Women and Depression

Depression is a common disabling disorder affecting more than 19 million Americans per year (Regier et al., 1993), and women are at least twice as likely as men to experience a major depressive episode within a lifetime (Kessler, McGonagle, Swartz, Blazer, & Nelson, 1993; Weissman, Leaf, Bruce, Florio, & Holzer III, 1988). Depression may occur at any stage during a woman’s life, and it occurs across educational, economic, and racial/ethnic groups. Significant personal costs are associated with depression, including loss of life by suicide, increased morbidity from medical illness, and attendant risk for poor self-care and reduced adherence to medical regimens.

Major depression, even without concurrent medical illness, impairs social and physical functioning, in some cases more severely than serious medical conditions such as hypertension, diabetes, and arthritis (Wells et al., 1989). Furthermore, depres- sion incurs a significant economic burden resulting from disability and consequent loss of income (Greenberg, Stiglin, Finkelstein, & Berndt, 1993). In fact, a recent World Health Organization report examining “The Global Burden of Disease” indi- cates that depression presents the greatest disease burden for women when compared with other diseases (Murray & Lopez, 1996).

Consequently, it is critically important to understand what has been learned from empirical investigation about depression, its treatment, and prevention,

and apply that knowledge to reducing risk for depression and maximizing interventions. Of equal importance are the incorporation of this new knowledge into health policy and the creation of a research agenda that will advance our knowledge on women and depression.

Summit on Women and Depression

Ten years ago, the American Psychological Association (APA) convened its first meeting of the Task Force on Women and Depression to review the knowledge base in this field (McGrath, Keita, Strickland, & Russo, 1990). Since that time, there have been great strides in depression research. Recognizing the need to update these findings and continue to move the field forward, the American Psychological Association convened a Summit on Women and Depression on October 5-7, 2000.

This Summit brought together over 35 internationally renowned experts from a variety of disciplines to provide a state-of-the-art review of research findings on women and depression, make recommendations on how these findings can be reflected in health policy and incorporated into practice, and generate a targeted research agenda on women and depres- sion. The form of depression on which we fo- cused was non-psychotic, that is, clinical major depression, which is the most common form of mood disorder and among the most disabling.

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Prior to the Summit, each expert was asked to prepare a manuscript on his or her area of expertise that would present state-of-the-art knowledge on women and depression; identify the conceptual and methodological challenges in studying women and depression; highlight the implications of available research in depression for treatment, prevention, service delivery, and mental health policy; and identify gaps in our knowledge that must be ad- dressed through future research.

Within this framework, the goal of the Summit on Women and Depression was to answer three critical questions:

  • What empirically based research findings need to be implemented to improve treatment and enhance prevention of depression in women?

  • What research findings are available to inform health care policy and enhance service delivery for women with depression?

  • What research studies should be funded in the next 5 years that would result in practical benefits for women with depression?

    Work of the Summit and Guiding Principles

    The work of the Summit was framed within four major discussion sessions: the etiology of sex and gender differences in depression; treatment and prevention; treatment and prevention for special populations of women; and services for women with depression. Formal presentations were limited to four “integrative” speakers — one for each session — to permit extensive exchange among

participants. The integrative speakers highlighted findings from each paper, discussed them in relation to the three major questions, and set the stage for the audience participation that followed. Following these sessions, the participants met in four smaller groups to consolidate and prioritize recommenda- tions made in the general session. Each group then reported back to all participants in a final session.

The Summit on Women and Depression resulted in a stimulating, enriching, and highly informative interaction among the assembled interdisciplinary group of experts. More importantly, it resulted in a renewed commitment to translate research knowl- edge into practical applications and health policy and to recommend future research directions that will advance our knowledge on women and depression.

As rapporteurs of this meeting, we have highlighted material from each presentation that we believe represents critical findings. We have also provided key recommendations from presentations and group discussions for future directions in research, treat- ment, and policy for women with depression.

Carolyn M. Mazure, PhD

Chair, Summit on Women and Depression Gwendolyn P. Keita, PhD
Mary C. Blehar, PhD

Acknowledgements:

Gabriele S. Clune for outstanding assistance in planning and implementation of the Summit on Women and Depression as well as in editing these proceedings.

