Vol. 15 •Issue 10
• Page 45
Transition to Depression?
Perimenopause, Menopause and Mental Health
By Deborah Antai-Otong, NP
Each year in the United States, approximately 1.3 million women reach menopause.1 Although menopause is permanent, most of its symptoms are transitory. During the transition from perimenopause to menopause, women may experience severe vasomotor symptoms, insomnia and major depression. At times, these symptoms may be severe enough to require treatment.
Estrogen deficiency and hormonal variance are clearly associated with depression during menopausal transition, but whether women generally experience an increased vulnerability to depression during this stage is unclear. Some research suggests that hormonal changes during midlife may contribute to depression, psychosocial impairment and decreased quality of life.2-6
Despite vulnerability to depression during menopausal transition, most women do not exhibit depression symptoms during this period.7,8 The extent to which clinical menopausal symptoms cause major depression during menopausal transition is not fully understood. Inconsistencies in research findings are the result of poor study design, lack of uniformity in subject selection, methodology limitations, different practice settings, and a lack of standardized instruments to evaluate clinical presentations.1,9
Findings from several community and clinic-based studies indicate that perimenopausal women report more depressive complaints than premenopausal or menopausal women, implicating biological changes during this stage as a risk for depression.10 Also during perimenopause, vasomotor symptoms often cause insomnia and depression.11,12
These data suggest that nurse practitioners must evaluate the severity of vasomotor symptoms and their impact on mental, physical, emotional and functional status. Nurse practitioners can improve their ability to evaluate and treat midlife women by building an understanding of the complexity of hormonal and neurotransmitter alterations that occur during menopausal transition.
Neurobiology
The natural course of menopause transition begins during the mid-40s and persists through the early 50s, often lasting 2 to 8 years. A growing amount of evidence suggests that perimenopause is the period of greatest vulnerability to depression. Some research shows that estrogen use can mitigate depressive symptoms during this time.13
Perimenopause occurs in the 2 to 8 years preceding menopause, and it is a time of significant neuroendocrine and clinical changes. Reductions in estradiol parallel increased follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH levels eventually plateau and provide a biological marker of menopause. Expanded noradrenergic activity and decreased serotonergic activity are also associated with the pathophysiology of vasomotor symptoms. Early manifestations of perimenopause vary, but they generally involve marked biological fluctuation arising from hormonal and physical changes.14,15
Estrogen has been implicated in depression and vasomotor symptoms because estrogen therapy has demonstrated efficacy in the management of these symptoms. But its safety as a long-term treatment remains controversial. The association between hormonal fluctuation and major depression and the role of estrogen, one of the most potent neuromodulators in the brain, therefore must be carefully considered in the treatment of depression during perimenopause or menopausal transition. The relationship of hormone therapy to coronary heart disease, stroke, pulmonary embolism and breast cancer continues to generate concerns.16 The biological basis of this stage can guide the treatment of women who present with depressive symptomatology.
Fluctuating estrogen levels have been implicated in the dysregulation of the thermoregulatory circuitry involved in the normalization of body temperature in the hypothalamus. Serotonin and norepinephrine are neuromodulators that may help regulate core body temperature and peripheral vasculature.17 Novel antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), show promise in the management of vasomotor symptoms, anxiety and depression in midlife women.
Vasomotor Symptoms
Some research has demonstrated an association between persistent vasomotor symptoms and increased depression in midlife women. In most women, hot flashes resolve after 1 to 5 years. The precise cause of vasomotor symptoms is poorly understood, but most scientists believe these events involve dysregulation of neurotransmitters including norepinephrine and luteinizing hormone.18 In addition, alterations in thermoregulation and subsequent core body temperature elevation have been associated with norepinephrine activation in perimenopausal women.19
Insomnia
About 40% of perimenopausal women report sleep problems, and as much as 80% may continue to experience insomnia after menopause. Insomnia is associated with reduced estrogen and progesterone secretion (sleep-promoting hormones) and increased activation of norepinephrine. Without treatment, insomnia poses a significant health care problem.20,21
Typically, perimenopausal women have difficulty falling asleep, staying asleep and achieving restorative sleep. Inadequate restorative sleep produces fatigue, irritability and daytime drowsiness. Eventually, a lack of restorative or restful sleep caused by hot flashes and night sweats produces chronic sleep problems, decreased alertness and diminished cognitive acuity.22
Psychosocial Factors
Psychosocial factors often contribute to depression in women across the life span and are not limited to midlife. But unique issues during midlife challenge women to deal with numerous role transitions and interpersonal issues. Increased self-awareness and stronger personal identity, spirituality and sexuality are a common focus of women during this time.
