Mood, depression, and reproductive hormones in the menopausal transition

Transcription

1 The American Journal of Medicine (2005) Vol 118 (12B), 54S 58S Mood, depression, and reproductive hormones in the menopausal transition Peter J. Schmidt, MD Behavioral Endocrinology Branch, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, Maryland, USA. KEYWORDS: Depression; Estradiol; Mood; Ovarian aging; Perimenopause This article focuses on a review of evidence related to the following 3 questions: (1) Does depression appear during the menopausal transition? (2) What factors influence the risk for depression during the menopausal transition? (3) Do age-related alterations in ovarian hormone secretion contribute to the development of depression in some middle-aged women? A brief background is provided on the importance of depressive disorders. Methodologic issues that have compromised previous studies investigating the possible relation between the menopausal transition and depression are discussed. Evidence is presented that suggests a relation between the perimenopause (the interval between the early menopausal transition and 1 year after the last menses), but not the postmenopause, and the onset of depressive illness. Finally, studies are reviewed that suggest an association between alterations in ovarian function and depression, including several randomized placebo-controlled trials examining the antidepressant efficacy of estradiol in depressed perimenopausal and postmenopausal women Elsevier Inc. All rights reserved. Major and minor depressions are the 2 most prevalent forms of acute depressive illness. Major depression has an estimated lifetime prevalence of 17% and affects approximately twice as many women as men. 1 The exact prevalence of minor depression is unclear because of differences in the diagnostic criteria used across studies; however, its Requests for reprints should be addressed to Peter J. Schmidt, MD, National Institute of Mental Health, Building 10-CRC, Room (SE), 10 Center Drive MSC 1276, Bethesda, Maryland The opinions offered at the National Institutes of Health (NIH) Stateof-the-Science Conference on Management of Menopause-Related Symptoms and published herein are not necessarily those of the National Institute on Aging (NIA) and the Office of Medical Applications of Research (OMAR) or any of the cosponsoring institutes, offices, or centers of the NIH. Although the NIA and OMAR organized this meeting, this article is not intended as a statement of Federal guidelines or policy. Publication of the online supplement was made possible by funding from the NIA and the National Center for Complementary and Alternative Medicine of the NIH, US Department of Health & Human Services. address: peterschmidt@mail.nih.gov. prevalence is thought to approximate that of major depression. 2 Recently, major depression was identified as a leading source of disease-related disability in developed countries. 3 Minor depressions, by definition, have fewer and less severe symptoms than do major depressions. Nonetheless, they are associated with disability comparable to that of major depression. 4 Treatments for both major and minor depression include psychotherapy (time-limited focused cognitive or interpersonal therapy), antidepressant medications, and other somatic therapies (e.g., electroconvulsive therapy for severe major depression). Reported response rates to therapy in major depression vary across studies; however, approximately 50% of ambulatory subjects with major depression will respond to treatment with either time-limited psychotherapy or antidepressant medication. 5 Nonresponders continue to experience symptoms and require additional treatment, which may include adjunctive therapy or an alternative treatment strategy. It is /$ -see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjmed

2 Schmidt Mood, depression, and reproductive hormones in the menopausal transition 55S noteworthy that 1 study reported that 50% of episodes of major depression remit within 3 months regardless of treatment. 6 Methodologic problems in previous studies of the relation between the menopausal transition and depression include the manner in which both reproductive status (see the article by Sherman 7 in this supplement) and mood syndromes were defined and characterized. Only limited confidence can be placed in the conclusions of studies that used neither endocrinologically meaningful evaluations of ovarian aging nor standardized criteria for measuring the presence of depression. Depressive symptoms differ from depressive syndromes in their instruments of detection, their duration, and their disease impact. In general, a structured diagnostic interview (e.g., the structured clinical interview for the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition 8 ) is the most reliable method for assessing the presence or past occurrence of a major or minor depression. In