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Depression is associated with significant personal and economic costs (Greenberg et al., 1993) and is the leading cause of disability among women in the world today (Murray & Lopez, 1996). Depression is more prevalent in women, a finding that has been consistently replicated in many well-designed epidemiological studies conducted in the United States (Kessler et al., 1994b; Robins & Regier, 1990) and throughout the world (Wolk & Weissman, 1995). Absolute rates of depression vary during adulthood and are highest in midlife; however, the relative difference in the rates of depression between women and men are maintained. Women have a higher risk of an initial or first onset episode of depression (Eaton & Muntaner, 1997; Kessler et al., 1993). and, although risk of recurrence is the same for women and men (Kessler et al., 1994a; H. B. Simpson, Nee, & Endicott, 1997), there are more women in the “pool” of those who could have a recurrence.

Childhood onset depression appears to confer similar risk of subsequent depression for girls and boys (Kovacs, Summit, 2000)2 . However, earlier onset in boys is associ- ated with greater comorbidity of psychiatric disorders, while earlier onset in girls is not associated with

comorbidity and suggests a “purer“ form of depressive disorder. Depressed girls report higher levels of mood disturbance and neurovegetative symptoms
than do boys, while boys report more irritability, which may have interpersonal ramifications and thus increase the rates of subsequent comorbid conditions. Gender differences in rates of depression emerge in early adoles- cence, at puberty (Nolen-Hoeksema & Girgus, 1994), raising questions about the role of biological factors, specifically sex hormones, as well as sociocultural influences in the etiology of depression (E. Frank & Young, 2000).

To improve the diagnosis, treatment and prevention of depression in women, we must better understand the etiology of depression for women, specifically the biological, psychological, and social origins of depres- sion, and better integrate data across these perspectives.

BIOLOGICAL FACTORS

Ample and increasing evidence indicates that biological factors contribute to the etiology of depression, and an array of biological factors have been the focus of study.

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THE ETIOLOGY OF SEX AND GENDER1 DIFFERENCES IN DEPRESSION

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1 We acknowledge contrasting opinions about the use and meaning of the terms sex and gender. For purposes of explicating

the discussion undertaken during the Summit, we use sex to connote the biological attributes of the individual and gender to encompass a combination of biological, psychological, social, and situational factors that vary across culture as well as within a particular culture over time. Gender is a multilevel construct that has been defined as the cultural package of factors assigned to the social categories of male and female. These factors are assigned by sex in most cultures (Bourne & Russo,

1998).
2 Within the text, references are made to the manuscripts written by Summit participants specifically for the Summit on

Women and Depression. These manuscripts are currently in press in various journals across disciplines. For a current list of publications or more information, please contact the APA Women’s Programs Office at http://www.apa.org/pi/wpo/.

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Genetics

Based on data that major depression clusters in families and that depression in a first degree relative is a risk factor for depression (Gershon & Nurnberger, 1982), researchers have sought to identify factors causing depression and, more recently, to determine if genetics may account for the higher rates of depression in women than men. To date, no specific genes responsible for depression have been identified nor have results of family and twin studies been conclusive in showing the exact genetic contribution to depression. However, accumulating data (Kendler, Neale, Kessler, Heath, & Eaves, 1992; Kendler, Thornton, & Gardner, 2001; Lyons et al., 1998) implicate genetic risk as an important factor in depression. Bierut et al. (1999) have also suggested that genes may play a larger role in the devel- opment of depression in women. Studies currently underway may clarify the role of genetics and help determine whether different genes contribute to depres- sion in women versus men or whether the same genes have a differential impact for women versus men in the development of depression. However, research on the role of genetics in depression is particularly labor intensive and must be carried out over generations.

Sex Hormones

Based on the perspective that the unique biology of women may explain, in part, the higher prevalence of depression, other investigators have focused on the role of sex hormones in initiating certain forms of depres- sion. The obvious difference in sex hormones between women and men, and the link between increased rates of depression for women after puberty, as well as the link between mood and the menstrual cycle or reproduction, suggest that gonadal (or sex) hormones may contribute to differences in depressive onset.

