Dr. Kornstein is professor of Psychiatry and Obstetrics/Gynecology, executive director of the Institute for Women’s Health, and executive director of the Mood Disorders Institute at Virginia Commonwealth University in Richmond. Dr. Culpepper is professor and chairman in the Department of Family Medicine at Boston University Medical Center in Massachusetts.
Disclosures: Dr. Kornstein is on the advisory boards of or receives honoraria from Biovail, Bristol-Myers Squibb, Eli Lilly, Forest, Neurocrine, Pfizer, Sepracor, and Wyeth; and receives research support from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, the Department of Health and Human Services, Eli Lilly, Forest, the National Institute of Mental Health, Novartis, Sanofi-Synthelabo, Sepracor, and Wyeth. Dr. Culpepper is a consultant to Eli Lilly, Forest, Pfizer, and Wyeth; and on the speaker’s bureaus of Forest, Pfizer, and Wyeth.
Acknowledgments: The authors would like to thank Grant Steen, PhD, for his assistance.
Please direct all correspondence to: Susan G. Kornstein, MD, Dept of Psychiatry, Virginia Commonwealth University, PO Box 980710, Richmond, VA 23298-0710; Tel: 804-828-5637; Fax: 804-828-5644; E-mail: firstname.lastname@example.org.
According to recent data, women are at increased risk for depression during the menopausal transition, even in the absence of a psychiatric history. As a result, it is important to identify biologic, psychiatric, and social risk factors for depression. An English language electronic literature search using the PubMed database (1986–2006) was conducted using the search terms depression, depressive, depressed, menopause, perimenopause, postmenopause, and climacteric. Relevant references were extracted and summarized. The authors of this article identified risk factors for menopausal depression reported in at least two primary references. It was found that a variety of biologic, psychiatric, and psychosocial factors interact to increase vulnerability to depression during the menopausal transition. These findings are consistent with a biopsychosocial model for perimenopausal depression. Depression in the context of the menopausal transition may be difficult to recognize. Thus, physicians should be aware of the various factors that can increase an individual patient’s risk for illness during this time period.
Currently, 21.5 million women 45–54 years of age live in the United States1 and virtually all of these women will have entered menopause within the next decade. Crude calculation suggests that nearly 2 million American women per year will go through the menopausal transition. The life expectancy of women is now approximately 80 years, so many women will live 33% of their lives after menopause.2 Successful transition into menopause enhances health-related quality of life3,4 and may increase satisfaction in the postmenopausal phase.4
This article will summarize relevant evidence regarding the risk of depression during the menopausal transition and discuss contributing factors that can assist clinicians in diagnosing and treating depression in midlife women. The authors conducted an electronic literature search using the PubMed database (1986–2006; English language) using the search terms depression, depressive, depressed, menopause, perimenopause, postmenopause, and climacteric. Relevant references (and cross-references) were extracted and summarized. Risk factors for menopausal depression reported in at least two primary references were identified.
The Menopausal Transition
The Stages of Reproductive Aging Workshop (STRAW) standardized terminology relating to menstruation and menopause.5 The final menstrual period typically occurs when women are 42–58 years of age (mean age=52), and this event is the zero point for the STRAW staging system. Menarche marks entry into the reproductive phase of a woman’s life (Stage –5, relative to the zero point), after which it can take several years for a regular menstrual cycle to become established. Reproductive maturity is associated with menstrual periods that occur every 21–35 days (Stages –4 and –3), with the late reproductive stage (Stage –3) characterized by a gradual increase in levels of follicle-stimulating hormone (FSH). The early menopausal transition (Stage –2) begins when rising FSH levels lead to variability in menstrual cycle length, with cycles varying by >1 week from the normal cycle length. The late phase of the menopausal transition (Stage –1) is associated with higher levels of FSH and greater variability of the cycle, with ≥2 skipped cycles and an interval of amenorrhea lasting at least 60 days (Figure 1).5
Female reproductive senescence is defined by the depletion of oocytes in the ovary,5 and reproductive aging thus consists of a progressive loss of oocytes through atresia or ovulation. Menopause begins at the final menstrual period, but this point cannot be recognized with surety until after 12 months of amenorrhea. The early postmenopause (Stage +1) lasts 5 years and includes the 12-month period of amenorrhea that defines the beginning of the menopause. The late postmenopause (Stage +2) lasts for the rest of a woman’s life. Many menopausal symptoms, especially vasomotor symptoms such as hot flashes, are most severe during Stage –1 or Stage +1, in what has been called the “perimenopause.”5
The transition to menopause is a normal facet of aging, and most women do not become clinically depressed during this phase.6 However, for some women it may be associated with mood changes, including depressive symptoms—similar to other reproductive life events associated with hormonal fluctuations, including the premenstrual phase of the cycle,7-10 pregnancy,11-13 and the postpartum period.8,12,14-17 Understanding and recognizing physical, psychosocial, and psychiatric factors that increase the risk for depression during the menopausal transition and how these factors interact to modulate the risk imparted by the menopausal transition itself is important, particularly for primary care physicians (PCPs) who are likely to be confronted by these issues frequently as increasing numbers of women approach menopause.
Risk of Depression During the Menopausal Transition
The menopausal transition is often associated with an increase in depressive symptoms,18-22 and recent evidence suggests that the transition to menopause is a risk factor for depression in and of itself.17,23 In fact, the menopausal transition has been associated with an increased risk of depression in women with or without a previous history of depression.
A prospective study following 29 asymptomatic premenopausal women through the transition to menopause examined the relationship between the onset of depressive symptoms and perimenopause.24 The study found that the risk of depression during the 2-year period centered at the final menstrual period was 14-fold higher than risk during a 31-year premenopausal phase, and that a psychiatric history was not necessary for women to experience depression during this time.
