Menopausal Medicine: For clinicians who provide care for women

Is the risk of depression greater during the menopause?

Behavioral Endocrinology Branch, National Institute of Mental Health, NIH, DHHS Bethesda, Maryland

Department of Psychiatry, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina

This work was written as part of Drs Schmidt and Harsh’s official duties as government employees. The views expressed in this article do not necessarily represent the views of the NIMH, NIH, DHHS, or the United States government.

Introduction

This review focuses on the relationship between the onset of depression and events surrounding the menopause transition. First, background information will be provided on depressive disorders, including their prevalence, impact, diagnostic methodologies, course, and treatment outcome. We then review the current literature that relates to the following three questions:

1) Is there an increased risk of depression during the menopause transition?

2) Are there identifiable risk factors for the onset of depression during the menopause transition?

3) Is depression during the menopause transition associated with abnormalities of ovarian hormone secretion?

Background

Prevalence of depression

Major and minor depression are prevalent forms of depressive illness. Major depression has an estimated lifetime prevalence of approximately 20% in women and affects women twice as often as men.¹ The lifetime prevalence of minor depression is estimated to be comparable, if not greater than, that of major depression.² There is considerable overlap between the clinical characteristics of major and minor depressions of moderate severity including family history, course (ie, both major and minor depressions occur in the same individual over their lifetime),³ as well as several biological characteristics. Indeed, minor depressions not only contribute to a substantial disability on their own but also increase a person’s risk for developing more severe forms of depressive illness. Finally, both major and minor depressions can present as mood disorders during reproductive endocrine transitions, such as the postpartum period and the menopause transition.

Impact of depression

The World Health Organization has determined that major depression is a leading source of years of life lived with disability worldwide⁴ and is associated with multiple forms of disability involving social function, work productivity, physical health, and emotional functioning,⁵ as well as higher rates of marital dissatisfaction and divorce. The estimated annual expenditure for major depression in the United States is $83 billion in workplace, mortality, and direct treatment costs.⁶

In addition to the functional disability that is directly attributed to major and minor depressions, adverse medical sequelae of depression have been identified, including increased risks of cardiovascular disease, Alzheimer disease, premature ovarian failure, osteoporosis, and the metabolic syndrome. Depression might also represent a modifiable risk factor for the onset of some of these medical conditions. For example, if depression exists as a comorbid condition, it will increase the morbidity and mortality of several medical illnesses including heart disease.⁷ Finally, several studies have identified a substantially increased health care utilization cost associated with a variety of medical conditions when they are comorbid with depression.

Criteria: Diagnosis of depression

Depression is both underdiagnosed and undertreated. Standardized criteria for diagnosing both major and minor depression have been developed to distinguish depressive symptoms (ie, sadness), which may be multidetermined, from depressive syndromes (ie, major or minor depression), which have particular familial patterns, biological features, and treatment response characteristics. The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV)⁸ specifies selected core symptoms of depression (five for major depression and three for minor depression), which must be present for at least two weeks, be associated with clinically significant distress or impairment in social or occupational functioning, and not be caused by medications, a medical condition (eg, hypothyroidism), or bereavement (TABLE 1). Structured diagnostic interviews are employed in research studies to establish the presence of a diagnosis of depression (eg, SCID⁹), and modifications of these diagnostic instruments have been developed to screen patients for the presence of depression in medical settings. For example, recent studies employing the PRIME-MD¹⁰ as a screening instrument identified rates of mood disorder in women of approximately 31% in primary care clinics and 13% in gynecologic clinics.

In addition to the symptoms of depressive illness listed in TABLE 1, a considerable proportion of depressed outpatients experience somatic symptoms including fatigue, generalized musculoskeletal pain, and weakness. Multiple somatic complaints have been observed in up to 50% of depressed men and women, with a greater proportion of depressed women reporting somatic complaints than depressed men.¹¹ Somatic symptoms occurring in the context of a depressive illness are clinically important since their presence could delay the diagnosis of depression, delay appropriate treatment, and may be associated with differential treatment response characteristics. Clinicians once believed that somatic symptoms caused depression; however, these symptoms also may be a manifestation of, rather than a cause of, depression.¹¹ Thus, depression (even minor depression) accompanied by somatic symptoms, as may occur in women who develop depression during the menopause transition and who also report hot flushes, should not be presumed to reflect an “appropriate” reaction to disturbing somatic symptoms.