Of particular interest is whether a disturbance in the interaction between the hypothalamic-pituitary-gonadal (HPG) axis and neuromodulators (e.g., serotonin) is a key contributor to depression in women. It has been hy- pothesized that women may be vulnerable to such dysregulation because of the neuroendocrine rhythmicity engendered in menstrual cyclicity or reproduction, and then subsequently more sensitive to psychosocial, environmental, and other physiological factors (Dunn & Steiner, 2000; Steiner, 1992; Steiner & Dunn, 1996). This hypothesis is supported by data indicating that depressive symptoms and syndromes are associated with periods when gonadal hormones are undergoing considerable change, mainly during the premenstrual period, the postpartum period, and at the initiation of menopause.

Epidemiological studies estimate that as many as 75% of women experience some premenstrual emotional and behavioral symptoms (Johnson, 1987), and the recent inclusion of premenstrual dysphoric disorder (PMDD) in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; 1994) is based on increasing data showing that some women can have significantly dis- abling depressive symptoms premenstrually. Although the etiology of PMDD is not known, it is increasingly hypothesized that normal cyclic ovarian function rather than hormone imbalance may trigger biochemical changes within the central nervous system or other sites (e.g., thyroid) in women vulnerable to mood disorders (Steiner, Summit , 2000). The positive response of women with PMDD to treatment with selective seroto- nin reuptake inhibitors (SSRIs) clearly suggests that serotonin may be altered in women with PMDD and supports the promising line of research investigating hormone-neurotransmitter interactions.

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The finding that ovarian axis functioning (i.e., estrogen and progesterone) is apparently normal during premen- strual symptomatology has expanded interest in the role of the metabolite of progesterone, allopregnanalone, as well as the role of androgens in depression. Some treatment studies have indicated that progesterone may provoke the cyclic symptoms of PMDD (Hammarback, Bäckström, Holst, von Schoultz, & Lyrenal, 1985), while allopregnanalone may produce an anxiolytic effect (Rapkin et al., 1997). Some preliminary studies suggest that women with PMDD have higher levels of serum testosterone in the luteal phase compared with controls, which may contribute to some symptomatology such as irritability (Dunn, Macdougall, Coote, & Steiner, 2001).

Depressive symptoms and syndromes associated with postpartum and perimenopausal periods have also begun to be studied with regard to hormonal influences and the interaction of hormones with neurobiological systems. It is well known that there are significant shifts in sex hormones and major changes in the hypothalamic- pituitary-adrenal (HPA) axis during these periods. Pregnancy and delivery produce dramatic changes in estrogen and progesterone levels, as well as major shifts along the HPA axis, and perimenopause results in critical fluctuations in estrogen as well as changes in other hormones (i.e., lutenizing hormone and follicular stimu- lating hormone). Although the direct and indirect effects of these changes have not been clearly linked to the onset of mood disorders, investigations continue to focus on the effects of neuroendrocrine changes on mood.

Animal Models

Some investigations have used animal models to elucidate underlying mechanisms of depression and to test

hypotheses about the higher incidence of depression in females. In particular, stress-inducing paradigms have been used to invoke behaviors in animals that mimic depressive symptoms. One series of studies found that exposure to acute stress induces dramatic and diametri- cally opposed effects on associative learning in males versus females (Shors & Horvath, Summit, 2000). Specifi- cally, acute inescapable stressors facilitate learning in males but impair conditioning in females (Wood & Shors, 1998). Interestingly, these negative effects of stress on conditioning are most apparent when there are extreme changes in estrogen levels either as a function of cyclicity or through chemically induced means. Further- more, stress increases estrogen levels (Shors, Pickett, Wood, & Paczynski, 1999), and the effect of stress on learning is prevented when ovarian hormones are removed via oopherectomy (Beylin, 1998) or by adminis- tering an estrogen antagonist, such as tamoxifen.

Biology clearly affects the risk for depression and biology is changed by depression. The biological maturation that occurs during puberty along with intensification of gender-specific social roles are believed to be key interac- tive processes in the emergence of sex differences in depression (Kovacs, Summit, 2000). Contemporary research is actively examining how biological factors may differ for women and men and identifying the psychoso- cial factors that likely mediate or moderate the risk incurred by biological influences.

PSYCHOLOGICAL AND SOCIAL FACTORS

Psychological and social variables of particular interest in understanding the etiology of depression and sex differences in rates of depression are the effects of stress and the relational and cognitive styles that increase vulnerability to depression.