More recently, two studies examined the risk for perimenopausal depression in women with no prior history of mood disturbance, with consistent findings. One study included 460 premenopausal women, who were followed prospectively for 3 years; menopausal status was determined every 6 months based on menstrual cycle changes ascertained through patient interviews.17 Among women who entered the menopausal transition, 32.5% had a new onset of depressive symptoms, whereas 20.0% of women who remained premenopausal became depressed. The adjusted odds ratio (OR) for depression among women who entered the perimenopause was 1.8, compared with premenopausal women.17 Findings were similar when a more stringent definition of depression was applied. The adjusted OR for severe first onset of depression (defined as women who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]25 criteria for major depressive disorder (MDD), self-reported depression most of the day nearly every day plus symptoms of anhedonia, or had a Center for Epidemiologic Studies Depression Scale score >24) in perimenopausal women compared with premenopausal women was 1.9, with incidence rates of 16.6% versus 9.5%, respectively.
The other study, an 8-year longitudinal study of 436 women, found that high depression scores were 4-fold more likely to occur during the menopausal transition (again determined based on menstrual cycle changes), relative to the premenopausal phase (P<.001).23,26 Increased levels of FSH and luteinizing hormone (LH) as well as increased variability of estradiol, FSH, and LH were all correlated with depressive symptoms. In a multivariate model, depressed women were 4.6-fold more likely to have elevated FSH levels and 3.0-fold more likely to have elevated LH levels (P<.002, for both).23 These relationships remained significant after adjusting for smoking, vasomotor symptoms, poor sleep, health status, employment, and marital status.
Studies that have included women with prior psychiatric diagnoses have found that those with a history of MDD prior to menopause are at particularly high risk for development of depression in the perimenopausal period.26-28 In addition, a history of prior depression related to the reproductive cycle, including premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), ovarian cancer-related dysphoria, and/or postpartum MDD is associated with depression during the menopausal transition.29-31
Taken together, these findings suggest that the changing hormonal milieu during the menopausal transition is associated with onset of depression, even among women with no history of mood disturbance. Furthermore, some women may be particularly vulnerable to developing depression during times of hormonal flux. However, the risk for depression during the menopausal transition is influenced by multiple factors, which will be discussed in more detail below.
Risk Factors for Depression During the Menopausal Transition
Women at midlife face a unique set of circumstances including physical changes related to aging in general and to the menopause in particular, psychosocial adjustments related to changing roles and responsibilities within the family, and a variety of potential life stressors.32 These issues, in addition to psychiatric considerations (eg, history of or current mood or anxiety disorder), have an impact on the likelihood of depression in women as they transition to menopause.33
Physical Context of the Menopausal Transition
Hormonal changes, such as the widely fluctuating hormone levels that are the hallmark of the menopausal transition,32 may be associated with mood changes. Hormonal fluctuations may have direct effects on mood. Although the mechanism is poorly understood, preclinical studies suggest that estrogen has effects on areas of the brain involved in regulation of mood including the prefrontal/frontal cortex, hippocampus, amygdala, hypothalamus, dorsal raphe, and locus coeruleus.34-36 Specifically, estrogens have been reported to influence monoamine systems via modulation of the firing rate, synthesis, release rate, and elimination pathways.37-44 There may also be indirect effects; for example, physical symptoms related to menopause, including hot flashes and insomnia, may be problematic enough to affect mood in a kind of “domino effect” of menopause-related depression.31 Alternatively, complications in the management of chronic medical conditions or comorbidities may also contribute to the risk of depression during the menopausal transition.
Ovarian hormones or fluctuations in hormone levels have been implicated in the regulation of mood and behavior.44 For example, women have about twice the risk of depression as men,15,27 and analysis of the age at onset of depression shows that the risk difference between females and males arises in early adolescence and persists through the mid-50s,27 roughly the ages that correspond to menarche and menopause. Furthermore, psychiatric illnesses—including depression, anxiety, bipolar disorder, schizophrenia, bulimia nervosa, and substance abuse—can undergo cyclic fluctuations in symptom severity, with worsening of symptoms during the premenstrual period.8 These exacerbations may reflect the intensification of an underlying psychiatric disorder and/or the onset of symptoms that occur only during the premenstrual phase of the cycle. In addition, hormonal fluctuations during the postpartum period can also lead to mood disturbance.45 During the menopausal transition, acute hormonal changes that occur during a normal menstrual cycle are superimposed upon gradual menopause-related changes in hormones.46 This hormonal unpredictability can potentially intensify the emotional lability that is a natural part of the menstrual cycle.
As previously mentioned, there is an increased risk of clinical depression associated with the menopausal transition.19,21,26,32,47-51 Yet, the heightened risk of depression related to menopause is transitory19 and changes over time, concurrent with the hormonal changes characteristic of each stage of the menopausal transition. Recent results suggest that the risk of depression increases during early to late perimenopause, but decreases afterward.26,52 The likelihood of depressive symptoms is lower for women with a rapidly increasing FSH profile.26 Since rapid changes in FSH are associated with a relatively short duration of the menopausal transition, this evidence is consistent with the finding that depression is less of a problem if the menopausal transition takes no longer than 27 months.19
In some women of reproductive age there is a cyclic exacerbation of chronic medical conditions during the menstrual cycle, including migraine, epilepsy, asthma, diabetes, rheumatoid arthritis, and irritable bowel syndrome, that is thought to be related to rapid changes in concentrations of circulating ovarian steroids.9,53,54 Likewise, the hormonal fluctuations associated with the menopausal transition may exacerbate symptoms or complicate management of some chronic medical conditions.54-57 Such challenges may have a negative impact on mood for some women.