DSM-IV Core Symptoms of Major and Minor Depressive Episodes

Course and treatment of depression

The occurrence of an episode of depression will increase an individual’s risk of developing recurrent episodes of depression. Thus, appropriate treatment could reduce future recurrences. Estimates of the length of a major depressive episode range from an average of four to eight months,¹² with one study reporting that 50% of episodes of major depression remit within three months, regardless of treatment.¹² However, in approximately 20% of patients with major depression, the episodes become chronic (ie, the duration of illness exceeds two years).¹²

Treatments for both major and minor depression include psychotherapy (time-limited focused cognitive or interpersonal therapy), antidepressant medications, and other somatic therapies (eg, electroconvulsive therapy for severe major depression).

In contrast to public perceptions that antidepressants are over-prescribed, recent epidemiologic evidence suggests that only 43% of people with depression in the US seek and receive treatment, and only 20% receive minimally adequate treatment (defined as either receiving an appropriate antidepressant agent for at least two months plus at least four visits to any medical doctor, or psychotherapy involving at least eight visits to a health care professional lasting an average of at least 30 minutes).¹³ Indeed, patients with major depression are nearly as likely to receive care from a non-health care provider (eg, religious or spiritual advisor), who generally would be less able to administer standard effective therapies than would a psychiatrist. The standard of practice for treatment of depression is full symptom remission with restoration of premorbid function; however, remission rates after a first antidepressant trial are low. In The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, persons receiving first line selective serotonin reuptake inhibitors (SSRIs) had a remission rate of only 28% to 33% and a response rate (defined as a 50% reduction in pretreatment symptoms of depression) of 47%.¹⁴

Does risk of depression increase during the menopause transition?

The majority of women do not develop depression during the menopause transition. Nonetheless, four community-based studies have documented that some women are at an increased risk of depression during the menopause transition.^15-19 First, the Study of Women’s Health Across the Nation (SWAN) observed, in an initial cross-sectional survey, that women in the menopause transition reported significantly more “psychological distress” than either premenopausal or postmenopausal women (defined by self-reported menstrual cycle status). Second, a longitudinal study by Freeman et al.¹⁶ found an increased risk of clinically significant depression (defined by elevated CES-D scale scores and the PRIME MD¹⁰) during the menopause transition compared with the premenopause or postmenopause, and this association remained after adjusting for several variables, including past history of depression, severe premenstrual syndrome, poor sleep, and hot flushes.¹⁶ Third, in a longitudinal study of women who had no history of depression, Cohen et al observed that the incidence of new-onset depression (defined by SCID-IV) in the menopause transition was nearly twice that observed in the premenopause (adjusted OR=1.8).¹⁷ Finally, in a similar study of women with no history of prior depression demonstrated, a 2½ times greater rate of new-onset depression during the menopause transition, compared with women who remained premenopausal.¹⁸ These data notwithstanding, the majority of women in these studies remained asymptomatic throughout the perimenopause.

In summary, epidemiological studies have documented that the majority of perimenopausal and post-menopausal women do not develop depression. However, community-and clinic-based surveys suggest that the menopause transition is relevant to the development of affective disorders and that a substantial number of perimenopausal women experience clinically significant depression.

Are there identifiable risk factors for the onset of depression during the menopause transition?

Several epidemiologic studies have surveyed the presence of depressive symptoms in women at midlife and have identified several variables associated with depression, including the following:²⁰

• Previous episodes of depression

• Longer duration of the menopause transition (defined by menstrual cycle irregularity)

• Presence of hot flushes

• Retrospective reports of premenstrual dysphoria (PMD) or post-partum depression (PPD)

• Stressful life circumstances

• Complaints of poor health

• History of smoking

• Disturbed sleep

• Reduced parity

• Absence of partner

Most of these factors also are associated with an increased risk of developing depression during other stages of life (ie, past history of depression, stressful life events, reports of PMD or PPD, smoking, and sleep disturbance) and, therefore, are not specific to depression during the menopause transition. 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.