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Life Stress and Trauma

Serious adverse life events are clearly implicated in the onset of depression. Both case-control and community- based studies, which have shown that more than 80% of community cases of major depression were preceded by a severe adverse life event have consistently demon- strated this relationship. Recent work, using multivariate models that account for other risk factors, also has confirmed the role of serious events in precipitating the onset of depression (Kendler, Neale, Kessler, Heath, & Eaves, 1993; Mazure, Bruce, Maciejewski, & Jacobs, 2000). Interestingly, most work investigating the relation- ship of stressful life events and major depression has largely or exclusively employed samples of women (Mazure, 1998), and few studies have examined sex differences in regard to stress and depression. However, initial research in this area has demonstrated that women are three times more likely than men to experience depression in response to stressful events (Maciejewski, Prigerson, & Mazure, 2001).

Traumatic stressors, such as childhood sexual abuse (Weiss, Longhurst, & Mazure, 1999), adult sexual assault, and male partner violence (Koss, Summit, 2000) also have been consistently linked to higher rates of depression in women, as well as to other psychiatric conditions (e.g., post traumatic stress disorder [PTSD]) and physical illnesses (Scholle, Rost, & Golding, 1998). As Koss points out (Summit, 2000), because approximately 85% of the victims of nonfatal intimate assault are women (Greenfield, Rand, & Craven, 1998), this is certainly a women’s health issue.

Pretrauma characteristics of the survivor of sexual assault often predict subsequent health consequences (Koss, Figueredo, & Prince, 2001). However, features of the abuse, including duration of exposure to abuse, use of force, and relationship to the perpetrator, are impor- tant factors in predicting outcome (Koss, Summit 2000), as are mediators such as event-related appraisals and beliefs (e.g., self-blame)(Barker-Collo, Melnyk, & McDonald-Miszczak, 2000; Wyatt & Newcomb, 1990). The National Violence Against Women Survey (Tjaden & Thoennes, 1998) estimated that approximately 15% of adult women in the United States had been raped and another 3% had been victims of attempted rape. The psychological impact of rape is severe and includes major depression, long-term depressive symptoms (i.e., dysthy- mic disorder), PTSD, increased rates of smoking, alcohol use, reduced activity, and physical injury (Koss, Koss, & Woodruff, 1991). Characteristics of sexual assault such as degree of physical force, use of weapons, and per- ceived fear of death or injury significantly affect psycho- logical outcome (Acierno, Kilpatrick, Resnick, Saunders, & Best, 1999).

Depression is also highly prevalent among women who experience male partner violence (Golding, 1999; McCauley et al., 1995) — the greatest single cause of injury to women requiring emergency medical treatment (Stark et al., 1981). Among the more worrisome aspects of this form of trauma is that it is repetitive. As Stark and colleagues have shown, nearly 1 in 5 abused women has presented for medical treatment of trauma more than 11 times, and another 23 % have been treated 6 to 10 times previously. Ongoing abuse is particularly pernicious in maintaining depressive symptom severity.

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Other chronic forms of severe stress that have been linked to higher rates of depression in women, include poverty, inequality, and discrimination. Women are more likely than men to have incomes below the poverty line, and depressive symptoms are common among low- income persons, particularly mothers with young children (Belle, Summit, 2000). Furthermore, adults in poverty are twice as likely to experience new episodes of major depression as adults who are not poor (Bruce, Takeuchi, & Leaf, 1991). Poverty is a pathway to depression for women in part because poor women have more frequent and uncontrollable adverse life events than the general population (G. Brown, Bhrolchain, & Harris, 1975; Dohrenwend, 1973), including increased exposure to crime and violence (Belle, 1982). Poverty also often brings with it including inadequate housing, dangerous neighborhoods, and financial uncertainties (Belle, Summit, 2000), and these stressors strain marital and parent-child relationships that otherwise would be sources of support (G. Brown & Moran, 1997).

Other contemporary research suggests that economic inequality, not just dire poverty, contributes to negative health outcomes (Adler et al., 1994; Wilkinson, 1996) and is associated with depression in women (Kahn, Wise, Kennedy, & Kawachi, in press). Differences between women and men in economic, social, and political status have also been correlated with female mortality and morbidity (Kawachi, Kennedy, Gupta, & Prothrow-Stith, 1999).