Approximately 40% of women seek medical attention to alleviate symptoms of the menopausal transition.58 Physical complaints associated with the hormonal fluctuations of the perimenopause include headache, insomnia, vasomotor symptoms (eg, hot flashes and night sweats), and genital atrophy. Hot flashes are the core symptom that reflect the brain’s response to the changing hormonal milieu, particularly fluctuating levels of estrogen.59 Evidence shows that vasomotor symptoms are strongly associated with depression during the menopausal transition. In a cohort of 309 women followed prospectively for 3 years, hot flashes and night sweats increased the odds of depression 1.8-fold and insomnia increased the odds of depression 4.0-fold.18 In another study, perimenopausal women with vasomotor symptoms were 4.4-fold more likely to be depressed than were women without vasomotor symptoms.21
Psychosocial Context of the Menopausal Transition
Depression at the menopausal transition may not necessarily be precipitated only by changes in hormones. Many women have a subjective experience of loss or “exit events” at this time, as children mature and leave the home, living circumstances change, elderly parents become ill or pass away, and marriages evolve or end.32 Race and ethnicity appear to influence the risk for depression in middle-aged women until adjustment is made for psychosocial factors such as poverty, at which point racial and ethnic differences are no longer significant.60 In general, having a social support network is protective from depression, whereas a sense of loss of control is a risk factor.61 In some studies, the importance of social factors such as inadequate income was greater than menopausal status in causing depression.20 Although the number of women living alone increases with age, many women report an improvement in mood after the last child leaves the home.62
Adverse life events can have a powerful impact on the risk of depression during the menopausal transition.17,31,63,64 Stressful life events, especially those of a chronic nature, generally increase the risk of depression.33 In addition, women with high levels of trait anxiety or a pessimistic outlook are more prone to depression and more vulnerable to stressful life events.63 Women with negative life events, low self-esteem, a troubled relationship with a life partner or children, or a weak social support network are at greater risk for depression.64 Presence of adverse life events increases the risk of depression during the menopausal transition by approximately 26% compared with women without such events, and the risk is even greater if the life events occur against a background of vasomotor symptoms.17 In short, life stressors such as aging, general health problems, caring for elderly parents, marital problems, career changes, children leaving home, and other life losses may contribute to depression, completely apart from other biologic and psychiatric risk factors.
A prospective cohort study investigated the determinants of depression in Dutch women going through the menopausal transition, after excluding women who used hormone therapy or who were status post hysterectomy or oophorectomy.50 Self-reported depressive symptoms from 2,103 women were analyzed to determine which social factors correlated with depression. A range of social factors was found to increase the risk of depression significantly. The OR for depression was higher in the context of job loss or unemployment (OR=3.1), inability to work (OR=1.7), financial difficulties (OR=2.9), death of a life partner (OR=2.6), death of a child (OR=5.9), or having a previous episode of depression (OR=2.0). It is important to note that because history of MDD was via self-report in this study, some women may have had earlier depressive episodes that remained undiagnosed (and thus were not reported); in addition, recall of social factors (eg, divorce, job loss) was likely to be stronger. Other studies, which will be reviewed in more detail in the next section, have shown stronger associations between psychiatric history and risk during the menopausal transition. Nevertheless, these data provide a clear demonstration of the importance of social factors in depression during menopausal transition.
Another important factor that contributes to the risk of depression is a woman’s attitude toward menopause. While research in the United States tends to focus on the negative aspects of menopause, some cultures are more attuned to the positive outcomes of the menopausal transition.46 For example, in certain African tribes, women are said to relish the increase in freedom and social influence that is attained after menopause.46 Menopause frees women from the burden of childbirth, the worries of contraception, and the cultural restrictions that may apply to women who still menstruate. Many reports suggest that the psychological reaction of women to menopause reflects the values of the society in which they live, and the social status assigned to aging women.46
Psychiatric Risk Factors for Depression During the Menopausal Transition
The most significant risk factor for developing depression during the menopausal transition is a history of depression.19 A 5-year longitudinal study tracked 2,565 women and found that prior depression is the single best predictor of depression during the menopausal transition, with an adjusted OR of 9.6 (P<.0001).19 Prior depression was a better predictor than was use of hormone replacement therapy (OR=1.0), stage of menopause (OR<2.1), or menopausal symptom severity (OR=3.6). In addition, women who became depressed during a prior reproductive event are at greater risk of menopause-related depression.28-31 For example, women with a history of severe PMS or PMDD appear to be more likely to suffer from depression during the menopausal transition.30,31,51 Interestingly, women with a lifetime history of MDD may be more likely to show an early decline in ovarian function,17,22 suggesting that the relationship between mood and the reproductive system is bi-directional (ie, hormonal changes associated with reproductive life events can influence mood and the presence of mood disorder can influence reproductive life events).
Although there has been no research specifically focused on a potential genetic risk for depression during the menopausal transition, genetic factors have been shown to interact with stress to influence the risk for depression. A study of 549 male and female twins found an interaction between stressful life events and a genetic liability for depression.65 Twins with one specific form of the serotonin transporter gene were at significantly greater risk of depression following common life stressors. Twins having alternative forms of the serotonin transporter gene were at lower risk.65 These results replicate an earlier prospective longitudinal analysis of a birth cohort which also found a functional polymorphism in the promoter region of the serotonin transporter gene that varies in a way that moderates the effect of stress on depression.66 People with one specific allele of the serotonin promoter were more likely to show depressive symptoms in relation to stressful life events. This vulnerability revealed a gene-by-environment interaction (ie, an individual’s response to the environment is moderated by their genetic makeup).66 A third analysis of the association between functional variation in the serotonin protein and depression confirmed that people with one particular variant of this gene are at increased risk of depression following relatively mild stressors.65
A second possible genetic component is a potential genetic vulnerability related to the menopausal transition. Although there is not yet direct evidence of a genetic risk specific to menopause, there is evidence demonstrating a genetic component related to premenstrual symptoms that is largely independent of the risk for MDD. Studies investigating the heritability of menstrual and premenstrual symptoms found that the environmental and genetic risk factors for premenstrual symptoms were not closely related to those associated with lifetime MDD.67,68 A similar phenomenon may be associated with other reproductive events including the menopause, ie, there may be a genetic predisposition to depressive symptoms during the menopausal transition.
