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. Author manuscript; available in PMC: 2019 Dec 1.
Published in final edited form as: Obstet Gynecol Clin North Am. 2018 Oct 25;45(4):663–678. doi: 10.1016/j.ogc.2018.07.007

Depression During and After the Perimenopause: Impact of Hormones, Genetics, and Environmental Determinants of Disease

Joyce T Bromberger 1,2, C Neill Epperson 3,4,5
PMCID: PMC6226029  NIHMSID: NIHMS1500454  PMID: 30401549

Synopsis:

Vulnerability to depression is increased across the menopause transition and in the early years after the final menstrual period. Clinicians should systematically screen women in this age group, and if depressive symptoms or disorder are present, treatment for depression should be initiated. Potential treatments include antidepressants for moderate to severe symptoms, psychotherapy to target psychological and interpersonal factors, and hormone therapy for women with first onset MDD or elevated depressive symptoms and at low risk for adverse effects. Behavioral interventions can improve physical activity and sleep patterns.

Keywords: Depression, Perimenopause, Hormones, Genetics, Environmental Determinants

Introduction

Epidemiologic research indicates that roughly 1 in 5 women will experience an episode of major depressive disorder (MDD) at some point in their lifetime.1 Importantly, for some females, depression can present or worsen during periods of dynamic hormonal flux such as the premenstruum, peripartum, and the perimenopause.2;3 Longitudinal research of women from the pre- to post-menopause stages of reproductive life, indicates that some women demonstrate a greater sensitivity to gonadal steroid shifts with respect to risk for negative mood symptoms such that a history of severe premenstrual mood symptoms is associated with increased risk for perimenopause onset or relapse of MDD.4 The focus of this article is on the period of a woman’s life when her reproductive system and its endocrine activity are changing and in transition (perimenopause) to a relatively hormonally quiescent stage (postmenopause). We will discuss the evidence that reproductive aging is associated with increased risk for depression as well as the varied endocrine, genetic, behavioral and social factors that may explain the association.

Defining Depression

Depression is a generic term used by the media, the general public and health care professionals to refer to negative mood symptoms that range in severity from unhappy psychological states to major depressive disorder (MDD). MDD is characterized in the Diagnostic Statistical Manual of Mental Disorders, fifth edition (DSM-5), by a range of mood, cognitive and behavioral symptoms that lead to clinically meaningful distress or functional impairment.5 The various symptoms and behaviors included in the DSM-5 diagnosis for major and minor depressive disorder are included in Table 1. The term, “depression” can also refer to a cluster of negative mood and behavioral symptoms that do not meet diagnostic criteria for MDD, but may be associated with impaired functioning or distress and is likely to be more consistent with the diagnosis of minor depressive disorder.6 Clinical (major and minor) depression and depressive symptoms are assessed in multiple settings, including primary care, gynecologic, and psychiatric. Depressive symptoms are typically assessed with self-report scales, of which there are many [e.g., Center for Epidemiological Studies of Depression (CES-D);7 Beck Depression Inventory (BDI)8 to name a few]. Self-report scales are useful to assess the number and severity of current symptoms and to identify individuals who should undergo additional screening, but are not diagnostic of major or minor depressive disorder. A standardized structured or semi-structured interview conducted by a trained clinician is the gold-standard for DSM-5 differential diagnosis of depressive disorders that include minor depression, dysthymia, premenstrual dysphoric disorder, or bipolar disorder-depressive episode. Clinicians may also utilize standard questionnaires such as the PRIME-MD, both clinician9 and patient administered10 and the Patient’s Health Questionnaire (PHQ, 2-item for screening, and 9-item for diagnosis).11 Most epidemiologic studies focusing on depression during the perimenopause rely on standardized patient-rated questionnaires to determine presence and duration of various depressive symptoms to quantify severity of symptoms and not a formal psychiatric evaluation or standardized interview to assess clinical depression. Therefore, we utilize here the term “depression” or “MDD” to connote a clinical condition that is evidenced by a standardized interview or the PRIME-MD or PHQ-9, which research has demonstrated to be consistent with a “probable diagnosis” of MDD. The term “depressive symptoms” will refer only to symptom levels or syndromes for which diagnosis of MDD or minor depression is doubtful or not confirmed.