contrast, the cross-sectional scales used in many studies measure the severity of depressive-like symptoms but do not assess either the longitudinal persistence of a core group of depressive symptoms or the level of functional impairment, both important constituents of a depressive syndrome. Additionally, cross-sectional rating scales, such as the Center for Epidemiological Studies Depression scale (CES-D), 9 have restricted sampling intervals, consisting of a 1- to 2-week window before the date the scale is completed. Thus, if 50% of major depressive episodes have remitted within 3 months, as reported previously, 6 then the administration of a cross-sectional rating on a yearly basis, for example, could not reliably assess the occurrence of depression during the previous year. Additionally, some commonly used scales have reported sensitivity rates of only 75%. 9 Finally, in addition to using standardized psychiatric diagnostic interviews for establishing the presence of current and past episodes of depression, the type of mood syndrome should be defined. For example, both major and minor depressions exist, yet many studies focus only on the presence of major depression, with the exclusion of minor depression justified on the basis of its lesser significance. However, this decision to exclude minor depression may no longer be justified, given recent evidence documenting the substantial disability associated with minor depressions. 4 Similarly, a cross-sectional rating scale cut-off score of 16 is used as a proxy for the presence of clinically significant depressive symptoms and as a selection criterion for both trials of antidepressant medications and some epidemiologic studies of midlife depression However, clinical significance also has been identified for considerably lower cut-off scores on these same cross-sectional ratings. For example, Beck Depression Inventory (BDI) cut-off scores of 10 (below the customary cut-off of 16) are associated with significantly increased mortality in patients with heart disease. 13 What is the evidence of an association between the menopausal transition and depression? The majority of women do not develop depression during the menopausal transition; therefore, the perimenopause is not uniformly associated with changes in a woman s mood. 11,12,14 17 In fact, epidemiologic studies examining sex- and age-related differences in the 6-month to 1-year prevalence of major depression reported no increased prevalence of major depression in women at midlife (age range, approximately 45 to 55 years). 1 Nonetheless, although the postmenopause is not associated with an increased risk for developing depression, 11,15,18 depressive symptoms have been observed more frequently in some perimenopausal women compared with postmenopausal women in several 12,14,17,19 (but not all 11,15,16 ) longitudinal, community-based studies as well as in women attending gynecology clinics. 20 Several other community-based studies reported the absence of an association between depressive symptoms and the perimenopause; these studies, however, did identify a significant association between perimenopausal symptoms (e.g., hot flashes and menstrual disturbances) and depressive symptoms, 18,21 23 leaving unanswered the question of whether the coincidence of depressive symptoms and the perimenopause is truly irrelevant. Similarly, community-based surveys of the prevalence of major or minor depression (i.e., syndromes) also suggest that the menopausal transition is a time of increased vulnerability for depression to develop. The Study of Women s Health Across the Nation (SWAN) 24 used a measure of psychological distress as a proxy for the syndrome of depression by requiring that core depressive symptoms (sadness, anxiety, and irritability) persist for 2 weeks. The SWAN initial cross-sectional survey observed that perimenopausal women reported significantly more psychological distress than either premenopausal or postmenopausal women (defined by self-reported menstrual cycle status). 24 A recent study found results similar to those of SWAN. Freeman and colleagues 10 identified an increased risk for significant depression (defined by elevated CES-D scores and the Primary Care Evaluation of Mental Disorders [PRIME-MD] 25 ) during the perimenopause compared with the premenopause or postmenopause. Moreover, this association remained after adjusting for several variables, including past history of depression, severe premenstrual syndrome, poor sleep, and hot flashes. Levels of depression were increased relative to those found in the postmenopausal women; however, only 3% of the sample (approximately 10 women) were followed through to the postmenopausal phase. In a recent prospective observational study, asymptomatic premenopausal (defined by self-report of regular menstrual cycle function with a cycle length between 22 and 35 days, and confirmed prospectively by a daily diary completed during a 3-month screening period) women were followed until 6 to 12 months after their final

