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Evidence-Based Reviews

Perimenopausal depression: Covering mood and vasomotor symptoms

Hormones, antidepressants, or psychotherapy—what would you recommend?

Vol. 7, No. 10 / October 2008

Symptoms of perimenopausal depression are not inherently different from those of depression diagnosed at any other time in life, but they present in a unique context:

  • Hormonal fluctuations may persist for a long duration.
  • Women experiencing hormonal fluctuations may be vulnerable to mood problems.
  • Psychosocial/psychodynamic stressors often complicate this life transition.

Managing perimenopausal depression has become more complicated since the Women’s Health Initiative (WHI) studies found fewer benefits and greater risks with hormone replacement therapy (HRT) than had been perceived. This article discusses the clinical presentation of perimenopausal depression, its risk factors, and treatment options in post-WHI psychiatric practice.

Who is at risk?

Perimenopausal depression is diagnosed when onset of major depressive disorder (MDD) is associated with menstrual cycle irregularity and/or somatic symptoms of the menopausal transition.1 Diagnosis is based on the overall clinical picture, and treatment requires a thoughtful exploration of the complex relationship between hormonal function and mood regulation.

Presentation. For many women, perimenopause is characterized by mild to severe vasomotor, cognitive, and mood symptoms (Table 1). Thus, in your workup of depression in midlife women, document somatic symptoms—such as hot flushes, vaginal dryness, and incontinence—and affective/behavioral symp toms such as mood and sleep disturbances.

Table 1

Vasomotor, cognitive, and mood symptoms of perimenopause


Cognitive and mood

Hot flushes

Decreased concentration



Heart palpitations


Painful intercourse

Mood lability

Vaginal dryness and discomfort

Memory difficulty

Sleep disruption




Explore psychiatric and medical histories of your patient and her close relatives. Ask about depression, dysthymia, hypomania, or mood fluctuations around hormonal events such as menses, pregnancy, postpartum, or starting/stopping oral contraceptives. In the differential diagnosis, consider:

  • Is low mood temporally connected with hot flushes and disturbed sleep?
  • Is low mood secondary to stressful life events?
  • Does the patient have another medical illness (such as thyroid disorder) with symptoms similar to depression?
  • Is low mood secondary to anxiety or another psychiatric disorder?

Screening. Menopause is considered to have been reached after 12 months of amenorrhea not due to another cause. Median ages for this transition in the United States are 47.5 for perimenopause and 51 for menopause, with an average of 8 years between regular cycles and amenorrhea.2 Therefore, begin talking with women about perimenopausal symptoms when they turn 40.

Evidence supports screening perimenopausal women for depressive symptoms even when their primary complaints are vasomotor. The Greene Climacteric Scale3 is convenient for quantifying and monitoring perimenopausal symptoms. It includes depressive symptoms plus physical and cognitive markers. The Quick Inventory of Depressive Symptomatology—Self Report (QIDS-SR)4 questionnaire:

  • takes minutes to complete
  • is easy to score
  • quantitates the number and severity of depressive symptoms (see Related Resources).

Psychosocial factors can predict depression at any time in life, but some are specific to the menopausal transition (Table 2).5 The “empty nest syndrome,” for example, is often used to explain depressive symptoms in midlife mothers, but no evidence links mood lability with the maturation and departure of children. What may be more stressing for women is supporting adolescents/young adults in their exit to independence while caring for aging parents.

Table 2

Risk factors for depression in women

Predictive over lifetime

High risk during menopausal transition

History of depression

History of PMS, perinatal depression, mood symptoms associated with contraceptives

Family history of affective disorders

Premature or surgical menopause


Lengthy menopausal transition (≥27 months)

Reduced physical activities

Persistent and/or severe vasomotor symptoms

Weight gain

Negative attitudes toward menopause and aging

Less education


Perceived lower economic status


Perceived lower social support


Perceived lower health status




Stressful life events


History of trauma


Marital dissatisfaction


PMS: Premenstrual syndrome

Sociocultural beliefs about sexuality and menopause may play a role in how your patient experiences and reports her symptoms. In some cultures, menopause elevates a woman’s social status and is associated with increased respect and authority. In others, such as Western societies that emphasize youth and beauty, women may view menopause and its physical changes in a negative light.6

Therefore, give careful attention to the psychosocial context of menopause to your patient and the social resources available to her. Questions to ask include:

  • Has your lifestyle changed recently?
  • Have your husband, family members, or close friends noticed any changes in your functioning?
  • Is there anyone in your life that you feel comfortable confiding in?