Table 1:

Major versus Minor Depressive Disorder

CHARACTERISTICS MAJOR MINOR
Symptoms
Depressed mood (e.g., sad, hopeless) X X
Decreased interest or pleasure X X
Weight change (>5% of body weight/month) or change in appetite +/− +/−
Sleep disturbance (insomnia/hypersomnia) +/− +/−
Fatigue +/− +/−
Feelings of worthlessness or excessive guilt +/− +/−
Difficulty concentrating +/− +/−
Psychomotor agitation or slowing +/− +/−
Recurrent thoughts of death +/− +/−
Number of Symptoms 5 or more 2–4
Most days
for at least 2 weeks
Most
days for at least 2
weeks
Significant distress or impairment in function X X
Not attributable to physiologic effect of a substance,
medication or general medical condition
X X
Does not occur exclusively during a psychotic disorder X X

Major and minor depression both require one of the two hallmark symptoms (italicized font) of depressed mood or decreased interest or pleasure in all, or almost all, activities. For both diagnoses, symptoms must be present most of the days during a two week period, cause clinically meaningful distress or impairment in social, occupational or other areas of function, and not be solely attributable to another disorder, medical condition or substance. The other symptoms are listed at +/− as they do not have to be present, though 5 symptoms are required for Major Depressive Disorder, while only 2–4 symptoms are required for Minor Depressive Disorder.

Women interface with their healthcare providers relatively often during their reproductive years, prefer to be treated for depression in the primary care setting, and should be screened for MDD and for elevated depressive symptoms. Indeed, the U.S. Preventive Services Task Force recommends that all individuals are screened for depression at every contact with their healthcare provider.12 Identifying a first episode of depression is critical, as the risk for recurrent episodes and chronicity of symptoms increases with failure to adequately treat patients with MDD. Fifty to 75% of individuals have recurring episodes of MDD.13;14 MDD and depressive symptoms are about twice as common among women as men,1 highlighting it as an important public health problem that significantly contributes to a bias in disease burden for women.

Depression and the Menopause Transition

Epidemiology

For many decades, there has been an ongoing debate about whether the menopause transition and/or postmenopause is associated with an increased risk for depressive symptoms or disorder. Though some studies failed to find a relationship between depression or depressive symptoms risk and the menopause transition,15;16 two well-designed longitudinal studies of clinical depression found a 2 to 5-fold increased risk for MDD during the peri- versus late premenopause.4;1720 The Study of Women’s Health Across the Nation (SWAN),17;18 utilized a standardized semi-structured interview (Structured Clinical Interview for DSM-IV (SCID) and the Penn Ovarian Aging Study (POAS)4;19;20 used standardized questionnaires (e.g. PRIME-MD and/or PHQ-9) and rating scales scores demonstrating sufficient severity (e.g. CES-D ⩾25), to confirm probable MDD. A similar increased risk for depressive symptoms was observed in other large, longitudinal studies (e.g., Harvard study of Mid-life Mood and Cycles,21 the Australian Longitudinal Study of Women’s Health (ASWH),22 and the Seattle Midlife Women’s Health Study;23. In addition to carefully characterizing the level of depressive symptom severity, each of these longitudinal studies utilized menstrual diaries and/or hormone levels to confirm menopause stage during which such symptoms were observed. Based on this literature, we conclude that there is a subset of women who are vulnerable to depressive disorder or symptoms during the menopause transition and early postmenopause. Importantly, the risk for depression appears to decline two to four years after the final menstrual period, particularly for those women whose only episode of depression occurred during the perimenopause17;24 indicating that the increase in risk for depression and depressive symptoms during the MT is not due to aging itself.