Neuroendocrine Effects of Estrogen
Estrogen is known to have very powerful neuroendocrine effects in the brain. Acute increases in estrogen can blunt the response to stress, whereas chronic increases in estrogen downregulate serotonin receptors and increase the risk of depression and anxiety.69 Estrogens exert an agonistic effect on serotonergic activity by increasing the number of serotonergic receptors and by increasing the transport and uptake of serotonin. Estrogens also increase synthesis of serotonin, upregulate serotonin receptors, downregulate serotonin receptors, and decrease the activity of an enzyme (monoamine oxidase) involved in serotonin metabolism.70 The cumulative effect of estrogen on the serotonin system is thus to enhance serotonergic activity.
Estrogens appear to also increase noradrenergic activity by increasing receptor turnover, decreasing noradrenergic reuptake, and decreasing both the number and the sensitivity of dopamine-2 receptors.71 Animal studies suggest that there are potent behavioral effects associated with estrogen withdrawal or fluctuations in estrogen; bilateral ovariectomy of mice increases the duration of immobility—which is often taken as a measure of behavioral depression—while estrogen replacement decreases depressive-like behavior.72
The Transition Triad: A Biopsychosocial Model of Depression
Women experience depression during the menopausal transition because of a wide range of factors. It is only by understanding biologic, psychiatric, and social risk factors that we can begin to evaluate depression in midlife women.
The morbidity associated with mood disorders during midlife may be quite significant; as life expectancy continues to increase, it will become increasingly important to prevent, recognize, and treat depression during the menopausal transition in order to reduce the possibility of long-term sequelae.31 Women report symptoms of physical illness at higher rates, visit physicians more often, and make greater use of healthcare services than do men.54 This gives PCPs the opportunity to intervene in the lives of women who may not realize that they have a treatable problem. Awareness of the biopsychosocial factors that can impact depression during the menopausal transition may assist clinicians in the challenge of distinguishing symptoms of MDD from menopausal symptoms, and may help in the diagnosis and treatment of women with new-onset depression.
Evaluating Depression During the Menopausal Transition
Recognizing depression in the context of the menopausal transition can be challenging. First, there is considerable overlap between menopause-related symptoms and symptoms of MDD, including diminished energy level, poor concentration, sleep disturbance, weight change, and decreased libido (Figure 2).59,73 In addition, it may be difficult to differentiate whether mood symptoms are simply reactions to the myriad life stressors that can affect midlife women or are indicative of a psychiatric diagnosis.
Screening for depression in primary care can be done relatively quickly and easily by asking just two questions: “During the past month, have you often been bothered by feeling down, depressed, or hopeless?” and “During the past month, have you been bothered by little interest or pleasure in doing things?”74 When 421 patients were given a psychiatric interview and a screening questionnaire comprised of 27 items, these two questions were clinically most useful, offering 97% sensitivity and 67% specificity for a diagnosis of clinical depression.73 If these questions are answered in the affirmative, a more thorough evaluation for depression is needed. Although the study sample included women and men of all ages and this was not a menopause-specific study, this screening tool for depression, used in conjunction with a clinical interview (which should include an assessment of reproductive status and history, current menopausal status, a review of changes in menstrual pattern, and a history of reproductive-related mood disturbance) and an evaluation of the presence and severity of somatic symptoms (which should include vasomotor symptoms, sleep disturbances, and changes in sexual function) provides an efficient and effective means of identifying depression during the menopausal transition in clinical practice.
Treating Depression During the Menopausal Transition
Management of depression during the menopausal transition should be part of a comprehensive treatment strategy designed to address the needs of the patient as a whole. As with depression at other times in a woman’s life, antidepressant therapy may be indicated. When selecting a therapy, it is important to consider whether treatment outcomes are affected by factors such as age, sex, and menopausal status.
As discussed previously, the neuroendocrine effects of estrogen are mediated at least in part by serotonergic activity in the brain.71,75 This mechanism could suggest that one therapeutic approach to menopausal depression would be to use antidepressants that modulate serotonin at the synapse.14 Alternatively, if estrogen serves to augment the serotonin system, it is possible that loss of this effect could result in a dampening of the efficacy of purely serotonergic agents in postmenopausal women compared with their use in premenopausal women.44 Unfortunately, relatively few studies have tested these hypotheses in a clinical setting. Of those that have evaluated the effect of gender and/or menopausal status on outcomes76-85 the evidence has not been entirely consistent, though differences could be attributable to small sample sizes and lack of statistical power to detect such interactions in some studies rather than discrepant findings.
