Menopause and Mood Disorders

Menopause and Mood Disorders

Background

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.

Menopausal transition, or perimenopause, is a defined period of time beginning with the onset of irregular menstrual cycles until the last menstrual period, and is marked by fluctuations in reproductive hormones.³ This period is characterized by menstrual irregularities; prolonged and heavy menstruation intermixed with episodes ofamenorrhea, decreased fertility, vasomotor symptoms; and insomnia. Some of these symptoms may emerge 4 years before menses ceases, 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. Postmenopause is the phase following the last menstrual period.

Depression during menopause

In the United States, 1.3 million women reach menopause annually. Although most women transition tomenopause without experiencing psychiatric problems, an estimated 20% have depression at some point during menopause.⁵

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, showed depressive symptoms increased during the menopausal transition, and decreased after menopause. The strongest predictors of depressed mood was a prior history of depression, along with fluctuations in reproductive hormone levels associated with depressed mood.⁶

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.⁷ 

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. Women who entered perimenopause were twice as likely as women who had not yet made the menopausal transition to have clinically significant depressive symptoms.⁸ 

Recent research has shown that reproductive hormones produced during menopause contribute to mood alterations, such as depression. Higher testosterone levels may directly lead to higher depressive symptoms during the menopausal transition. Menopausal status, however, remains an independent predictor of depressive symptoms.⁹

Problems with sleep during menopause

Insomnia occurs in 40-50% of women during the menopausal transition, and problems with sleep may or may not be connected to mood disorders.¹⁰ Women with insomnia are more likely than others to report problems such asanxiety, stress, tension, and depressive symptoms.

Sleep disturbances during menopause have been associated with estrogen deficiency, as exogenous estrogen has been shown to improve both subjective and objective sleep, attributed to a decrease in hot flashes. A recent study proposed elevated LH levels during late menopause produce poor sleep quality through a thermoregulatory mechanism, resulting in high core body temperatures.¹¹ 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 compared with women who were premenopausal.¹² 

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 relationship to postmenopausal weight gain or to decreased progesterone levels because progesterone stimulates respiration.^13,14 In addition to undergoing changes in estrogen and progesterone levels, postmenopausal women experience a decline in melatonin andgrowth hormone levels, both of which have effects on sleep.¹⁵

Schizophrenia during menopause

In most cases, schizophrenia first manifests in young adulthood, with the rate of new cases declining in both male and female individuals after early adulthood. A second peak in the incidence of schizophrenia is noted among women aged 45-50 years; this second peak is not observed in men.¹⁶

Some researchers have observed a worsening of the course of schizophrenia in women during the menopausal transition. These observations may suggest that estrogen plays a modulatory role in the pathophysiology of schizophrenia.¹⁷

Panic disorder during menopause

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.¹⁸ 

In a cross-sectional survey of 3,369 postmenopausal women aged 50-79 years, panic attacks were most prevalent among women in the menopausal transition. Panic attacks were associated with negative life events, functional impairment, and medical comorbidity.¹⁹ 

Obsessive-compulsive disorder during menopause

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.²⁰

Bipolar disorder during menopause

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.²¹ Earlier studies suggested an increase in rapid cycling during the menopausal transition; however, this finding has not been reproduced.²²

Pathophysiology

Depression during perimenopause is likely due to fluctuating and declining estrogen levels in part. Steroid hormones, such as estrogen, act in the CNS by means of various mechanisms. For instance, they stimulate the synthesis of neurotransmitters, the expression of receptors, and influence membrane permeability.²³

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 break down 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 due to inhibition of the enzymes MAO and catechol O-methyltransferase.²⁴

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.^2,23,24Changes in estrogen levels, perhaps due to mechanisms involving these neurotransmitters, may be related to depressive symptoms in the menopausal transition of some women.

Frequency

United States

Each year, 1.3 million women reach menopause. An estimated 20% of these women experience depression.⁵

Mortality/Morbidity

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.²⁵ In the Global Burden of Disease Study, unipolar major depression was second to only ischemic heart disease in terms of associated morbidity and mortality.²⁶

Race

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.

Sex

Depression is approximately twice as common in women as in men (21% vs 12.7%). Moreover, depressive are more recurrent, longer, worse, and more impairing for women and for men.^27,28 In addition, the prevalence of dysthymia and minor depression is increases among women. These differences have not been noted for mania. Sex-related differences emerge at the age of 11-15 years.²⁵

Age

The mean age of onset for the menopausal transition is 47.5 years.⁴

Clinical

History

Perimenopause

• 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

Major depression
Essential criteria include the following:

• Depressed mood and/or
• Decreased interest or pleasure in activities

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

• Low energy
• Impaired concentration
• Sleep disturbances
• Weight changes
• Libido changes

Depression (with the 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 of perimenopause include urogenital atrophy, as well as flushing and diaphoresis during hot flashes.

Causes

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

Hormonal changes

Depression seems to be significantly linked to times of hormonal change in women. Several observations and study data support this theory. For example, the disparity between rates of depression in women and men begins at puberty. Also, hormonal changes are thought to be major contributors to premenstrual dysphoric disorder, as well as mood changes experienced in the postpartum period and at the menopausal transition.^27,28 Furthermore, estrogen affects both serotonin and norepinephrine, the 2 neurotransmitters thought to be most directly associated with depression.

Of note, 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.²⁹ Rather, a certain subset of women seem to be predisposed to have 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.^23,30,6

Life stressors

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^5,28 :

• 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.³¹

An Australian study of women transitioning to menopause revealed more depression in women with the following states³² :

• 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

Psychological or social conditions

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 (However, surveys have indicated that women whose children have moved out of the house tend to report more happiness and enjoyment in life than do others.)
• Societal value of youth (In societies where age is valued, women tend to report having fewer symptoms at the menopause transition.)

Preexisting tendency to develop depression

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.⁵ However, perimenopausal depressive syndrome is a risk even in women without a history of depression.