Psychosocial and Health Related Factors

Current research is focused on elucidating why some women are more vulnerable to depression and depressive symptoms during the perimenopause, a time of changing and unpredictable patterns of gonadal steroid levels and menstrual cycles. A common hypothesis is that endocrine changes driving the menopause transition and affecting numerous tissues and biological systems including those in the brain are primarily responsible for unmasking the risk for depression symptoms or disorder in susceptible women. Nevertheless, there are numerous and varied other domains and factors that are associated with depressive disorder and symptoms in general and during the perimenopause (Table 2) and (Figure 1).

Table 2.

: PSYCHOSOCIAL AND HEALTH-RELATED RISK FACTORS FOR DEPRESSION AND/OR DEPRESSION SYMPTOMS DURING THE MENOPAUSE TRANSITION

CATEGORIES OF RISK DOMAINS SPECIFIC RISK FACTOR
Demographic Race/ethnicity;
Income;
Education; Marital
status
Minority status
Low Income
Low education attainment
Unmarried, divorced, widowed
Psychological Personality traits;

Attitudes toward
menopause, aging
Trait anxiety
Pessimism
Rumination
Social/environmental Adverse life events;
Chronic adverse
conditions; Social
relationships
Childhood and lifetime adversity, trauma
Current stressful situations
Poor social supports
Health-related Health behaviors;
Chronic conditions;
Physical symptoms;
Functioning
Smoking, Physical inactivity,
Sleep disturbance or disorders
Lifetime psychiatric disorder(s)
Co-morbid medical conditions
Chronic pain
Vasomotor symptoms
Limitations in functioning due to physical
or emotional problems

Figure 1:

Figure 1:

Intersection of multiple risk factors for depression during the menopause transition (MT).

Demographic Characteristics

Studies have shown that being unmarried (e.g., divorced, single, widowed), having a high school education or less and experiencing financial hardships are major risk factors for depressive symptoms during the menopause transition.2427 Results for race/ethnic differences in associations with depression symptoms are mixed and most observed differences for black and white women are no longer significant when adjusted for socio- demographic and health factors such as education, medical conditions, current significant stressors, and financial strain.2830

Psychological Characteristics

Personality traits are predispositions that reflect cognitive, affective, or behavioral tendencies that are relatively stable across time and situations. While there are a greater number of such traits, only a small number have been examined in the context of depressive symptoms during midlife, instrumentality (task/action oriented), pessimism, trait anxiety, and rumination. Middle-aged women characterized by being highly action oriented showed less of an increase in depressive symptoms over three years than women less instrumental, after controlling for potential confounders, in one longitudinal study.31 Studies of midlife women have also suggested that trait anxiety/neuroticism (a tendency to experience chronic negative emotions), rumination/self-consciousness, and pessimism are significantly associated with risk for MDD and/or depressive symptoms.18;32;33 It is also the case that negative attitudes toward menopause and/or aging are conceptually related to neuroticism and pessimism and predict depressive, anxious and negative mood in midlife women.26;3436

Social factors

Similar to other times in life, the quality of one’s social environment can impact risk for depression and depressive symptoms during menopause.26 Social risk factors include acute and chronic stressors, daily hassles, lack of environmental resources and poor social relationships.34,3739 Midlife women with depression report higher prevalence of interpersonal problems, major events happening to significant others, and financial difficulties, compared to their non-depressed counterparts.40 Stressful events have been associated with depressive symptoms in peri- compared to premenopausal women.21 Among perimenopausal women, there were a greater number of adverse events in the 6 months before clinical depression occurrence than in the same period of time in non-depressed women.41 Though vasomotor symptom severity is often correlated with depressive symptoms, they are not predictive,42 and adverse life events are a more significant risk factor for MDD among perimenopausal women.17 Hence, the fluctuating hormonal milieu of perimenopause may reduce the threshold for depression in the presence of adverse life events,21;4345 perhaps due to hormonal effects on neurotransmitters and brain regions implicated in the regulation of mood, cognition and the stress response.4648