In general, several studies have shown that compared with men, women may respond differently to some antidepressants,77,79,81,82 and postmenopausal women may respond differently than premenopausal women.76-83 For example, when the efficacy of sertraline, a selective serotonin reuptake inhibitor (SSRI), was compared to imipramine, a tricyclic antidepressant (TCA), gender- and menopause-related differences in response rates were found. Women were significantly more likely to show a favorable response to the SSRI, whereas men were more likely to benefit from the TCA; among the women, the difference between the two agents was found only in premenopausal women.82 More recently, a study in primary care patients found that menopause negatively affected response to SSRIs in depressed women.79 Specifically, the likelihood of responding to SSRIs was two times greater in premenopausal women compared with postmenopausal women. Other studies evaluating age as a proxy for menopausal status have found that antidepressant response in younger and older women differs, with younger women generally more treatment-responsive to SSRIs.76,80,83 Martenyi and colleagues81 reported that women in their reproductive years (defined in this study as <44 years of age) tended to be more responsive to SSRI treatment than to the predominantly noradrenergic tetracyclic antidepressant maprotiline. A meta-analysis of eight double-blind clinical trials of 2,045 patients randomized to treatment with the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine, SSRIs, or placebo76 found poorer response in the older women compared with the younger women taking SSRIs, with no such difference observed among women taking the SNRI. However, older women taking SSRIs and concomitant hormone therapy had a comparable response to younger women taking SSRIs alone.76
These results are controversial, as some studies have failed to replicate the finding of gender and/or menopausal status differences in antidepressant response.78,80,84 For example, a re-analysis of data from two clinical studies found no evidence that women have a preferential response to SSRIs or that men have a better TCA response.80 Another analysis of data from nine clinical trials found that women and men in all age groups had comparable response rates to TCAs and to the SSRI fluoxetine, although older women did show a superior response to TCAs compared with younger women.78 Finally, a post-hoc analysis of a study in 184 depressed women treated with fluoxetine failed to find a significant difference in response or remission rates among the pre-, peri-, and postmenopausal groups.84 Postmenopausal women did have significantly more residual symptoms following acute-phase treatment, though this difference was no longer significant when adjusted for baseline severity. It is important to note that the lack of statistical differences in this study might have been a function of the small sample sizes in the peri- (N=28) and postmenopausal (N=35) groups and hence low statistical power to detect differences in outcomes.84
It also remains unclear if the potentially diminished antidepressant efficacy in older or postmenopausal women is limited to SSRIs. Available studies suggest that the response to SNRI treatment is comparable in older and younger women.76,85 Prospective studies designed to specifically address the issue of a treatment-by-menopausal-status interaction are warranted to confirm the preliminary data described above.
Use of Estrogen in Treatment of Menopausal Depression
Hormone therapy has been used for many years to treat menopausal symptoms, and in more recent years tested as an option for peri- and postmenopausal mood disturbance.16,44,48,59,86 The value of hormone therapy as augmentation for antidepressant response has been evaluated in a handful of studies, with mixed results. In a double-blind study of fluoxetine in elderly depressed patients,87 fluoxetine treatment was significantly more effective than placebo in women who were taking concomitant estrogen therapy but not among those women who were not taking estrogen. A similar analysis in a study of sertraline demonstrated that older depressed women (>60 years of age) taking estrogen had significantly greater global improvement and quality of life than those not receiving estrogen.88 In contrast to these results, a reanalysis of data from a relapse prevention study found similar efficacy in fluoxetine-treated women ≥45 years of age with and without estrogen therapy.89 Finally, a small recently published pilot trial in postmenopausal women found that hormone therapy did not alter the response rate to treatment with sertraline, though hormone therapy may accelerate the treatment effect.90
The efficacy of estrogen as a monotherapy for depression also has been assessed in peri- and postmenopausal women. Preliminary data by Schmidt and colleagues86 suggested a role for estradiol in a double-blind, placebo-controlled, randomized clinical trial of 34 perimenopausal women with predominantly minor depression. These preliminary findings have since been replicated in a somewhat larger group of perimenopausal women91 with MDD, dysthymic disorder, or minor depressive disorder randomized to treatment with transdermal estradiol or placebo. Results were consistent regardless of DSM-IV diagnosis. However, evidence does not support the efficacy of estrogen as monotherapy for postmenopausal depression. In a randomized controlled trial of mild-to-moderate depression in postmenopausal women92 there was no difference between estrogen and placebo after 8 weeks of treatment. The authors concluded that estradiol cannot be considered effective treatment for postmenopausal depression.92
In summary, available evidence suggests a possible role for hormone therapy as monotherapy in perimenopausal women. The use of hormone therapy as an augmenting agent for antidepressant therapy is interesting but remains to be demonstrated prospectively in a randomized controlled trial. A careful consideration of the risks and benefits of these options should be made in conjunction with the patient, particularly in light of the widely publicized potential risks associated with hormone therapy for some patients.93 Although hormone therapy has been the mainstay of treatment for menopausal symptoms for many years, women are now increasingly likely to treat menopausal symptoms with nonhormonal treatments (eg, antidepressants; gabapentin; and alternative therapies, including exercise, herbal products, dietary supplements, and mind-body techniques).94 As such, there may be similar reluctance among some patients to consider estrogen as a therapeutic option for depression. Recently published data from the Women’s Health Initiative trial suggest there is a differential risk-benefit profile depending on years since menopause.95,96 These data should be taken into consideration when assessing options for short-term treatment during the menopausal transition.97
Although we now have a clearer understanding of the risk for depression during the menopausal transition, many unanswered questions remain regarding the approach to treatment in peri- and postmenopausal women. Whether estrogen can be prescribed safely for a brief period of time at the menopausal transition warrants continued study. Some of the larger, prospective clinical trials of antidepressants such as fluoxetine, sertraline, venlafaxine, and duloxetine should be replicated with a larger sample size before recommendations for one treatment class over another can be made with confidence. We must also continue to search for antidepressants that work by different mechanisms, which may prove more effective for perimenopausal women. Finally, management of depression during the menopausal transition should be part of a comprehensive treatment strategy that addresses the needs of the patient as a whole. PP
1. U.S. Census Bureau. American FactFinder 2005. Available at: http://factfinder.census.gov/servlet/STTable?_bm=y&-geo_id=01000US&-qr_name=ACS_2005_EST_G00_S0101&-ds_name=ACS_2005_EST_G00_. Accessed September 10, 2007.
