Menopause and Mood Disorders

Menopause and Mood Disorders

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Menopause is the permanent cessation of menstruation resulting in the loss of ovarian follicle development. It is considered to occur when 12 menstrual cycles are missed. [1, 2]

Menopausal transition, or perimenopause, is the period between the onset of irregular menstrual cycles and the last menstrual period. This period is marked by fluctuations in reproductive hormones [3] and is characterized by the following:

Menstrual irregularities

Prolonged and heavy menstruation intermixed with episodes of amenorrhea

Decreased fertility

Vasomotor symptoms

Insomnia

Some of these symptoms may emerge 4 years before menses cease, with a perimenopausal mean age of onset of 47.5 years. [4] During the menopausal transition, estrogen levels decline and levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) increase. [5, 6]

Postmenopause is the phase following the last menstrual period.

Depression

In the United States, 1.3 million women reach menopause annually. Although most women transition to menopause without experiencing psychiatric problems, an estimated 20% have depression at some point during menopause. [7]

Studies of mood during menopause have generally revealed an increased risk of depression during perimenopause, with a decrease in risk during postmenopausal years. The Penn Ovarian Aging Study, a cohort study, found depressive symptoms to be increased during the menopausal transition and decreased after menopause. [8] The strongest predictor of depressed mood was a prior history of depression, along with fluctuations in reproductive hormone levels associated with depressed mood.

In a cross-sectional population survey from the Netherlands, 2103 women were asked to rate their symptoms of depression before menopause and 3.5 years later, during the menopausal transition; the women experienced most symptoms of depression during the menopausal transition. In the United States, a study of a community sample of women undergoing natural menopause also demonstrated an increase in depressive symptoms during perimenopause. [9]

Investigators from the Harvard Study of Moods and Cycles recruited premenopausal women aged 36–44 years with no history of major depression and followed up these women for 9 years to detect new onsets of major depression; they found that women who entered perimenopause were twice as likely to have clinically significant depressive symptoms as women who had not yet made the menopausal transition. [10]

Research has shown that reproductive hormones produced during menopause contribute to mood alterations, such as depression. [11] Higher testosterone levels may directly lead to higher depressive symptoms during the menopausal transition. Menopausal status, however, remains an independent predictor of depressive symptoms. [12]

Problems with sleep

Insomnia occurs in 40–50% of women during the menopausal transition, and problems with sleep may or may not be connected to mood disorders. [13] Women with insomnia are more likely than others to report problems such as anxiety, stress, tension, and depressive symptoms.

Sleep disturbances during menopause have been associated with estrogen deficiency; exogenous estrogen has been shown to improve both subjective and objective sleep, attributed to a decrease in hot flashes. [14] One study suggested that elevated LH levels during late menopause produce poor sleep quality through a thermoregulatory mechanism, resulting in high core body temperatures. [15]

Whether the sleep problems are associated with age-related changes in sleep architecture, hormonal status, or other symptoms of menopause (eg, vasomotor symptoms) is unclear. However, in the Medical Research Council National Survey of Health, women who were transitioning into menopause were more likely to report severe sleep difficulty than women who were premenopausal. [16]

Rates of sleep apnea increase with age, rising from 6.5% in women aged 30–39 years to 16% in women aged 50–60 years. The pathophysiology is not known, but theories include a relation to postmenopausal weight gain or to decreased progesterone levels (because progesterone stimulates respiration). [17, 18] Besides undergoing changes in estrogen and progesterone levels, postmenopausal women experience declines in levels of melatonin and growth hormone, both of which have effects on sleep. [19]

Schizophrenia

In most cases, schizophrenia first manifests in young adulthood, with the rate of new cases declining in both male and female individuals after this time. A second peak in the incidence of schizophrenia is noted among women aged 45–50 years; this second peak is not observed in men. [20]

Some researchers have observed a worsening of the course of schizophrenia in women during the menopausal transition. These observations suggest that estrogen may play a modulatory role in the pathophysiology of schizophrenia. [21]

Panic disorder

Panic disorder is common during perimenopause. New-onset panic disorder may occur during menopause, or preexisting panic disorder may worsen. Panic disorder may be most common in women with many physical symptoms of menopause. [22] In a cross-sectional survey of 3369 postmenopausal women aged 50–79 years, panic attacks were most prevalent among women in the menopausal transition. These attacks were associated with negative life events, functional impairment, and medical comorbidity. [23]