Sex discrimination in the workplace and elsewhere is associated with well-being and increased depressive and anxiety symptoms (Klonoff, Landrine, & Campbell,

2000). Women of color can face the dual problem of sexual and racial/ethnic discrimination, thus, raising the level of stress associated with discrimination (Reskin, 2000).

Interpersonal Relationships and Cognitive Styles
Many psychological and biological perspectives on depression have adopted a stress-diathesis model that focuses primarily on the vulnerability factors that predis- pose some individuals to depression in the face of an apparent life stressor. As pointed out by Hammen (Summit, 2000), the major stress-diathesis models stem- ming from a cognitive approach to depression have focused on dysfunctional beliefs, learned helplessness, and, more recently, hopelessness (e.g., Abramson, Alloy, & Metalsky, 1989; Beck, 1967; Ingram, Miranda, & Segal, 1998) as the diatheses provoked by the stressor. These models have provided insight into the types of cognitive or relational styles that are associated with depression, as well as greater understanding of the complex interplay of stress and depression with regard to cognitive mediators. One cognitive style that has been consistently shown to confer increased risk for depression and that is more common in women is ruminative thinking, that is, a repetive and passive mental focus on symptoms of distress and their possible causes and consequences. Those who ruminate excessively in response to distress have longer periods of depressive symptoms, are more impaired in their problem solving, and are less likely to engage in instrumental behaviors that might help one regain control. Rumination is also associated with longer and more severe episodes of depression and an increased likelihood of being diagnosed with major depressive disorder (Nolen-Hoeksema, 2000).

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Another style that may confer risk for depression has been termed “unmitigated communion.” This concept is built upon the notion that relationships are more central to women’s self-concept than men’s and that this inter- personal orientation is one of the most consistent psychological differences found between women and men (Helgeson & Fritz, 2000; Nolen-Hoeksema, 2000). The combination of sensitivity to relationship-based stressors and dependence on the external environment for validation of self-worth may create a focus on others to the exclusion of the self. Women with this character- istic (i.e., unmitigated communion) become unduly upset at the stressful events of others, take on others’ prob- lems as their own, and neglect the self in efforts to please and serve others. This style has been associated with depression and also may help to account for the gender difference in depressive symptoms.

In addition to focusing on what happens within the individual, there is a growing interest in understanding the interpersonal context in which depression occurs. As noted, poverty, discrimination, and inequality are ex- amples of contextual factors; interpersonal functioning is another important factor. Studies of the nongenetic transmission of depression have shown that many depressed mothers were raised in dysfunctional families with parental psychopathology (Hammen, 1991a). Also, women with histories of depression tend to be more critical toward their adolescent children, and this finding mediates the association between maternal depression and children’s behavior disorders (Nelson, Hammen, & Brennan, 2001). Consequently, dysfunctional parenting that is secondary to active depressive symptoms (e.g.,

hopelessness, irritability, fatigue, etc.) is associated with depression in children, and this pattern may be replicated across generations.

Depressed women also experience more marital discord and divorce (Hammen, 1991a), in part because of their own difficult course, but also because depressed women are more likely to marry men with psychiatric disorders (Hammen, Rudolph, Weisz, Rao, & Burge, 1999). A woman’s problematic marital, family, and friendship relationships can also persist even when she is no longer depressed. Her enduring motivations, beliefs, and expectations about herself and others and her strategies for interpersonal interactions constitute “interpersonal vulnerability,” which may put the woman at risk for developing depression when negative interpersonal life events occur ( Hammen & Brennan, 2001; Weissman & Paykel, 1974). Furthermore, data now show that de- pressed women, even in remission, report significantly more stressful events to which they have contributed in part by their own action or attitudes (Hammen, 1991b). Thus, in turn, negative interpersonal events may precipi- tate depressive reactions (Davila, Hammen, Burge, Daley, & Paley, 1995), contributing to a cycle of continuing difficulty.

The etiology of differential rates of depression in women and men almost certainly results from complex and reciprocal interactions of biological, psychological, and social factors. At this juncture, researchers are moving in the direction of developing models that integrate these factors to explain both the epidemiologi- cal data on sex differences in depression and the emer- gence of gender differences in early adolescence.

