisner, MD, MS
Norman and Helen Asher Professor of Psychiatry and Behavioral Sciences at Northwestern
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