Obsessive-compulsive disorder

New-onset obsessive-compulsive disorder (OCD), a relapse of OCD, or a change in OCD symptoms may occur during menopause. Fluctuations in OCD have been correlated with the menstrual cycle and with pregnancy, suggesting that hormone levels may contribute to the disorder. [24]

Bipolar disorder

Exacerbation of mood symptoms during menopause has been noted in women with preexisting bipolar disorder. Research has suggested that women with bipolar disorder have higher rates of depressive episodes during the menopausal transition. The frequency of depressive episodes in this population appears to be higher than during premenopausal years. [25] Earlier studies suggested an increase in rapid cycling during the menopausal transition; however, this finding has not been reproduced. [26]

Depression during perimenopause is likely due to fluctuating and declining estrogen levels in part. Steroid hormones, such as estrogen, act in the central nervous system (CNS) by means of various mechanisms. For instance, they stimulate the synthesis of neurotransmitters, the expression of receptors, and influence membrane permeability. [27]

Estrogen increases the effects of serotonin and norepinephrine, which are thought to be the neurotransmitters most related to the physiologic cause of depression. Among other mechanisms, estrogen decreases monoamine oxidase (MAO) activity in the CNS, hindering the breakdown of serotonin and norepinephrine. [2]

In addition, estrogen increases serotonin synthesis, upregulates 5-hydroxytryptamine (5-HT)-1 (5-HT1) receptors, and downregulates 5-HT2 receptors. Estrogen also increases norepinephrine activity in the brain, perhaps by decreasing reuptake and degradation through inhibition of the enzymes MAO and catechol O-methyltransferase. [28]

Although the precise mechanisms are yet unknown, regulation of serotonin and norepinephrine may change as estrogen levels fluctuate and thus contribute to depression. Because estrogen facilitates the actions of serotonin and norepinephrine, a decline in estrogen concentrations may, in turn, decrease levels of these hormones. [2, 27, 28] Changes in estrogen levels, perhaps due to mechanisms involving these neurotransmitters, may be related to depressive symptoms in the menopausal transition of some women.

Causes of menopause-related mood disorders may include hormonal changes, life stressors, psychological or social conditions, and a preexisting tendency toward depression.

Observations and data suggest that depression is significantly linked to times of hormonal change in women. [29]  For example, the disparity in depression rates between women and men begins at puberty. Also, hormonal changes are thought to contribute to premenstrual dysphoric disorder, as well as mood changes post partum and in perimenopause. [30, 31]

Furthermore, estrogen affects both serotonin and norepinephrine, the 2 neurotransmitters thought to be most directly associated with depression. However, absolute levels of gonadal hormones are not correlated with depression. Estrogen and progesterone levels do not distinguish a woman with depression from one without depression.

When hormone concentrations were measured in perimenopausal or postmenopausal women with depression, no abnormal levels were found. [32] Rather, a certain subset of women seem to be predisposed to experience mood disturbances triggered by hormonal fluctuations. This subset includes women with a history of mood disorders or of premenstrual and postpartum mood-related symptoms.

The risk of depression appears to be higher during perimenopause, when hormone levels are changing, than during postmenopause, when estrogen and progesterone levels are low but stable. [27, 33, 8]

Societal roles and expectations may contribute to the heightened rate of depression in women. Women with particular types of stressors seem to be at increased risk for perimenopausal depression. Such stressors include the following: [7, 31]

Lack of social support

Unemployment

Surgical menopause

Poor overall health status

Dysphoric mood during the early perimenopausal transition is most common in women with relatively low educational status. Therefore, low levels of education may be a marker for other stressors, such as ongoing low socioeconomic status. [34]

An Australian study of women transitioning to menopause revealed more depression in women with the following states: [35]

Negative mood before menopause

Negative attitude toward menopause and aging

Smoking

Little or no exercise

No partner

A number of bothersome symptoms

Poor self-perceived health

Negative feelings toward partner

A number of perceived problems

Interpersonal stress

Other stressors that tend to correspond with perimenopause and that are postulated to relate to depression include the following:

Onset of illness in self or others

Care of aging parents

Changes in employment

Numerous psychological and social theories have been proffered to explain why women may become depressed during perimenopause. Some of these are related to the following factors:

Change in the childbearing role

Loss of fertility, which may be associated with a loss of an essential meaning of life

Empty-nest syndrome – Surveys have indicated, however, that women whose children have moved out of the house tend to report more happiness and enjoyment in life than others do

Societal value of youth – In societies where age is valued, women tend to report having fewer symptoms at the menopause transition

A personal or family history of major depression, postpartum depression, or premenstrual dysphoric disorder seem to be a major risk factor for depression in the perimenopausal period. [7] However, perimenopausal depressive syndrome is a risk even in women without a history of depression.