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TREATMENT OF DEPRESSION IN WOMEN ACROSS THE LIFE SPAN

Among the overall aims of the Summit was encouraging translation of research on depression into improved interventions for women with depression. Because the literature in this area is particularly rich, the papers on treatment solicited for the Summit were divided into two major sections. The first section was devoted to general issues in intervention research. A second section focused more intensively on treatment issues in special popula- tions of women defined in terms of demographics, clinical characteristics, or developmental life span phase. The following summary provides highlights from the papers and the panels on these topics with particular reference to the role of sex and gender in moderating course of depression and response to therapeutic intervention.

PSYCHOTHERAPEUTIC TREATMENTS FOR DEPRESSION
The efficacy of a variety of psychotherapies in treating depression has been clearly demonstrated. Controlled clinical trials have provided strong evidence for the efficacy of interpersonal and cognitive behavioral interventions. Evidence also suggests that some struc- tured behavioral marital and family therapies are effective in the treatment of depression (Hollon, Summit 2000). Dynamic and eclectic therapies have been less frequently studied, and data are limited for these forms of treat- ment. There is also some evidence that psychotherapy may be useful in the prevention of relapse or recurrence of major depression in patients successfully administered acute antidepressant treatment. Cognitive behavior therapy appears to have an enduring effect that prevents

subsequent onset or symptom return regardless of whether medications are used. An National Institute of Mental Health (NIMH) funded study of recurrent depression (Ellen Frank, Primary Investigator; Study No. MH 49115) is currently underway to assess the utility of maintenance interpersonal psychotherapy in patients who have remitted from an acute episode of depression.

In reviewing the literature on psychotherapy of depres- sion, Hollon (Summit, 2000) found little indication for gender differences in moderating psychotherapy out- comes. Yet, as Hollon points out, there are a number of possible explanations as to why gender differences have not been found. For example, it may be that despite the difference in rates of depression between women and men, once depressed, the genders respond similarly to psychotherapies. Or it is possible that men and women do respond differently but that most empirically sup- ported interventions are flexible enough to allow thera- pists to adjust their interventions to the different needs of males and females. Few studies have looked explicitly for gender differences, so they may exist but are yet to be detected. The sexes differ in co-occurring conditions such as anxiety disorders and PTSD (more common in depressed women), which may complicate outcome of depression treatment. Comorbidities have traditionally been grounds for exclusion from depression trials. A promising future line of research will be to study thera- pies in patients with co-occurring disorders. Nonethe- less, there is no doubt that psychotherapies are currently available that are effective interventions for women with depression.

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PHARMACOLOGICAL TREATMENTS FOR DEPRESSION
The efficacy of antidepressant pharmacotherapies for treating depression has been clearly demonstrated. Emerging evidence indicates gender may moderate response to antidepressants (Yonkers, Summit, 2000). These differences in response to antidepressant agents may be due to sex differences in endogenous central nervous system levels of serotonin (Nishizawa et al., 1997). This hypothesis is consistent with findings that women with chronic depression respond preferentially to selective serotonin reuptake inhibitors (SSRIs) and men to tricyclics (Kornstein, Summit, 2000). This difference is accounted for by the superiority of the SSRIs in pre- menopausal but not postmenopausal women. There is also evidence that hormone replacement therapy in postmenopausal women restores this preferential re- sponse to the SSRIs (Thase, 2001).

Psychotherapy and antidepressants have been found to be equally effective for mild to moderate depression in a number of studies in which the two were directly com- pared (Elkin et al., 1989).

HORMONAL TREATMENTS FOR DEPRESSION
Epidemiological studies show increased risk for depres- sion in females at the time of puberty and evidence of increased mood lability in relation to menstruation, perimenopause, and childbirth (Epperson, Wisner, & Yamamoto, 1999). Despite the face validity of estrogen as a factor in mood modulation in women, until recently few studies have examined its utility as a monotherapy or as an adjunct to other treatments. Evidence, however, is emerging of its possible utility as a treatment in

perimenopausal and postpartum depression (Gregoire, Kumar, Everitt, Henderson, & Studd, 1996).
In addition to estrogens, Fabian and Kroboth (Summit, 2000) reviewed evidence for the role of other hormones in the treatment of depression in women. They found a small literature on the mood modulatory effects of progesterone or its metabolites on central nervous system (CNS) activity. Studies (Majewska, Harrison, Schwartz, Barker, & Paul, 1986; McAuley, Reynolds, Stiff, & Kroboth, 1991) have indicated that binding of proges- terone metabolites at the gamma aminobutyric acid
(GABA) receptor complex, a locus on neurons respon- sible for CNS inhibitory effects, produced an anxiolytic hypnotic effect similar to that experienced from adminis- tration of benzodiazepines.