Treatment Considerations
Baseline diagnostic studies for women with symptoms of perimenopausal or menopausal depression include complete blood count with differential, thyroid function tests (e.g., T3, T4, thyroid-stimulating hormone and free thyroxine index), urinalysis, electrocardiogram and blood chemistries to rule out medical and psychiatric conditions.
Ask questions about premenstrual symptoms, duration of symptoms, severity of hot flashes, sleep disturbances and night sweats. The use of complementary therapies, such as St. John's Wort, black cohosh (and any other herbs), soy isoflavones and dietary supplements may mitigate menopausal symptoms. To ensure an accurate diagnosis and appropriate treatment, ask whether the patient is using any of these products.
A comprehensive psychosocial history should include the following information:
reasons for seeking treatment at this time
duration, frequency and nature of current symptoms
impact of symptoms on quality of life and functional status
current stressors
past history of depression and any treatment for it
quality of support systems
coping patterns
assessment of suicide and homicide risk.
A cultural assessment is an integral part of the initial discussion, and findings must be integrated into the plan of care. Include a history of relevant mood changes during menses, the postpartum period and other reproductive cycles.
The absence of a major depressive history is just as significant as a positive history, since the former may increase depression risk during perimenopause.23 A thorough sleep history and evaluation are critical and should include questions about the following:
quality of sleep
frequency and duration of sleep disturbances
severity of vasomotor symptoms
all strategies used in attempts to achieve restful sleep (alcohol, medication, etc.).
If possible, gather supplementary information from the patient's sleeping partner.
Pharmacotherapy
The high correlation between vasomotor symptoms and sleep disturbances and vasomotor symptoms and depression makes early recognition and treatment of hot flashes an important health issue. Nurse practitioners in a wide range of settings treat women who show symptoms of mood changes. Empowering women to explore and discuss available holistic treatment options and to become active participants in decisions about symptom management is critical to their sense of control, self-esteem and overall quality of life.
Estrogen therapy, novel antidepressants, mood stabilizers and alpha-adrenergic receptor agonists are the primary pharmacotherapy options used to treat depression in perimenopause and menopause (see table). Considering the potential adverse effects of estrogen use to manage vasomotor symptoms, conduct a risk-versus-benefit analysis before prescribing it for this use.24,25 To optimize patient acceptance and continuation, learn how and when to prescribe lower dosages of hormone therapy. Despite the controversy over estrogen therapy, some research shows that low-dose (e.g., 0.625 mg/day), short-term use can improve depression symptoms.13,24
Combination therapy with estrogen and SSRIs or SNRIs produces a synergistic effect by modulating serotonin binding. Women with a history of severe premenopausal depression or postpartum depression may be particularly susceptible to mood changes as a result of estrogen fluctuations, and they may benefit from adjuncts to novel antidepressants. Be prepared to assess the risks and benefits of estrogen in the context of reproductive events, including perimenopausal or menopausal transition. Consider other pharmacotherapies for women at risk for breast cancer (e.g., a positive family history of breast cancer or past history of breast cancer).
Mounting data suggest that monotherapy with SSRIs and SNRIs mitigates depressive symptoms, reduces baseline vasomotor symptoms and improves quality of sleep, functional status and quality of life in perimenopausal women.21,26,27 These agents are well tolerated and have a relatively safe side effect profile. The precise mechanisms of their actions are unknown, but vasomotor symptoms are linked to dysregulation of serotonin and norepinephrine.28 When prescribing short-term SSRIs and SNRIs to treat vasomotor symptoms, start with a low dose (e.g., 10 mg citalopram [Celexa], 37.5 mg venlafaxine [Effexor]) and titrate based on response. When prescribing it for major depression, follow current American Psychiatric Association guidelines to determine whether continuation and maintenance treatment (e.g., 6 to 12 months) are indicated.29 Due to the risk of suicide in patients with depression, assess for suicide and homicide risk initially and throughout treatment.
In addition to estrogen and antidepressants, gabapentin (Neurontin), a gamma-aminobutyric acid (GABA) agonist anticonvulsant, can be an effective therapy for hot flashes.30 The normal starting dose for gabapentin is 300 mg three times a day for 12 weeks. Major side effects of this agent are sedation and dizziness.31 Clonidine (Catapres), an alpha-adrenergic receptor agonist, has exhibited modest efficacy in the treatment of vasomotor symptoms. Data indicate that 0.1 mg of clonidine daily for 8 to 12 weeks produces modest reduction in vasomotor symptoms. Its action is believed to be associated with clonidine's ability to reduce noradrenergic activity and decrease arousal.30 Common side effects associated with clonidine include expense, skin irritation, dry mouth and eyes, hypotension, constipation and sedation.