Each year in the United States, 1.3 million women reach menopause. An estimated 20% of these women experience depression. [7] The mean age of onset for the menopausal transition is 47.5 years. [4]

Depression is approximately twice as common in women as in men (21% vs 12.7%). Moreover, depressive episodes are more recurrent, longer, worse, and more impairing for women than for men. [30, 31] In addition, the prevalence of dysthymia and minor depression is increased among women. These differences have not been noted for mania. Sex-related differences emerge at the age of 11–15 years. [36]

The racial distribution of perimenopausal depression is not known. However, in countries where older women are highly valued, women experience fewer symptoms overall during menopause.

Symptoms of perimenopause include the following:

Hot flashes

Cold sweats

Irregular menstrual bleeding

Urogenital atrophy and dryness with resultant dyspareunia (see Gynecologic Pain), itching, and urinary urge incontinence

Cognitive and affective disturbance

Essential criteria for major depression include depressed mood, decreased interest or pleasure in activities, or both. Additional criteria include the following:

Increased or decreased appetite

Weight change

Insomnia or hypersomnia

Psychomotor agitation or retardation

Feelings of worthlessness or guilt

Decreased concentration

Indecisiveness

Suicidal ideation and plans

Homicidal thoughts and plans

Overlapping symptoms of depression and perimenopause include the following:

Low energy

Impaired concentration

Sleep disturbances

Weight changes

Libido changes

Symptoms of depression may includethe following suggestive features from a Mental Status Examination:

Motor retardation or agitation

Latency of response to questions

Slowed thought process

Diminished prosody of speech

Poor eye contact

Poor grooming or hygiene (may indicate advanced depression)

Physical findings associated with perimenopause include urogenital atrophy, as well as flushing and diaphoresis during hot flashes.

Problems to be considered in the differential diagnosis include the following:

Adjustment Disorders

Anemia

Depression

Dysthymic Disorder

Hypothyroidism

Dementia

Depression secondary to a general medical condition

Endocrine disorders (eg, hypothyroid)

Substance abuse

Use of medications, such as beta-blockers

Thyroid-stimulating hormone (TSH) levels should be determined. Monitor patients for hypothyroidism because thyroid disease is an independent risk factor for depression in menopausal women. [9]

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels should also be measured. Because ovarian production of inhibin and estrogen declines during perimenopause (see Ovarian Insufficiency), FSH and, later, LH levels begin to increase. An FSH level higher than 40 IU/L is often used as a marker of menopausal changes. Patients may begin to notice changes before laboratory values reflect the changes.

A hematocrit should be obtained; anemia can be associated with depressive-type symptoms. Dual-energy X-ray absorptiometry (DEXA) scanning is indicated to evaluate bone mineral density (BMD). Depression may be a risk factor for osteoporosis in postmenopausal women. A Mental Status Examination (MME) must be performed.

In treating mood disorders that arise in association with menopause, primary care providers, gynecologists, and psychiatrists often find it helpful to work collaboratively.

Drugs used to treat perimenopausal depression include antidepressants and hormones.

Antidepressant therapy

For major depression, standard antidepressants are first-line treatments. Selective serotonin reuptake inhibitors (SSRIs) are the antidepressants most commonly used in the treatment of perimenopausal depression. These drugs act by inhibiting serotonin reuptake transporters in the presynaptic neuron, making more serotonin available at the synaptic cleft. The time to onset of action is 4–6 weeks.

SSRIs are thought to be generally safe and effective. They do pose a risk of serotonin syndrome, as well as several common adverse effects (eg, nausea, diarrhea, anorexia, excessive sweating, decreased libido or anorgasmia, headache, jitteriness, dizziness, sedation or activation, insomnia, and akathisia). Several of these medications inhibit the cytochrome P450 (CYP450) enzymes; therefore, it is prudent to check for drug interactions.

Hormone replacement therapy

For mild depression, hormone replacement therapy alone may be appropriate. Estrogen may be used when traditional antidepressants failed, when patients refuse psychotropic medications, or when patients experience other clinically significant vasomotor symptoms. [21, 37] Women who have surgically induced menopause have an increased risk of depression, [38] and they may be especially likely to benefit from hormone replacement therapy.