Explaining the complexity of this life transition may ease her anxiety by normalizing her experience, helping her understand her symptoms, and validating her distress.

What might be the cause?

Although the exact pathophysiology of perimenopausal depression is unknown, hormonal changes,7 general health, the experience of menopause,8 and the psychosocial context2 likely work together to increase vulnerability for depressive symptoms (Figure).

Figure Biopsychosocial milieu of depression during perimenopauseHormonal fluctuation. The estrogen withdrawal theory7 explains depressive symptoms as resulting from a sustained decline in ovarian estrogen in tandem with spiking secretions of follicle-stimulating hormone by the pituitary. The finding that women with surgical menopause have a higher incidence of depressive symptoms than women with natural menopause supports this hypothesis.

Mood disorders occur across various female reproductive events, and increased risk appears to be associated with fluctuating gonadal hormones. Thus, declining estrogen may be less causative of perimenopausal depression than extreme fluctuations in estradiol activity.9,10

Estrogen interacts with dopamine, norepinephrine, beta-endorphin, and serotonin metabolism. In particular, estrogen facilitates serotonin delivery to neurons across the brain. These findings—and the success of selective serotonin reuptake inhibitors (SSRIs) in treating mood disorders—support the theory that fluctuating estrogen affects the serotonergic system and may cause depressive symptoms.

‘Domino theory.’ Others have hypothesized that depressive symptoms are the secondhand result of somatic symptoms of perimenopause. In a “domino effect,” hot flushes and night sweats disrupt women’s sleep, bringing fatigue and impaired daytime concentration, which lead to irritability and feelings of being overwhelmed.8

This theory, which incorporates perimenopausal hormone changes, is supported by elevated levels of depression in women who report frequent and intense vasomotor symptoms persisting >27 months.2

The psychosocial theory suggests that depression results from increased stress or adverse events.2 Midlife women with depressive symptoms report many possible sources of stress:

  • demanding jobs
  • family responsibilities
  • dual demands of career and family
  • little time for self
  • poverty or employment stressors
  • not enough sleep
  • changing social relationships.

Negative interpretations of aging or the menopausal transition also have been implicated in cross-cultural studies.6 The predictive nature of psychosocial issues for depression during perimenopause supports this theory.

Evidence-based treatment

HRT. Research and clinical reports suggest that estrogen may have antidepressant effects, either alone or as an adjunct to antidepressant medication.11 Before the WHI studies, expert consensus guidelines on treating depression in women recommended HRT as first-line treatment for patients experiencing a first lifetime onset of mild to moderate depression during perimenopause.12 WHI findings since 2002 that associated HRT with increased risk of stroke, deep vein thrombosis, and pulmonary embolism—without clear protection against coronary heart disease or cognitive decline—have left HRT a controversial option for treating perimenopausal depression. In the WHI trials:

  • 10,739 postmenopausal women age 50 to 79 without a uterus received unopposed conjugated equine estrogens, 0.625 mg/d, or placebo for an average 6.8 years.13
  • 16,608 postmenopausal women age 50 to 79 with an intact uterus received combination HRT (conjugated equine estrogens, 0.625 mg/d, plus 2.5 mg of medroxyprogesterone), or placebo for an average 5.6 years.14

The study using combination HRT found increased risks of breast cancer, ischemic stroke, blood clots, and coronary heart disease.15 A follow-up study showed that vasomotor symptoms returned in more than one-half the women after they stopped using combination HRT.15

A companion WHI trial found that estrogen, 0.625 mg/d—given unopposed or with a progestin—did not prevent cognitive decline in women age 65 to 79 and may have been associated with a slightly greater risk of probable dementia.16,17

The FDA recommends that women who want to use HRT to control menopausal symptoms use the lowest effective dose for the shortest time necessary.18