2. Brody JA, Grant MD, Frateschi LJ, Miller SC, Zhang H. Reproductive longevity and increased life expectancy. Age Ageing. 2000;29(1):75-78.
3. Matthews KA, Bromberger JT. Does the menopausal transition affect health-related quality of life? Am J Med. 2005;118(suppl 12B):25-36.
4. Lai JN, Chen HJ, Chen CM, Chen PC, Wang JD. Quality of life and climacteric complaints amongst women seeking medical advice in Taiwan: assessment using the WHOQOL-BREF questionnaire. Climacteric. 2006;9(2):119-128.
5. Soules MR, Sherman S, Parrott E, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Fertil Steril. 2001;76(5):874-878.
6. Woods NF, Mariella A, Mitchell ES. Depressed mood symptoms during the menopausal transition: observations from the Seattle Midlife Women’s Health Study. Climacteric. 2006;9(3):195-203.
7. Endicott J. The menstrual cycle and mood disorders. J Affect Disord. 1993;29(2-3):193-200.
8. Hendrick V, Altshuler LL, Burt VK. Course of psychiatric disorders across the menstrual cycle. Harv Rev Psychiatry. 1996;4(4):200-207.
9. Case AM, Reid RL. Effects of the menstrual cycle on medical disorders. Arch Intern Med. 1998;158(13):1405-1412.
10. Kornstein SG, Harvey AT, Rush AJ, et al. Self-reported premenstrual exacerbation of depressive symptoms in patients seeking treatment for major depression. Psychol Med. 2005;35(5):683-692.
11. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499-507. Erratum in: JAMA. 2006;296(2):170.
12. Kumar R, Robson KM. A prospective study of emotional disorders in childbearing women. Br J Psychiatry. 1984;144:35-47.
13. Kelly R, Zatzick D, Anders T. The detection and treatment of psychiatric disorders and substance use among pregnant women cared for in obstetrics. Am J Psychiatry. 2001;158(2):213-219.
14. Cohen LS. Pharmacologic treatment of depression in women: PMS, pregnancy, and the postpartum period. Depress Anxiety. 1998;8(suppl 1):18-26.
15. Kornstein SG, Sloan DM, Thase ME. Gender-specific differences in depression and treatment response. Psychopharmacol Bull. 2002;36(4 suppl 3):99-112.
16. Stahl SM. Natural estrogen as an antidepressant for women. J Clin Psychiatry. 2001;62(6):404-405.
17. Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of depression during the menopausal transition: The Harvard Study of Moods and Cycles. Arch Gen Psychiatry. 2006;63(4):385-390.
18. Avis NE, Crawford S, Stellato R, Longcope C. Longitudinal study of hormone levels and depression among women transitioning through menopause. Climacteric. 2001;4(3):243-249.
19. Avis NE, Brambilla D, McKinlay SM, Vass K. A longitudinal analysis of the association between menopause and depression. Results from the Massachusetts Women’s Health Study. Ann Epidemiol. 1994;4(3):214-220.
20. Bosworth HB, Bastian LA, Kuchibhatla MN, et al. Depressive symptoms, menopausal status, and climacteric symptoms in women at midlife. Psychosom Med. 2001;63(4):603-608.
21. Joffe H, Hall JE, Soares CN, et al. Vasomotor symptoms are associated with depression in perimenopausal women seeking primary care. Menopause. 2002;9(6):392-398.
22. Harlow BL, Wise LA, Otto MW, Soares CN, Cohen LS. Depression and its influence on reproductive endocrine and menstrual cycle markers associated with perimenopause: the Harvard Study of Moods and Cycles. Arch Gen Psychiatry. 2003;60(1):29-36.
23. Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry. 2006;63(4):375-382.
24. Schmidt PJ, Haq N, Rubinow DR. A longitudinal evaluation of the relationship between reproductive status and mood in perimenopausal women. Am J Psychiatry. 2004;161(12):2238-2244.
25. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
26. Freeman EW, Sammel MD, Liu L, Gracia CR, Nelson DB, Hollander L. Hormones and menopausal status as predictors of depression in women in transition to menopause. Arch Gen Psychiatry. 2004;61(1):62-70.
27. Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the National Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence. J Affect Disord. 1993;29(2-3):85-96.
28. Hay AG, Bancroft J, Johnstone EC. Affective symptoms in women attending a menopause clinic. Br J Psychiatry. 1994;164(4):513-516.
29. Stewart DE, Boydell KM. Psychologic distress during menopause: associations across the reproductive life cycle. Int J Psychiatry Med. 1993;23(2):157-162.
30. Gregory RJ, Masand PS, Yohai NH. Depression across the reproductive life cycle: correlations between events. Prim Care Companion J Clin Psychiatry. 2000;2(4):127-129.
31. Feld J, Halbreich U, Karkun S. The association of perimenopausal mood disorders with other reproductive-related disorders. CNS Spectr. 2005;10(6):461-470.
32. Rasgon N, Shelton S, Halbreich U. Perimenopausal mental disorders: epidemiology and phenomenology. CNS Spectr. 2005;10(6):471-478.
33. Bromberger JT, Matthews KA, Schott LL, et al. Depressive symptoms during the menopausal transition: The Study of Women’s Health Across the Nation (SWAN). J Affect Disord. Feb 27, 2007 [Epub ahead of print].