Results from studies of hormone treatments for depression have been inconsistent. Data from several studies suggested that estrogen replacement therapy had antidepressant effects or that it enhanced the effects of antidepressant treatment in perimenopausal women. [37, 39, 40, 41, 42, 43] Other studies did not show that estrogen adds to the effects of SSRIs. [42, 44] In general, such treatments appear to be helpful for managing depressive symptoms in perimenopause but not in postmenopause. [4, 21, 45]

Debate exists regarding whether the antidepressant effect is attributable to the effect of estrogen on vasomotor symptoms. Some studies reveal an antidepressant benefit only in women with vasomotor symptoms. Results of other studies suggest an independent antidepressant effect. [46, 47]

In women with mild mood-disorder symptoms that do not meet the criteria for depression, hormone replacement therapy may be considered. The effects of estrogen treatment have been studied in perimenopausal women without depression to see if it has a positive effect on mood or quality of life. Results from small studies have suggested a small positive impact on mood. [48, 49] However, most data suggest that, among healthy women without depression, estrogen has no favorable effect on quality of life or mood. [46, 50, 51]

SSRIs are sometimes used to treat hot flashes. Paroxetine, controlled-release paroxetine, extended-release venlafaxine, and escitalopram may provide some benefit. [3, 52, 53] Clonidine and gabapentin have been shown to reduce hot flashes. [52]

Estrogen may be helpful in relieving vasomotor symptoms that disrupt sleep or that may have a direct effect on sleep itself. [18]

In a study of postmenopausal women with hot flashes, night sweats, insomnia, anxiety, or mood swings, low-dose estrogen and low-dose micronized progesterone improved sleep to a greater extent than could be explained by a reduction in vasomotor symptoms. [48]

One study using polysomnographic analysis found that isoflavone treatment is also effective in reducing insomnia symptoms. [54]

Data from observational studies suggest that estrogen may prevent or delay the onset of dementia, including Alzheimer disease, especially when estrogen therapy is started in young postmenopausal women. [21]

The data do not suggest that estrogen is helpful for maintaining cognitive function in all perimenopausal and postmenopausal women. The Women’s Health Initiative Memory Study (WHIMS) was a study of postmenopausal women older than 65 years who were unlikely to have preexisting dementia. The women were monitored by means of serial Mini Mental Status Examinations. No improvement in global cognitive functioning was observed with estrogen treatment. [55]

Negative anticipation of menopause seems to be associated with elevated rates of depression and physical symptoms of menopause. Educational groups that help women learn what to expect during menopause decrease anxiety, depression, and irritability, both immediately after the group therapy and 1 year later. [56]

Psychiatric hospitalization is indicated for patients who are at imminent risk of harming themselves or others and for those whose depressive symptoms render them unable to care for themselves.

A healthy, balanced diet is advisable. Regular exercise is thought to be helpful in diminishing the symptoms of depression.

Although morbidity and mortality secondary to perimenopausal depression has not been studied, depression is known to be a significant health problem in women. According to the World Health Organization’s Global Burden of Disease Study, unipolar depression is the leading cause of disease-related disability in women. [36] In this study, unipolar major depression was second to only ischemic heart disease in terms of associated morbidity and mortality. [57]

The Study of Women’s Health Across the Nation suggests that women are at higher risk for major depression during and immediately after the menopausal transition and that the risk is smaller when they are premenopausal. [58]

Patients may benefit from learning that mood symptoms are not uncommon during menopause. Providing education about depressive symptoms can help women understand their experiences and recognize depression as a treatable illness. Family members may also benefit from learning about the symptoms of major depression and the association of its onset with the menopausal transition. This information may help them understand changes they observe in their family member.

Patients should be educated about emergency mental health services that are available in their area. They should be aware of how to obtain help if they have suicidal thoughts. Useful patient education resources include the following:

Menopause Center from eMedicineHealth, which addresses numerous topics related the change of life, such as causes, symptoms, when to seek medical care, self-care at home, and prevention of problems associated with menopause

Menopause Health Center from WebMD

Midlife Transitions: A Guide to Approaching Menopause from The American College of Obstetricians and Gynecologists (ACOG)

National Institute on Aging 

Menopause from Medline Plus, a service of the US National Library of Medicine and the National Institutes of Health (NIH)

Menopause Age Page also available in Spanish, from the National Institute on Aging

NIH State-of-the Science Conference Statement on Management of Menopause-Related Symptoms

Women’s Health Initiative, conducted by the US Department of Health and Human Services (DHHS), the NIH, and the National Heart, Lung, and Blood Institute – In particular, see Questions and Answers About Estrogen-Plus-Progestin Hormone Therapy, Facts About Menopausal Hormone Therapy, and Health Recommendations for Postmenopausal Women

Menopause & Hormones informational materials (also available in Spanish) from the US Food and Drug Administration (FDA)

Understanding Menopause from The National Women’s Health Information Center and the DHHS

The North American Menopause Society

Menopause Support Group message boards hosted by WebMD

Overview

How is menopause defined?