Adequate social support can buffer the individual from the adverse effects of stressful life events and daily hassles. There are different types of support, instrumental (e.g., help with chores), structural/social network (e.g., number of close friends or relatives, organization memberships) and emotional (e.g., someone to confide in or talk to). The most salient type of social support, is emotional support. Research has shown that an adequate number and quality of social relationships can protect perimenopausal women from depression and depressive symptoms. For example, the Melbourne Women’s Health Study35 found that the magnitude of negative mood reported across the menopause transition was associated with the woman’s negative feelings for her partner or lack of a partner entirely. Similarly, in the SWAN cohort, having low social support, marital dissatisfaction, and few close family members and friends was significantly associated with high depressive symptoms and MDD even after adjusting for multiple confounders (stressful events and negative attitudes toward aging and menopause). 18;34

Psychosocial Stress and Adversity

Child adversity includes, but is not limited to abuse/neglect, family problems, and low childhood SES, poverty and unsafe environments. These and other significantly early life stressors or traumatic events can have enduring effects on stress-sensitive biological systems as well as behaviors that are detrimental to mental and physical health,44;49;50 Childhood adversity is associated with increased lifetime risk for MDD as well as new onset MDD and depressive symptoms during the perimenopause.45;5153 Cumulative burden of depressive symptoms over 15 years has been shown to be greater for middle-aged women who grew up impoverished and had parents with low educational attainment versus those with parents of low educational attainment only.51 Five adult factors (financial strain, lower education, low social support, low social function, and high bodily pain) jointly attenuated the association, suggesting a potential pathway between early adversity and midlife depressive symptom burden.51

Health-related factors

Depression and depressive symptoms are associated with suboptimal health behaviors, including smoking, inactivity, and sleep problems during midlife.25;54;55 Prospective studies of middle-aged women indicate that physical activity and depression and depressive symptoms are inversely associated.5658 The SWAN57 and the ASWH58 reported that the ‘dose’ of moderate intensity physical activity that is consistent with public health guidelines is protective for depressed mood. Sleep difficulties are more frequently reported during perimenopause (50%) than premenopause (30%).59 Although sleep disturbance is one of the cardinal symptoms of depression, the relationship between the two is bidirectional.60 There is some evidence that sleep disturbance predicts subsequent depression61 and a more severe depression course. In midlife women, those who reported sleep problems at study entry were 8 times more likely to experience a persistent or recurrent pattern of major depression over 13 years, independent of lifetime depression history and other covariates, than a single episode, minor depression, or no depression.62 Additionally, in a clinical study, improvement in perceived sleep quality was associated with improvement in depressive symptoms among women with depression during the menopause transition.63

Poor self-reported physical health and functioning are associated with depressive symptoms in midlife women.18;64 Depression often is associated with medical illnesses and risk factors, including subclinical cardiovascular conditions such as coronary and aortic calcification65 and carotid atherosclerosis66 as well as physical functioning.67 While it is difficult to disentangle the direction of the relationship between depression and decline in physical functioning, evidence supports a reciprocal relationship in older populations.68 Depressive symptoms are also correlated with somatic symptoms in peri- and postmenopausal women in numerous cross-sectional studies6971 including dizziness, headaches, tiredness, aches and stiff joints, and urinary incontinence. While some studies find VMS are correlated with depressive symptoms or disorder,72 others do not17 or they note that the onset of depressive symptoms precedes the onset of VMS when they co-occur.42 In SWAN, stressful life events were a stronger predictor of subsequent major depression than were VMS.17

Biological Factors

Similar to psychosocial and health related factors, the biological factors contributing to risk and resilience for depression during the menopause transition are complex and inter-related. For example, genetic vulnerability may be observed solely in the context of having experienced childhood adversity or significant stressful events during adulthood.73;74 Research focusing on this gene by environment (G x E) interaction has rarely considered the potential for sex differences, despite the female bias for affective disorders, sex differences in response to early life stress, and the potential for sex to modify risk associated with specific genetic polymorphisms.44 Perhaps for some women, the risk associated with this G x E interaction is sufficient to result in an episode of MDD in the absence of hormonal flux/reproductive transitions. For others, the erratic fluctuations of gonadal steroids during the perimenopause may be necessary to unmask risk for MDD either alone or in concert with stress history and genetics for a gene x environment x sex hormone interaction.45