3 56S The American Journal of Medicine, Vol 118 (12B), December 19, 2005 menstrual period (FMP) to determine the timing of onsets of mood disorders relative to specific stages of the menopausal transition. A 14-fold increase in the rate of onset of depression was observed during the 12 months before and the 12 months after the FMP, relative to the 31-year period of risk (defined on the basis of the maximum number of years before the FMP at which time the first depression occurred in our subjects) used as a comparison time period, suggesting an increased risk of depression in women during both the late menopausal transition and the early postmenopause relative to the premenopause. Consistent with communitybased studies, the majority of the women in this study remained asymptomatic throughout the perimenopause. The small sample size and observational design of this study prevents conclusions about whether the perimenopause is a risk factor for depression in women. Nonetheless, these data suggest that events surrounding the FMP may predispose some women to develop depression. Although several factors can precipitate depression in these women, endocrine events are suggested by the stage of the perimenopause (i.e., late menopausal transition and first year postmenopause) during which depressions appeared. The late menopausal transition is characterized by more prolonged hypogonadism than is the early menopausal transition, during which estradiol secretion may be increased. Indeed, the late menopausal transition and the first year postmenopause may represent the phases of the menopausal transition most correctly characterized by estradiol withdrawal compared with the postmenopause and early perimenopause. 27 Thus, the timing of appearance of the depression episodes observed 26 suggests an endocrine mechanism related to the menopausal transition/perimenopause (estradiol withdrawal and/or recent onset of hypogonadism) in the pathophysiology of perimenopausal depression. What factors influence the risk for depression during the menopausal transition? As described in the previous section, several epidemiologic studies have surveyed the presence of depressive symptoms in women at midlife and identified rates of depressive symptoms ranging from 8% to 40%. 18,28 However, the samples in these studies consisted of women at midlife who were in different phases of reproductive aging, and depressive symptoms often were assessed independently of the presence of clinically meaningful depressive syndromes. These findings, therefore, are not directly translatable into either prevalence figures or risk factors for depressive syndromes associated with the reproductive endocrine changes characterizing the menopausal transition. Nonetheless, these studies in women who become depressed during midlife have identified several variables associated with risk for depression, including the following: previous episodes of depression, 29 longer duration of the perimenopause (defined by menstrual cycle irregularity), 18 presence of hot flashes, 18,19 retrospective reports of premenstrual depressive symptoms or postpartum depression, 29 stressful life circumstances, 11,23 complaints of poor health, history of smoking, disturbed sleep, reduced parity, and absence of a partner. Many of these factors also are associated with an increased risk for developing depression during other stages of life (i.e., past history of depression, stressful life events, reports of premenstrual or postpartum depression, smoking, and sleep disturbance) and therefore are not specific to depression during the menopausal transition. As discussed earlier, recent studies have identified the menopausal transition as an independent risk factor for depression at midlife in women. 10,24,28 These findings suggest that in some women, ovarian aging and the events surrounding the menopausal transition increase vulnerability to depression. Finally, several proposed risk factors such as insomnia, increased stress, and complaints of poor health may be symptoms of, but are not necessarily a cause of, a current depressive episode. In summary, several factors including perimenopausal reproductive status are associated with developing depression at midlife. Indeed, many of these same factors are frequent accompaniments of perimenopausal depression; however, none is uniformly present in depressed women. As a caveat, however, the inability to identify predictors of the onset of depression may reflect the small sample sizes of depressed perimenopausal women examined. Future studies will clarify whether specific factors exist that predict or increase the risk of developing depression during the menopausal transition, independent of those factors that increase a woman s risk for depression at midlife or at other times across the life cycle. What is the evidence that age-related alterations in ovarian hormone secretion contribute to the development of depression in some middle-aged women? There have been no differences in plasma levels of reproductive or adrenal (i.e., dehydroepiandrosterone) hormones identified consistently in women with perimenopausal depression compared with control subjects. Thus, depression during the perimenopause is not distinguished by abnormally low plasma levels of estrogens or androgens. 