Depression during the menopause transition could be caused by the accompanying endocrine or physiologic events (eg, vasomotor symptoms). However, neither of these phenomena would explain why depression occurs in only some women and, therefore, the risk of depression related to these events is not uniform. Alternatively, the onset of depression could reflect a vulnerability to developing recurrent depression in women with a past depression or in those women with a past reproductive endocrine-related depression (eg, PMD, PPD). The relationship between depression during the menopause transition and these potential risk factors has been examined in several recent studies. First, as stated earlier, 2 community-based longitudinal studies have prospectively followed women with no prior history of depression and observed risks of depression that are approximately 2- to 2½-fold greater during the menopause transition compared with the premenopause. Similarly, in a longitudinal study by Schmidt et al,²¹ a similar percentage of incident depressions occurred in women with no prior history of depression (6/20), as in those with a past history (3/9) (small sample size notwithstanding). Nor did the three women with histories of PPD develop depression during the menopause transition, suggesting that the presence of one episode of a reproductive endocrine-related mood disorder (ie, PPD) does not predict the uniform occurrence of depression during a subsequent hormonal transition (ie, the menopause transition). Similarly, a cross-sectional study found no association between the onset of major or minor depression during the puerperium and the development of depression during the menopause transition.²² Schmidt et al²¹ used daily symptom ratings to prospectively evaluate self reports of the onset of premenstrual dysphoria in women entering the menopause transition and found that PMD rarely accompanied depression in these women. Nonetheless, recent cross-sectional data²³ suggest a higher than expected co-occurrence of prospectively confirmed PMD and perimenopausal depression. In this study, women who developed depression during the menopause transition (n=70) (and who were not amenorrheic) were significantly more likely to meet criteria for PMD than an asymptomatic matched comparison group (n=35) (21% compared with 3%). Thus, PMD is neither a uniform accompaniment nor a necessary antecedent of depression during the menopause transition; however, the presence of PMD could be a risk factor for the development of depression during the menopause transition as suggested by Freeman et al.¹⁸

Hot flushes often accompany the menopause transition and are associated with depression during this phase of life. Consistent with the domino or cascade theory, hot flushes are hypothesized to disturb sleep and, therefore, contribute to daytime mood symptoms. However, as stated earlier, only some women develop depression during the menopause transition, and not all of those who do experience hot flushes. Indeed, data from both cross-sectional²² and longitudinal studies^16-18 demonstrate that hot flushes and the menopause transition are independent risk factors for depression. Thus, in contrast to the “domino” or “cascade” hypothesis, existing evidence suggests that hot flushes appear to be neither a necessary nor a sufficient accompaniment of depression during the menopause transition, and depression cannot be dismissed as epiphenomenal to hot flushes.

Finally, stressful life events are a frequent accompaniment of depression and, in some depressed subjects, may contribute to its onset. Stressful events have been reported in association with depressive symptoms at midlife as well as in women with major and minor depression during the menopause transition.^17,24 However, women with depression during the menopause transition do not report a greater number of exit events (ie, personal losses) than asymptomatic perimenopausal women.²⁴ Thus, although stressful events are an accompaniment of both midlife depression and depression during the menopause transition, there is no evidence to support the concept that depression at this time in a woman’s life is caused by the “empty nest” syndrome.

In summary, many factors accompany depression during the menopause transition; however, none is uniformly present in these depressed women. Our inability to identify predictors of the onset of depression may reflect the small sample sizes of depressed women examined. Future efforts will clarify whether specific factors exist that predict or increase the risk of developing depression during the menopause transition, independent of those factors that increase a woman’s risk for depression at other times across the life cycle.

Is there an association with abnormalities of ovarian hormone secretion?