Genes, Environment and Race/Ethnicity

The heritability of MDD is approximately 35% to 40%.75;76 As with MDD occurring in the general population, there is some evidence that multiple “hits”, genetic (G) risk and environmental (E) factors such as childhood adversity and/or significant current stressors (E), are required in order to unmask risk for MDD during the perimenopause. Not surprisingly, genetic targets for investigation related to perimenopause or mid-life onset of depression are those related to estrogen receptors and steroid metabolizing enzymes in addition to estradiol’s downstream targets such as the serotonin (5-HT) transporter (5-HTT), post-synaptic 5-HT type 2 receptor density, and tryptophan hydroxylase (TH), monoamine oxidase A (MAO-A) and catechol-methyl transferase (COMT) gene expression.77;78 TH is the rate limiting enzyme for the conversion of tryptophan to serotonin, while COMT and MAO-A are the primary enzymes responsible for synaptic amine degradation. Overall, estradiol appears to promote increased neurotransmitter synthesis and/or decrease degradation, essentially prolonging synaptic neurotransmitter levels.46

Though a recent review of the literature provides strong support for a G x E with respect to depression in the general population and a functional polymorphism in the SCL6A4 gene,74 the impact of sex and/or reproductive status (pre vs peri vs postmenopause) on this genetic polymorphism, which modulates the transcription and efficiency of the 5-HTT, has not been fully explored. The one study that examined polymorphisms in this gene, as well as the gene encoding MAO-A, and risk for depression among menopausal women failed to find an association between genotype and depression risk.79 Whether the findings would have been similar had the investigators focused specifically on depression onset during the perimenopause is not known.

As the genomic activity of estradiol is mediated through ER-α and ER-β, polymorphisms in the ER1 and ER2 genes could have a significant impact on receptor transcription and binding efficacy. Moreover, the antidepressant effects of estradiol are thought to be mediated primarily through ER-β. Several polymorphisms in ER1 and ER2 (which encode ER-α and ER-β, respectively) have been studied in relation to risk for late-life depression among 3525 women who would have been postmenopausal at the time of depression onset. Presence of the A allele for ER2 rs1256049 polymorphism was associated with onset of late-life depression, but only in women not currently using hormone therapy (HT), suggesting a protective effect of HT even in the face of a potential genetic risk factor.80 Similarly, in a study of unmedicated reproductive-aged women (ages 18–39 years) and “menopausal” women (ages 40–60 years) experiencing their first episode of MDD and with a minimum score of 21 (at least moderate severity) on the Hamilton Depression Rating Scale (HAM-D), a genetic polymorphism in the gene encoding ER-β distinguished those with and without MDD regardless of reproductive stage. However, when lifetime adverse life event scores were considered, a G x E interaction was observed for both the ER2 polymorphisms studied (rs1256049 and rs4986938),81 but only in the menopausal group. These data are interesting in light of additional findings from the POAS that childhood adversity was associated with a two- to three-fold increased risk for lifetime depression as well as new onset depression during the menopause transition.82 Together these data support the need to consider a G x E x H (hormones) for depression during the menopause transition.

Findings from the POAS and SWAN implicate not only genetic variations in steroid metabolizing enyzmes in risk for perimenopausal depression, but highlight the potential modifying effect of race/ethnicity.78;83 In the POAS, which included a community cohort of women [50% African American (AA), 50% European American (EA)] assessed yearly from pre to post menopause over 14 years, interactions between the cytochrome p450 enzymes CYP1B1*3 and CYP1B1*4 and menopause stage were observed for depressive symptoms among AA women only. CYP1B1s, which are highly expressed in estrogen target tissue, are responsible for the hydroxylation of estradiol. This process creates 4- hydroxyestradiol, which generates free radicals that could negatively affect target tissues.84 Outside of altering local estradiol levels, the mechanism by which of CYP1B1s could impact depression during the perimenopause is unknown. In contrast, the sulfotransferase SULT1A1*3, which converts estradiol to the biologically inactive estradiol sulfate, was associated with a decreased risk for depressive symptoms, but increased risk of hot flashes among EA females. This disconnect between depressive symptoms and VMS is interesting, given that depressive symptoms are often (41% in the POAS cohort), but not always, comorbid with severe VMS.42 No significant relationship between depression, menopause stage and genes encoding catechol-O-methyltransferase (COMT), CYP19, CYP1B1, CYP1A2, CYP1A1, or CYP3A4 were found for the entire group or by race.78