30 However, 3 double-blind placebo-controlled trials using similar methodologies and identical preparations of estrogen (i.e., 17 -estradiol), have examined the efficacy of estradiol in perimenopausal and postmenopausal women meeting standardized criteria for major and minor depressions First, the therapeutic efficacy of 17 -estradiol was examined in a double-blind placebo-controlled trial in 34 perimenopausal women (i.e., late menopausal transition and first year postmenopause, operationally defined by selfreport of 6 months of menstrual cycle irregularity but not 1 year of amenorrhea, and elevated plasma follicle-stimulating hormone levels) who also met standardized diagnostic criteria for major and minor depression. 31 After 3 weeks

4 Schmidt Mood, depression, and reproductive hormones in the menopausal transition 57S of estradiol therapy, depression rating scale scores were significantly decreased compared with baseline scores and significantly lower than scores in the women receiving placebo. Moreover, those women initially randomized to placebo showed a similarly significant decrease in depression ratings after 3 weeks of estradiol administration. A full or partial therapeutic response was seen in 80% of subjects taking estradiol and in 22% of those receiving placebo, consistent with the observed effect in a meta-analysis of studies examining the effects of estrogen on mood. 34 The therapeutic response to estrogen was observed in both major and minor depressions as well as in women with and without hot flashes. Finally, neither baseline nor posttreatment estradiol levels predicted the observed therapeutic response. These data suggest that the effect of estrogen on depression is not solely a product of an ability to reduce the distress of hot flashes, consistent with the findings of recent community-based cross-sectional surveys. 24 These findings also are consistent with data from Montgomery and coworkers 35 and Saletu and colleagues 36 suggesting the beneficial effects of estradiol on mood in perimenopausal women reporting depressive symptoms. A randomized, double-blind, placebo-controlled study by Soares and associates 32 confirmed the observations of Schmidt and colleagues. 31 Soares and associates 32 reported a significant beneficial effect of estradiol therapy compared with placebo in women with perimenopause-related major depression (defined by the PRIME-MD 25 ) and, additionally, found that baseline plasma estradiol levels did not predict response to estrogen treatment. In contrast, using a study design similar to that in studies of perimenopausal women, 31,32 a recent investigation in depressed women who were 5 to 10 years postmenopausal failed to observe a significant antidepressant effect of estradiol relative to placebo. 33 Estrogen s antidepressant efficacy in depressed women in the perimenopause but not in those who are 5 to 10 years postmenopausal suggests that mood disorders occurring in perimenopausal women are caused by changes in hormones (e.g., withdrawal or fluctuations) rather than prolonged ovarian steroid deficiency. Nonetheless, such a conclusion is clearly premature and must await confirmation of the antidepressant efficacy of estradiol in larger clinical trials. Summary Recent evidence from prospective epidemiologic studies suggests that for some women the endocrine events (e.g., alterations in gonadotropin secretion, decreased estradiol secretion) during the perimenopause are associated with the onset of depression. Additionally, although perimenopausal depression is not characterized by abnormalities of basal ovarian hormone secretion, 2 randomized controlled trials reported therapeutic benefits of estradiol in perimenopausal depressed individuals. The potential importance of changes in reproductive endocrine function in the pathophysiology of perimenopausal depression is suggested by the lack of antidepressant action of estradiol therapy in postmenopausal depressed women (thus arguing against a nonspecific psychotropic effect of estradiol). Future studies must identify the factors underlying the differences between those women who remain asymptomatic during the menopausal transition and those who develop depression. Acknowledgment The author acknowledges the thoughtful contributions to the manuscript provided by Dr. David R. Rubinow. References 1. Kessler RC, McGonagle KA, Zhao S, et al. 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