34. Gundlah C, Kohama SG, Mirkes SJ, Garyfallou VT, Urbanski HF, Bethea CL. Distribution of estrogen receptor beta (ERbeta) mRNA in hypothalamus, midbrain and temporal lobe of spayed macaque: continued expression with hormone replacement. Brain Res Mol Brain Res. 2000;76(2):191-204.
35. McEwen BS. Invited review: estrogens effects on the brain: multiple sites and molecular mechanisms. J Appl Physiol. 2001;91(6):2785-2801.
36. Pau CY, Pau KY, Spies HG. Putative estrogen receptor beta and alpha mRNA expression in male and female rhesus macaques. Mol Cell Endocrinol. 1998;146(1-2):59-68.
37. Gonzales GF, Carrillo C. Blood serotonin levels in postmenopausal women: effects of age and serum oestradiol levels. Maturitas. 1993;17(1):23-29.
38. Gundlah C, Lu NZ, Bethea CL. Ovarian steroid regulation of monoamine oxidase-A and -B mRNAs in the macaque dorsal raphe and hypothalamic nuclei. Psychopharmacology (Berl). 2002;160(3):271-282.
39. Karkanias GB, Etgen AM. Estradiol attenuates alpha 2-adrenoceptor-mediated inhibition of hypothalamic norepinephrine release. J Neurosci. 1993;13(8):3448-3455.
40. Pau KY, Hess DL, Kohama S, Bao J, Pau CY, Spies HG. Oestrogen upregulates noradrenaline release in the mediobasal hypothalamus and tyrosine hydroxylase gene expression in the brainstem of ovariectomized rhesus macaques. J Neuroendocrinol. 2000;12(9):899-909.
41. Pecins-Thompson M, Brown NA, Kohama SG, Bethea CL. Ovarian steroid regulation of tryptophan hydroxylase mRNA expression in rhesus macaques. J Neurosci. 1996;16(21):7021-7029.
42. Pecins-Thompson M, Bethea CL. Ovarian steroid regulation of serotonin-1A autoreceptor messenger RNA expression in the dorsal raphe of rhesus macaques. Neuroscience. 1999;89(1):267-277.
43. Smith LJ, Henderson JA, Abell CW, Bethea CL. Effects of ovarian steroids and raloxifene on proteins that synthesize, transport, and degrade serotonin in the raphe region of macaques. Neuropsychopharmacology. 2004;29(11):2035-2045.
44. Halbreich U, Kahn LS. Role of estrogen in the aetiology and treatment of mood disorders. CNS Drugs. 2001;15(10):797-817.
45. Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry. 2000;157(6):924-930.
46. World Health Organization. WHO Technical Report Series: Research on the Menopause in the 1990s. Geneva, Switzerland: World Health Organization; 1996. Series #866.
47. Bromberger JT, Meyer PM, Kravitz HM, et al. Psychologic distress and natural menopause: a multiethnic community study. Am J Public Health. 2001;91(9):1435-1442.
48. Burt VK, Altshuler LL, Rasgon N. Depressive symptoms in the perimenopause: prevalence, assessment, and guidelines for treatment. Harv Rev Psychiatry. 1998;6(3):121-132.
49. Hunter MS. Psychological and somatic experience of the menopause: a prospective study [corrected]. Psychosom Med. 1990;52(3):357-367. Erratum in: Psychosom Med. 1990;52(4):410.
50. Maartens LW, Knottnerus JA, Pop VJ. Menopausal transition and increased depressive symptomatology: a community based prospective study. Maturitas. 2002;42(3):195-200.
51. Novaes C, Almeida OP, de Melo NR. Mental health among perimenopausal women attending a menopause clinic: possible association with premenstrual syndrome? Climacteric. 1998;1(4):264-270.
52. Bosworth HB. Depression increases in women during early to late menopause but decreases after menopause. Evid Based Ment Health. 2004;7(3):90.
53. Case AM, Reid RL. Menstrual cycle effects on common medical conditions. Compr Ther. 2001;27(1):65-71.
54. Ensom MH. Gender-based differences and menstrual cycle-related changes in specific diseases: implications for pharmacotherapy. Pharmacotherapy. 2000;20(5):523-539.
55. Harden CL, Pulver MC, Ravdin L, Jacobs AR. The effect of menopause and perimenopause on the course of epilepsy. Epilepsia. 1999;40(10):1402-1407.
56. Keck M, Romero-Aleshire MJ, Cai Q, Hoyer PB, Brooks HL. Hormonal status affects the progression of STZ-induced diabetes and diabetic renal damage in the VCD mouse model of menopause. Am J Physiol Renal Physiol. 2007;293(1):F193-F199.
57. Szoeke CE, Cicuttini F, Guthrie J, Dennerstein L. Self-reported arthritis and the menopause. Climacteric. 2005;8(1):49-55.
58. McMillan TL, Mark S. Complementary and alternative medicine and physical activity for menopausal symptoms. J Am Med Womens Assoc. 2004;59(4):270-277.
59. Joffe H, Soares CN, Cohen LS. Assessment and treatment of hot flushes and menopausal mood disturbance. Psychiatr Clin North Am. 2003;26(3):563-580.
60. Bromberger JT, Harlow S, Avis N, Kravitz HM, Cordal A. Racial/ethnic differences in the prevalence of depressive symptoms among middle-aged women: the Study of Women’s Health Across the Nation (SWAN). Am J Public Health. 2004;94(8):1378-1385.
61. Voils CI, Steffens DC, Flint EP, Bosworth HB. Social support and locus of control as predictors of adherence to antidepressant medication in an elderly population. Am J Geriatr Psychiatry. 2005;13(2):157-165.
62. Dennerstein L, Dudley E, Guthrie J. Empty nest or revolving door? A prospective study of women’s quality of life in midlife during the phase of children leaving and re-entering the home. Psychol Med. 2002;32(3):545-550.