What causes new-onset panic disorder in menopause?

What is perimenopause?

What is the prevalence of depression in menopause?

What is the role of testosterone in the etiology of menopausal depression?

What is the prevalence of insomnia in menopause?

What causes sleep disturbances in menopause?

What causes sleep apnea in menopause?

What causes a peak in the incidence of schizophrenia during menopause?

What causes new-onset OCD in menopause?

What triggers exacerbations of mood symptoms in bipolar disorder during menopause?

What is the pathophysiology of mood disorders in menopause?

What are causes of menopause-related mood disorders?

What is the role of hormonal changes in the etiology of mood disorders during menopause?

Which stress factors may increase the risk of mood disorders during menopause?

What are risk factors for depression during menopause?

Which psychological or social conditions increase the risk for mood disorders during menopause?

How does a personal or family history of depression affect the risk for perimenopausal depression?

What is the prevalence of mood disorders during menopause?

Which clinical history findings are characteristic of perimenopausal depression?

Which findings on a mental status exam suggest perimenopausal depression?

Which physical findings are characteristic of perimenopause?

Which conditions are included in the differential diagnoses of menopause?

What is the role of lab tests in the workup of mood disorders during menopause?

Which specialist consultations are beneficial in the treatment of mood disorders during menopause?

How is perimenopausal depression treated?

What is the role of antidepressant therapy in the treatment of perimenopausal depression?

What is the role of HRT in the treatment of perimenopausal depression?

What is the role of HRT in the treatment of mood disorders during menopause?

How are hot flashes in menopause treated?

How are sleep disorders in menopause treated?

How does HRT for menopause affect cognitive functioning?

What is the role of group therapy in the treatment of mood disorders during menopause?

When is psychiatric inpatient treatment indicated for mood disorders during menopause?

Which dietary modifications are used in the treatment of mood disorders during menopause?

What is the prognosis of perimenopausal depression?

What is included in the patient education about mood disorders during menopause?

Where are patient education resources regarding mood disorders during menopause found?

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Nita V Bhatt, MD, MPH Assistant Professor, Associate Clerkship Director, Department of Psychiatry, Wright State University, Boonshoft School of Medicine

Nita V Bhatt, MD, MPH is a member of the following medical societies: American Medical Association, American Psychiatric Association, Ohio Psychiatric Physicians Association

Disclosure: Nothing to disclose.

Ana Hategan, MD, FRCPC Associate Clinical Professor, Department of Psychiatry and Behavioral Neurosciences, Division of Geriatric Psychiatry, McMaster University School of Medicine; Geriatric Psychiatrist, St Joseph’s Health Care Hamilton, Canada

Ana Hategan, MD, FRCPC is a member of the following medical societies: Canadian Academy of Geriatric Psychiatry, Canadian Coalition for Seniors’ Mental Health, Canadian Psychiatric Association, International Psychogeriatric Association, Ontario Medical Association, Royal College of Physicians and Surgeons of Canada

Disclosure: Book royalties and/or honoraria for articles from American Psychiatric Publishing, Springer, and Current Psychiatry.

Stacey B Gramann, DO, MPH Adult Psychiatry Resident, Psychiatry Residency Training Program, University of Massachusetts Medical School

Stacey B Gramann, DO, MPH is a member of the following medical societies: American Osteopathic Association, American Psychiatric Association, Massachusetts Medical Society, Phi Beta Kappa

Disclosure: Nothing to disclose.

Sarah C Langenfeld, MD Assistant Professor, Department of Psychiatry, University of Massachusetts Medical School; Attending Psychiatrist, Community HealthLink

Disclosure: Nothing to disclose.

Rebecca S Lundquist, MD Consulting Staff, Department of Psychiatry, UMass Memorial Medical Center

Rebecca S Lundquist, MD is a member of the following medical societies: American Psychiatric Association

Disclosure: Pfizer Salary Employment; Biogen Salary Employment

Mohammed A Memon, MD Chairman and Attending Geriatric Psychiatrist, Department of Psychiatry, Spartanburg Regional Medical Center

Mohammed A Memon, MD is a member of the following medical societies: American Association for Geriatric Psychiatry, American Medical Association, and American Psychiatric Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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