Similarly, a SWAN sub-study demonstrated a relationship between estrogen-metabolizing enzymes and depression risk which differed by race. Though the sample size was large (n=1538), menopause status was not considered with respect to depression onset (i.e., women may have also experienced MDD during the premenopause). In contrast to the POAS, SWAN found that EAs with the CYP1A1 rs2606345 CC and AC genotypes had two-fold greater odds of having depressive symptoms than those homozygous for the A allele. This relationship between the CC genotype was even greater for AA women (ten-fold). Among Japanese women, those homozygous for the T allele in the SNP CYP19 rs936306 were nearly five times as likely to have depressive symptoms as those with CC genotype. For Chinese women, the TT genotype at the SNP rs615942 for the 17 hydroxysteroid dehydrogenase gene was associated with a seven to eleven-fold increase risk.83

Finally, genetic analyses from the Seattle Midlife Women’s Health Study focused on the estrogen synthesis pathway, specifically CYYP19 and 17-HSD, but this time in relationship to severity of symptom clusters identified through a latent class analysis of typical perimenopausal symptoms.85 Though hot flash severity served as the basis for these clusters, depressed mood was included. Investigators found that a 17-beta hydroxysteroid dehydrogenase gene polymorphism was associated with the high-severity group, which included women with high-severity hot flashes and moderate sleep, mood, cognitive and pain symptoms. Again, unlike the POAS, analyses conducted in the Seattle Midlife Study did not consider menopause stage with respect to depression onset in their analyses and clustering of symptoms limits interpretation of their findings with respect to the genetics of perimenopause depression.

Gonadal Steroid Levels and Fluctuations

The fact that the years leading up to the final menstrual period are characterized by enhanced depression risk compared to subsequent years,24 particularly among women with only perimenopausal onset of MDD, implicates dynamic hormonal changes in endogenous reproductive steroids versus absolute hypogonadism in this heightened risk. Given the robust impact of estradiol on brain neurochemistry, structure and function,46 it isn’t surprising that investigators have examined the timing of onset of menopause, rapidity of progression through menopause, the degree of hormonal fluctuations and absolute levels of gonadal steroids in the pathophysiology of perimenopause depression. Reproductive steroids [estradiol, progesterone, testosterone and dihydroepiandrosterone sulfate (DHEA-S)] levels at discrete time points or across the menopause transition are associated with depressive symptoms in some,37;8690 but not all studies.23;91 Directionality of this relationship also varies by study, hormone and sample population. Increase in follicle-stimulating hormone and the variability of estradiol across the menopause transition, particularly in relationship to her own mean fluctuations, were significantly associated with greater risk for incident perimenopausal depression after controlling for smoking status, body mass index, poor sleep, hot flashes, and history of premenstrual syndrome.19 Likewise, postmenopausal women with a decline in estradiol levels over a 2-year follow-up period were three times as likely to experience depressive symptoms, suggesting that changes in estradiol levels even after the final menstrual period (FMP) can impact depression risk.91 Finally, studies including a recent meta-analysis indicates that a longer reproductive period, defined as later age at the time of final menstrual period, or greater number of years between menarche and onset of the menopause transition was associated with reduced risk for mid-life depression. 92;93

Clinical Studies of Estradiol Treatment

Two double-blind, placebo-controlled studies indicate that conventional HT estradiol doses are more effective than placebo in reducing depressive symptoms among women who presented with perimenopausal MDD.94;95 In a similar randomized clinical trial in postmenopausal women, estradiol did not differ in effectiveness from placebo.96 Moreover, a recent study in which euthymic perimenopausal women randomized to receive estradiol (0.1 mg/d) plus intermittent progesterone (200 mg/d for 12 days every 3 months) versus those randomized to placebo were less likely to have potentially clinically significant depressive symptoms at any time during the 12-month assessment period. 97 On average, Center for Epidemiological Studies - Depression (CES-D) scores were higher in the placebo versus estradiol group across the study. When considering menopause stage, the positive effect of the hormone regimen on mood was limited to those in the early menopause transition versus those in the late perimenopause or early postmenopause stages. These findings support the notion of a “window of opportunity” during which women are more likely to be responsive to the anti-depressant effects of estradiol.98