The stage of the menopause transition during which depressions occur could suggest a pathophysiologic role for hormonal events surrounding the final menstrual period. For example, the late menopause transition is characterized by estradiol “withdrawal” relative to either the later postmenopause or the early perimenopause.²⁵ In a prospective study, we followed a group of asymptomatic premenopausal women until 6 to 12 months after their last menstrual period and observed a clustering of both new-onset and recurrent depressive episodes during the 24 months surrounding the final menstrual period, relative to the 31 years used as a comparison period. Thus, the timing of the observed depressive episodes suggests an endocrine trigger that is related to the later stages of reproductive aging (ie, estradiol withdrawal and/or recent onset of prolonged hypogonadism).

No consistent abnormalities of basal ovarian or adrenal hormones have been identified in women with perimenopausal depression compared with asymptomatic controls. Thus, women with depression during the menopause transition are not distinguished from non-depressed perimenopausal women by being more estrogen deficient. Nonetheless, the changes in pituitary-ovarian function characteristic of the menopause transition appear to be relevant to the onset of depression in some women, as mood symptoms may change concurrently with FSH levels²⁶ and estradiol therapy (ET) improves mood symptoms in perimenopausal depressed women.^27,28

In a longitudinal study, we observed several women with depression who presented to the NIMH midlife clinic and whose plasma FSH levels declined over six weeks, concurrent with spontaneous improvements in mood.²⁶ We found that incremental declines in FSH levels paralleled improvements in depression symptom scores in this group of women whose initial symptom scores decreased by at least 50% during this six-week period.

An association between the endocrine events related to the menopause transition and the onset of depression is also indirectly supported by reports of the mood-enhancing effects of estradiol in depressed perimenopausal women. Recently, three double-blind, placebo-controlled trials examined the efficacy of ET in perimenopausal and postmenopausal women with major and minor depressions.^27-29 First, the therapeutic efficacy of estradiol (ie, 17 beta estradiol alone) was demonstrated²⁷ by significantly decreased depression rating scale scores in women after three weeks of estradiol compared with baseline scores and compared with scores in the women receiving placebo. We observed a full or partial therapeutic response in 80% of perimenopausal women on estradiol compared with 22% of those on placebo,²⁷ consistent with the observed effect size (.69) in a meta-analysis of studies examining estrogen’s effects on mood.³⁰ These findings were replicated in a separate double-blind, randomized, controlled trial by Soares et al.²⁸ However, a similar trial in older depressed women, who were 5-10 years postmenopausal, failed to observe a significant antidepressant effect of ET compared with placebo.²⁹

In addition to trials of ET as monotherapy in depressed perimenopausal and postmenopausal women, several studies evaluated ET as an augmentation strategy.³¹ The best evidence to date (albeit limited to open trials) supports ET’s efficacy used in combination with SSRIs in perimenopausal women only.^32,33

Finally, the evidence that younger perimenopausal women respond to ET but that older postmenopausal depressed women do not, suggests that the mood disorders occurring in the menopause transition are caused by changes in hormones (eg, withdrawal or fluctuations) rather than prolonged ovarian steroid deficiency.

Summary

For many years, the nature of the relationship between the menopause and depression has been controversial. Recent longitudinal studies focusing on the menopause transition provide more consistent evidence that better defines this relationship. First, the majority of women do not develop a depressive disorder during the menopause transition or early postmenopause. Second, a subgroup of women are at an increased risk of developing depression during the menopause transition. For some women, these depressions occur for the first time in their lives. Finally, at present, few if any characteristics predict those women who are at risk of developing depression during the menopause transition. Future studies should focus on documenting the number of women who are at risk and the markers of susceptibility for developing depression during the menopause transition. Moreover, increasing evidence documenting the safety of ET in symptomatic perimenopausal women also suggests that a better understanding of both the potential risks and therapeutic benefits of ET in depression during the menopause transition could lead to a viable alternative therapy to traditional antidepressants.

Sexuality, Reproduction & Menopause ©2008 Quadrant HealthCom Inc.