Antidepressants. SSRIs may be more useful than estrogen for producing MDD remission in perimenopausal women.19 SSRIs and other psychotropics may reduce perimenopausal vasomotor symptoms in addition to addressing depressive symptoms (Table 3). When choosing antidepressant therapy, consider the patient’s dominant presenting perimenopausal symptoms and side effects associated with treatment.20

Table 3

Nonhormone medications for perimenopausal depression: Evidence-based dosages and target symptoms


Dosage effective for perimenopausal depression

Symptoms assessed



40 to 60 mg

Depressive and vasomotor


5 to 20 mg

Depressive and vasomotor


20 to 40 mg

Depressive and vasomotor


12.5 or 25 mg

Depressive and vasomotor


100 mg

Depressive and vasomotor

Other antidepressants


60 to 120 mg

Depressive and vasomotor


75 to 225 mg

Depressive and vasomotor


30 to 60 mg

Severe depressive symptoms; used as an adjunct to estrogen



3 mg

Depressive and vasomotor; insomnia


5 to 10 mg




300 to 900 mg


SSRIs: selective serotonin reuptake inhibitors

Source: Reference Citations

Nonpharmacologic interventions are viable options for women who are reluctant to begin HRT or psychotropics.

Psychotherapy. Interpersonal psychotherapy (IPT) and cognitive-behavioral therapy (CBT) have been recommended to address psychosocial elements of perimenopausal mood lability.21 For women with climacteric depression, IPT focuses on role transitions, loss, and interpersonal support, whereas CBT focuses on identifying and altering negative thoughts and beliefs.

Although no randomized trials have examined psychotherapies for perimenopausal depression, a pilot open trial provided group CBT—psychoeducation, group discussion, and coping skills training—to 30 women with climacteric symptoms. Anxiety, depression, partnership relations, overall sexuality, hot flushes, and cardiac complaints improved significantly, based on pre- and post-intervention surveys. Sexual satisfaction and the stressfulness of menopausal symptoms did not change.22

Integrative medicine. Plant-based substances and herbal remedies such as phytoestrogens, red-clover isoflavones, black cohosh, and evening primrose oil have been included in a few research investigations, and the evidence is equivocal. Because of potential interactions between alternative therapies and medications, inquire about their use. Although a comprehensive review of integrative medicine for perimenopausal symptoms is beyond the scope of this article, see suggested readings (Box).


Integrative medicine treatments for perimenopausal symptoms: Suggested resources

  • Albertazzi P. Non-estrogenic approaches for the treatment of climacteric symptoms. Climacteric 2007;10(suppl 2):115-20.
  • Blair YA, Gold EB, Zhang G, et al. Use of complementary and alternative medicine during the menopause transition: longitudinal results from the Study of Women’s Health Across the Nation. Menopause 2008;15:32-43.
  • Freeman MP, Helgason C, Hill RA. Selected integrative medicine treatments for depression: considerations for women. J Am Med Womens Assoc 2004;59(3):216-24.
  • Mischoulon D. Update and critique of natural remedies as antidepressant treatments. Psychiatr Clin North Am 2007;30:51-68.
  • Thachil AF, Mohan R, Bhugra D. The evidence base of complementary and alternative therapies in depression. J Affect Disord 2007;97:23-35.
  • Tremblay A, Sheeran L, Aranda SK. Psychoeducational interventions to alleviate hot flashes: a systematic review. J North Am Menopause Soc 2008;15:193-202.

Clinical recommendations

Explore options with your patient; discuss side effects, risks, and expected minimum duration of treatment. Antidepressants, hormonal therapies, psychotherapy, and complementary and alternative treatments each might have a role in managing perimenopausal depression. A patient’s preferences, psychiatric history, and depression severity help determine which options to consider and in what order. How she responded to past treatments also can help you individualize a plan.

HRT may be appropriate for women who express a preference for HRT, have responded well to past hormone therapy, and have no personal history or high-risk factors for breast cancer. Based on the WHI findings, we consider a history of breast cancer in the patient or a first- or second-degree relative a contraindication to HRT.

Estrogen can be used alone or with an antidepressant. Studies support 17β-estradiol, 0.1 to 0.3 mg/d, for 8 to 12 weeks.11,23 Concomitant progesterone may be indicated to offset the effects of unopposed estrogen in women with an intact uterus. This option calls for an informed discussion with the patient about risks and benefits.

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