Clinical Implications

This review highlights the importance of clinical screening for depression among middle-aged women as risk for MDD and depressive symptoms are increased during the MT even among those without a personal history of depression. Multiple factors contribute to risk for depression. Social factors play a critical role in depression onset and persistence. As mid-life women are often in transition with respect to interpersonal relationships, adequacy of social support, and current stressors, gynecologists treating menopausal women should periodically assess current stressors, as well as quality of their patients’ intimate relationships and friendships. Current stressors among mid-life women often include caring for aging parents at the same time that women are managing their children’s transitions to adulthood, stressful job changes, and conflict with spouse/partner. Given the association of lifetime traumas or childhood adversity with depression, clinicians may want to screen for these as well.

There are numerous screening instruments for clinicians to use in the routine assessment of depression symptoms and their severity. While self-rated scales are not diagnostic for MDD or minor depressive disorder, they can give the clinician an understanding of the range of symptoms and their individual severity. For example, the CES-D can be used to measure both key symptoms of MDD (anhedonia and low mood) as well as symptoms of anxiety and sleep disturbance which can also impair quality of life. Women scoring 16 or greater on the CES-D should be evaluated by their clinician for potential treatment in the primary care setting and/or referral to specialty behavioral health.

Though genetic polymorphisms and reproductive hormone fluctuations play a role in the manifestation of risk for MDD during the perimenopause, the measurement of these genetic differences is not yet recommended. Future research is needed to confirm the relationship between genotype and risk for depression during periods of dynamic hormonal flux such as the perimenopause.

Estradiol treatment was shown to be more effective than placebo for perimenopausal women meeting criteria for MDD.95 The impact of estradiol treatment on depression appeared to be independent of the hormone’s effect on vasomotor symptoms and sleep.

For menopausal women who experienced premenopausal episodes of MDD requiring psychiatric treatment, moderate-severe symptoms for the first time during the perimenopause or those with suicidal thinking, the standard of care would be treatment with antidepressants (assuming no history of bipolar disorder or current hypomania) and referral to a behavioral health specialist if one is available. Antidepressants may be started in the primary care setting in uncomplicated cases when the diagnosis is clear and there is no suicidal thinking. However, follow-up should occur within 1–2 weeks to assess for side effects and potential dose titration.

Conclusions

Depressive symptoms and diagnosis are common during the menopause transition and early postmenopause. Multiple psychosocial and biological factors are involved. Evaluation for depression and treatment may be conducted in the primary care practice and includes consideration of hormone therapy and antidepressants, alone or in combination, and cognitive behavioral therapy.

Key Points:

  • Longitudinal studies, conducted across the world and in diverse populations, confirm that women are 2–5 times more likely to experience a depressive disorder during the peri versus the late premenopausal years.

  • Screening for depressive symptoms or disorder in the primary care setting is recommended and can be accomplished easily with standard patient-rated scales.

  • Treatment for depression or depressive symptoms during the peri and early postmenopause includes use of standard antidepressants, hormone therapy, and behavioral modifications to sleep patterns and exercise.

  • As current and early life stressors/adversity are often contributing factors, many women may benefit from psychotherapy or cognitive behavioral or trauma-focused therapy.

Acknowledgements:

This chapter has been written with financial support for Dr. Epperson’s effort from the NIH Office of Research on Women’s Health (P50 MH099910) and NIMH (P50 MH099910. And with financial support for Dr.Bromberger’s effort from the NIA (AG012546)

Footnotes

Disclosures: Dr. Epperson consults to Sage Therapeutics and Shire Pharmaceuticals, and has investments in Pfizer, Merck, Johnson and Johnson, Abbott and Abbvie.

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