Psychotherapeutic Interventions
Psychotherapeutic interventions are based on target symptoms or behaviors. Collaborate with a mental health professional when working with women who experience depression during perimenopause or menopause. Primary care strategies include encouragement of healthy eating habits, regular exercise, stress management and relaxation techniques. These steps are integral to the treatment of women who complain of depression during hormone transitions. A primary strategy to promote sleep at this time of life is to stay cool at night by drinking cool water, wearing light, breathable sleepwear and controlling aches with nonprescription analgesics.
Cognitive behavioral therapy (CBT) can target low self-esteem associated with psychosocial issues and distorted cognition, such as negative self-talk or "all-or-none" thinking that maintains depression and anxiety. Coupling psychotherapeutic techniques with pharmacotherapy offers women choices for diminishing depression and vasomotor symptoms. It is imperative to enlist women's active participation in decision making when weighing the benefits and risks of treatment options.
Putting It Into Practice
As women enter perimenopause, they are faced with changes and challenges that may include vasomotor symptoms, mood changes and impaired or altered interpersonal relationships. In combination, these factors place many women at risk for major depression in midlife. Nurse practitioners are poised to identify midlife women who are at risk for depression and to offer strategies that will improve sleep, reduce vasomotor symptoms and strengthen coping skills.
References
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2. Halbreich U. Gonadal hormones, reproductive age, and women with depression. Arch Gen Psychiatry. 2000:57(12);1163-1164.
3. Hlatky MA, et al. Quality of life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the Heart and Estrogen/Progestin Replacement Study (HERS) Trial. JAMA. 2002;287(5):591-597.
4. Kaufert PA, et al. The Manitoba Project: a re-examination of the link between menopause and depression. Maturatis. 1992;14(2):143-155.
5. Maartens LW, et al. Menopausal transition and increased depressive symptomatology: a community-based prospective study. Maturatis. 2002;42(3):195-200.
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9. Loh FH, et al. The age of menopause and the menopause transition in a multiracial population: a nation-wide Singapore study. Maturitas. 2005;52(3-4):169-180.
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13. Rossouw JE, et al. Risks and benefits of estrogen plus progestin in healthy menopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
14. World Health Organization. Research on the menopause in the 1990s: report of a WHO scientific group. Geneva, Switzerland: WHO Technical Report Series. No. 866; 1996.
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16. Teede H, Burger HG. The menopausal transition. In: Studd JWW, ed. The Management of Menopause — Annual Book Review. London, England: Parthenon Publishing Group; 1998:221-12.
17. Deecher DC. Physiology of thermoregulatory dysfunction and current approaches to the treatment of vasomotor symptoms. Expert Opin Investig Drugs. 2005;14(4):434-448.
18. Shunji S, Takeuchi T. plasma adenosine levels in peri-menopausal women having frequent hot flushes. Circulation Journal. 2005;69(12):1540-1542.
19. Freedman RR. Pathophysiology and treatment of menopausal hot flashes. Semin Reprod Med. 2005;23(22):117-125.
20. Obermeyer CM, et al. Therapeutic decisions for menopause: results of the DAMES project in central Massachusetts. Menopause. 2004;11(4):456-465.
21. Ohayon MM. Severe hot flashes are associated with chronic insomnia. Arch Intern Med. 2006;166(12):1262-1268.
22. Soares CN. Insomnia in women: an overlooked epidemic? Arch Women's Ment Health. 2005;8(4):205-213.
23. Freeman EW, et al. Associations of hormones and menopausal status in depressed mood in women with no history of depression. Arch Gen Psychiatry. 2006;63(4):375-382.
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25. Freedman RR. Biochemical, metabolic, and vascular mechanisms in menopausal hot flashes. Fertil Steril. 1998;70(2):332-337.
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28. Loprinzi CL, et al. Phase III evaluation of fluoxetine for the treatment of hot flashes. J Clin Oncol. 2002;20(6):1578-1583.
29. Fochtmann L, Gelenberg AJ. Guideline Watch: Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 2nd ed. Chicago, Ill.: American Psychiatric Association; 2005: 1-15. Available at: http://www.psych.org/psych_pract/treatg/pg/MDD.watch.pdf. Accessed July 17, 2007.
30. Guttoso T Jr, et al. Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2003;101(2):337-345.
31. Nelson HD, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006;295(17):2057-2071.
Deborah Antai-Otong is a psychiatric-mental health nurse practitioner and psychotherapist at the Veterans Affairs Medical Center in Fort Worth, Texas, where she is program manager of the Care Coordination Home Telehealth Program, a division of the Veterans Integrated Systems Network. She is a member of the ADVANCE for Nurse Practitioners editorial advisory board.
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