63. Bromberger JT, Matthews KA. A longitudinal study of the effects of pessimism, trait anxiety, and life stress on depressive symptoms in middle-aged women. Psychol Aging. 1996;11(2):207-213.
64. Deeks AA. Psychological aspects of menopause management. Best Pract Res Clin Endocrinol Metab. 2003;17(1):17-31.
65. Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B. The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry. 2005;62(5):529-535.
66. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386-389.
67. Kendler KS, Karkowski LM, Corey LA, Neale MC. Longitudinal population-based twin study of retrospectively reported premenstrual symptoms and lifetime major depression. Am J Psychiatry. 1998;155(9):1234-1240.
68. Kendler KS, Silberg JL, Neale MC, Kessler RC, Heath AC, Eaves LJ. Genetic and environmental factors in the aetiology of menstrual, premenstrual and neurotic symptoms: a population-based twin study. Psychol Med. 1992;22(1):85-100.
69. Charney DS. Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry. 2004;161(2):195-216.
70. McEwen BS, Alves SE. Estrogen actions in the central nervous system. Endocr Rev. 1999;20(3):279-307.
71. Garlow S, Musselman D, Nemeroff C. The neurochemistry of mood disorders: clinical studies. In: Charney D, Nestler E, Bunney B, eds. Neurobiology of Mental Illness. New York, NY: Oxford University Press; 1999:348-364.
72. Bekku N, Yoshimura H. Animal model of menopausal depressive-like state in female mice: prolongation of immobility time in the forced swimming test following ovariectomy. Psychopharmacology (Berl). 2005;183(3):300-307.
73. Soares CN, Cohen LS. Perimenopause and mood disturbance: an update. CNS Spectr. 2001;6:167-174.
74. Arroll B, Khin N, Kerse N. Screening for depression in primary care with two verbally asked questions: cross sectional study. BMJ. 2003;327(7424):1144-1146.
75. Soares CN, Prouty J, Born L, Steiner M. Treatment of menopause-related mood disturbances. CNS Spectr. 2005;10(6):489-497.
76. Thase ME, Entsuah R, Cantillon M, Kornstein SG. Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions. J Womens Health (Larchmt). 2005;14(7):609-616.
77. Raskin A. Age-sex differences in response to antidepressant drugs. J Nerv Ment Dis. 1974;159(2):120-130.
78. Quitkin FM, Stewart JW, McGrath PJ, et al. Are there differences between women’s and men’s antidepressant responses? Am J Psychiatry. 2002;159(11):1848-1854.
79. Pinto-Meza A, Usall J, Serrano-Blanco A, Suarez D, Haro JM. Gender differences in response to antidepressant treatment prescribed in primary care. Does menopause make a difference? J Affect Disord. 2006;93(1-3):53-60.
80. Parker G, Parker K, Austin MP, Mitchell P, Brotchie H. Gender differences in response to differing antidepressant drug classes: two negative studies. Psychol Med. 2003;33(8):1473-1477.
81. Martenyi F, Dossenbach M, Mraz K, Metcalfe S. Gender differences in the efficacy of fluoxetine and maprotiline in depressed patients: a double-blind trial of antidepressants with serotonergic or norepinephrinergic reuptake inhibition profile. Eur Neuropsychopharmacol. 2001;11(3):227-232.
82. Kornstein SG, Schatzberg AF, Thase ME, et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry. 2000;157(9):1445-1452.
83. Grigoriadis S, Kennedy SH, Bagby RM. A comparison of antidepressant response in younger and older women. J Clin Psychopharmacol. 2003;23(4):405-407.
84. Cassano P, Soares CN, Cusin C, Mascarini A, Cohen LS, Fava M. Antidepressant response and well-being in pre-, peri- and postmenopausal women with major depressive disorder treated with fluoxetine. Psychother Psychosom. 2005;74(6):362-365.
85. Burt VK, Wohlreich MM, Mallinckrodt CH, Detke MJ, Watkin JG, Stewart DE. Duloxetine for the treatment of major depressive disorder in women ages 40 to 55 years. Psychosomatics. 2005;46(4):345-354.
86. Schmidt PJ, Nieman L, Danaceau MA, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol. 2000;183(2):414-420.
87. Schneider LS, Small GW, Hamilton SH, Bystritsky A, Nemeroff CB, Meyers BS. Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Fluoxetine Collaborative Study Group. Am J Geriatr Psychiatry. 1997;5(2):97-106.
88. Schneider LS, Small GW, Clary CM. Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry. 2001;9(4):393-399.
89. Amsterdam J, Garcia-Espana F, Fawcett J, et al. Fluoxetine efficacy in menopausal women with and without estrogen replacement. J Affect Disord. 1999;55(1):11-17.
90. Rasgon NL, Dunkin J, Fairbanks L, et al. Estrogen and response to sertraline in postmenopausal women with major depressive disorder: a pilot study. J Psychiatr Res. 2007;41(3-4):338-343.
91. Soares CN, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry. 2001;58(6):529-534.
92. Morrison MF, Kallan MJ, Ten Have T, Katz I, Tweedy K, Battistini M. Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial. Biol Psychiatry. 2004;55(4):406-412.
93. Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
94. Ma J, Drieling R, Stafford RS. US women desire greater professional guidance on hormone and alternative therapies for menopause symptom management. Menopause. 2006;13(3):506-516.
95. Manson JE, Allison MA, Rossouw JE et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356(25):2591-2602.
96. Rossouw JE, Prentice RL, Manson JE et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297(13):1465-1477.
97. Burger HG. WHI risks: any relevance to menopause management? Maturitas. 2007;57(1):6-10.