Fabian and Kroboth also identified a few studies on the mood elevating influence of an adrenal steroid, dehydroepiandrosterone (DHEA), and its sulfated conjugate, DHEA-S. There are both age and sex differ- ences in levels of DHEA-S in that levels decline with age, and concentrations of DHEA-S in women are only about 50% to 70% of those in men. Despite some controversy regarding the exact role of endogenous DHEA in depression, several studies have demonstrated beneficial effects of DHEA administration to women on mood (Morales, Nolan, Nelson, & Yen, 1994), well being (Wolf, Kudielka, Hellhammer, & Kirschbaum, 1998; Arlt et al., 1999), and as either monotherapy or adjunctive treatment for dysthymia (Bloch, Schmidt, Danaceau, Adams, & Rubinow, 1999), and depression (Wolkowitz et al., 1999). Though encouraging, the beneficial effects of DHEA administration must be interpreted with caution until further research has been conducted. Additional studies are needed to evaluate rigorously the potential

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antidepressant effects of DHEA and to identify which patient populations will benefit most from administration of these hormones. The relative importance of absolute concentrations versus diurnal variations and whether or not there is a therapeutic range for DHEA and/or DHEA-S is yet to be determined.

ALTERNATIVE TREATMENTS FOR DEPRESSION
Depression is among the most common conditions for which alternative treatments are sought. Approximately 30% to 35% of individuals completing research proto- cols involving antidepressant drugs do not respond to treatment (Keller, Gelenberg, & Hirschfeld, 1998; Keller et al., 2000). Many patients terminate prematurely because of adverse effects or intolerance. Reasons for discontinuing psychotherapy differ from those for discontinuing medication; nonetheless, discontinuation rates are similar (Keller et al., 2000). For other persons with depression, treatments may be inaccessible or too expensive. Therefore, many individuals turn to alternative remedies. Alternative treatments in common use include meditation and relaxation, exercise, acupuncture, and herbal agents (Manber, Summit, 2000).

Stress management, in the form of meditation, relaxation and massage, is the most common alternative treatment sought by individuals with symptoms of depression (Eisenberg et al., 1998). However, there are few random- ized trials testing the efficacy of these methods. Thera- peutic massage has short-term effects on depressive symptoms, but there is no evidence that it has longer- term benefits or that it helps those with DSM-IV major

depression. Similarly, with few exceptions, evidence for meditation and relaxation in the treatment of depression is limited.

Exercise is commonly viewed as an antidepressant ,and many individuals engaging particularly in aerobic exercise report an enhanced feeling of well-being. Research indicates that exercise elevates mood and reduces other depressive symptoms (North, McCullagh, & Tran, 1990), but there is little evidence for the efficacy of exercise in clinical major depression. The limited evidence available in clinical depression indicates smaller effect sizes than those observed for standard antidepressant treatments. Motivation and adherence issues, inherent to the depres- sive illness, often hinder the utility of exercise as a single intervention for depression. This limitation may be overcome by integrating exercise with psychotherapy. Some evidence supports the efficacy of acupuncture in depression. In China, acupuncture is commonly used to treat what is diagnosed as “neurasthenia,” a condition reported to be present in about 50% of psychiatric outpatients in that country. However, empirical evidence of its utility in the clinical management of major depres- sive episodes is limited, with only one randomized double-blind pilot study supporting its efficacy as a single modality (Allen, Schnyer, & Hitt, 1998) and another randomized controlled study concluding that it does not improve standard clinical management with a tetracyclic antidepressant medication (Roschke, et al., 2000). A federally funded study is currently underway to test the efficacy of acupuncture in a controlled trial (John Allen, Primary Investigator; Study No. NCT00010517).

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St. John’s Wort is the most commonly used herbal treatment for outpatient depression. The evidence for its efficacy appears moderate, based on European literature and two randomized control trials (Harrer, Schmidt, Kuhn, & A. B., 2000; Philipp, Kohnen, & Hiller, 1999).
A meta-analysis (Linde, 1996) and a recent selective review (Gaster & Holroyd, 2000) found St. John’s wort to be superior to placebo controls, and comparable to standard tricyclic antidepressants. However, the latter study noted several major methodological limitations in the studies reviewed. Two large scale multi-site double- blind randomized control trials completed since these meta-analyses/reviews found conflicting results. The first (Philipp, Kohnen, & Hillier, 1999), found that hypericum extract (one of the variety of compounds contained in St. John’s wort) was superior to placcebo and statistically indistinguishable from imipramine. The other study (Harrer, 2000) found no difference between St. John’s wort extract and placebo. Consequently, the published literature to date regarding the efficacy of St. John’s Wort in the treatment of major depression is inconclusive and awaits additional empirical evidence.

The popularity of alternative treatments, many of which are untested or not sufficiently tested, creates an urgent need for research examining efficacy, effectiveness, and safety of these methods and agents. Optimal treatment strategies, including dosing, frequency, and duration of single modality or combination treatments, require attention. Moreover, research ought to pay special attention to efficacy, safety, and other implementation issues that are specific to women across the life span, because women are more frequent users of alternative therapies than men and because use of alternative treatments during pregnancy, lactation, and concomitant

hormone replacement regimens introduce additional treatment challenges.

PREVENTIVE INTERVENTIONS FOR DEPRESSION
Treatment interventions alone may not be sufficient to reduce the high prevalence of major depression in women. Some experts recommend a concerted effort to develop, evaluate, and implement interventions that will prevent the onset of major depressive episodes (Muñoz & Ying, 1993). Munoz and colleagues (Summit, 2000) suggest prioritizing three groups of women in whom prevention would have a major public health impact: (a) adolescent females; (b) women about to become moth- ers; and (c) women at risk for substance abuse problems, especially smoking.

Epidemiological and prospective studies have established that the risk for depression increases for many women entering adolescence and suggest that prevention efforts during these years are likely to yield an important payoff. In addition, the negative consequences of having an antenatal and postpartum depression have been well- documented (e.g., Field, 1995), indicating the need for prevention of depression during those periods. Because most pregnant women have access to health care, screening for depression in health care settings has considerable promise.

Women using or at risk for abusing substances also require prevention interventions for depression as well as substance abuse interventions. Among the substances linked to depression is nicotine. Depression can increase the risk for smoking, and vice versa (Choi, Patten, Gillin, Kaplan, & Pierce, 1997; Rao, Daley, & Hammen, 2000).

Summit on Women and Depression

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Smokers with a history of depression have greater dependency on nicotine (Breslau, 1995), more difficulty quitting smoking (Abrams, Monti, Pinto, & Elder, 1987), and higher relapse rates following initial smoking absti- nence (Anda et al., 1990; Kinnunen, Doherty, Militello, & Garvey, 1996) than never depressed smokers. Recent evidence suggests that depression and depressive symp- toms affect success with smoking cessation in women more so than men (Blake, Klepp, Pechacek, & Folsom, 1989; Borrelli et al., 1999; Royce, Corbett, Sorensen, & Ockene, 1997; Wetter et al., 1998). Because of the high rate of depression among smokers and the importance of managing depressive symptoms during initial smoking abstinence, smoking cessation interventions targeting depression have yielded up to twice the quit rate of interventions without this component (Hall et al., 1998; Muñoz, Marin, Posner, & Pérez-Stable, 1997; Prochaska, 2000).

Future depression prevention research should target women across the life span. The identification of groups at imminent high risk for major depressive episodes may be effective in increasing the utility of preventive inter- ventions. Studies should explicitly observe effects on collateral public health problems, such as smoking, other substance abuse, unplanned pregnancies, marital prob- lems, school performance, job performance, and physical health. These preventive interventions may need to address multiple outcomes, including healthy develop- ment as well as prevention of psychopathology, and involve the collaboration with community and multiple systems settings, in order to provide the maximal benefit for participants.