Compared to men, women experience 1.7 times the prevalence of depression, largely because of fluctuations in reproductive hormones.1 Even without a prior history of depression, vulnerability to depressive symptoms may be especially increased during the menopausal transition as a result of greater sensitivity to the extreme fluctuating levels of estrogen, other hormonal influences, and single nucleotide polymorphisms that are unique to women.2–4 PAs need to understand the varying presentations for women with depression, a major health burden and component of the National Commission on Certification of Physician Assistants Blueprint, and to appreciate the nuances of treatment if underlying hormonal fluctuations are driving symptoms. Emerging science is redefining the initial treatment approaches, and traditional therapies for major depression may be inadequate to control the symptom burden of patients with menopausal depression. The purpose of this article is to aid PAs in understanding the hormonal and genetic influences as well as the symptoms of menopausal transition that overlap with symptoms of major depression and to discuss effective assessment and multidisciplinary management of major depression during perimenopause.
HORMONES, MONOAMINES, AND MAJOR DEPRESSION
Fluctuating estrogen levels may play a significant role in the pathogenesis of major depression during the menopausal transition.1 The highest concentrations of estrogen receptors are found in the hippocampus, hypothalamus, cerebral cortex, brainstem, and amygdala, all of which are involved in mood, memory, and cognition. Estrogen enhances the structure of neurons; promotes neuronal growth and firing; increases glucose metabolism in the brain; and enhances levels of key neurotransmitters affecting mood, including the monoamines serotonin, norepinephrine, and dopamine. Serotonin enhances mood and sleep; norepinephrine regulates appetite, libido, and sleep; and dopamine contributes to enhanced interest and pleasure.5 Therefore, precipitous decreases in estrogen may cause depressive symptoms in women during the menopausal transition, even without a prior psychiatric history.1,6
Altered levels of circulating testosterone (both high and low) have also been linked to depressive symptoms, anxiety, and low sexual desire.79 Some women may experience increased sensitivity to circulating testosterone levels as a result of ovarian decline during the menopausal transition. Thyroid hormones as well as L‐methylfolate may also play significant roles in modulating levels of monoamines.10
GENETIC INFLUENCE ON MAJOR DEPRESSION
Advances in gene mapping and pharmacogenomics have begun to inform treatment choices for women experiencing major depression during the menopausal transition. For example, women may carry an estrogen‐dependent galanin polymorphism that contributes to hypothalamic‐pituitaryadrenal axis disruption leading to vegetative depressive symptoms, increased anxiety, and poorer response to antidepressant medications compared with men.4 The presence of an estrogen receptor alpha gene polymorphism unique to women has resulted in worse cognitive and mood outcomes compared with men.3 In addition, a genetic variance in the liver CYP‐450 enzyme system that is responsible for the metabolism of antidepressant medications may also affect treatment response and choice of medication dosage in some women.5
MENOPAUSAL TRANSITION, VASOMOTOR SYMPTOMS, AND DEPRESSION
At about age 47 years, women may begin to experience irregular menses, and by approximately 51 years of age, menstruation may cease. The Stages of Reproductive Aging Workshop (STRAW) defined the perimenopausal stages as follows:
* Early menopausal transition—a change of 7 or more days in menstrual cycle length
* Late menopausal transition—two or more skipped menstrual cycles and 60 or more days of amenorrhea
* Postmenopause—at least 12 months of amenorrhea.11
During the late menopausal transition, women may experience vasomotor symptoms related to estrogen fluctuations for approximately 5 to 7 years. Symptoms that arise during the menopausal transition often include hot flushes, night sweats, heart palpitations, depressed mood, anxiety, poor memory and concentration, dizziness, fatigue, headache, insomnia, joint pain, paresthesias, urogenital atrophy, dyspareunia, osteoporosis, and cardiovascular disease. During the transition, women are two to four times more likely to experience depression even without a prior relevant history, in part because some women are particularly sensitive to the chaotic estrogen fluctuations that regulate the monoamines and therefore the effect they have on both depressive and vasomotor symptoms.1,2 Findings from the Harvard Study of Mood Cycles suggest that women in menopausal transition who experience vasomotor symptoms are at significant risk for onset of symptoms of major depression.2
Disrupted sleep may also contribute to depressive symptoms during the menopausal transition.12 Findings from a recent study comparing depressed women and nondepressed controls with vasomotor symptoms found that depressed women reported worse sleep quality compared with nondepressed women.12 According to the classic “domino theory,” depressive symptoms during menopausal transition may occur as a result of night sweats and hot flushes, which in turn disrupt sleep.12 However, hot flushes are not a universal phenomenon among all women who experience depression during the menopausal transition.13
Whereas major depression is characterized by depressed mood, loss of interest, agitation, a subjective feeling of being slowed down, and suicidal ideation, vasomotor symptoms are characterized by hot flushes and vaginal dryness. Both major depression and vasomotor symptoms share manifestations of low energy, poor concentration, weight gain, insomnia, and decreased libido. Interestingly, results from current evidence‐based research have suggested that residual vasomotor symptoms in women experiencing menopausal transition may be a sign of impending depression relapse.14 In addition, women who experience more severe vasomotor symptoms may be more likely to experience major depression.15 Thus, treating vasomotor symptoms in perimenopausal and menopausal women who have experienced depressive symptoms may be critical in preventing major depression relapse and enhancing remission.
Other factors that may contribute significantly to the onset of major depression during the menopausal transition include a personal history of sexual abuse, prior depression, premenstrual dysphoric disorder, or postpartum blues or postpartum depression; family history of depression; life stress; poor social support; race (increased risk in African American and decreased risk in Asian women); negative attitude toward menopause; poor education; smoking; and increased body mass index (BMI).1,2,14,16,17
- Both major depression and vasomotor symptoms share manifestations of low energy, poor concentration, weight gain, insomnia, and decreased libido.
- Cognitive behavior therapy, psychoeducation, exercise, and sleep hygiene can be beneficial for depression during the menopausal transition.
- Selective serotonin reuptake inhibitors and serotonin‐norepinephrine reuptake inhibitors comprise first‐line therapy for depression during the menopausal transition.
Screening measures The Primary Care Evaluation of Mental Disorders (PRIME‐MD) is a 25‐item questionnaire specifically designed for nonpsychiatric primary care providers.18 The tool is useful for diagnosing depression, alcohol abuse or dependence, binge eating, and somatoform disorders and for ruling out bipolar disorder, depression, and anxiety due to medical conditions. A clinical evaluation guide assists clinicians in follow‐up of positive answers on the one‐page questionnaire, which is completed by the patient prior to the health care appointment. The PRIME‐MD takes approximately 15 minutes to formulate a diagnosis.
The Patient Health Questionnaire‐2 (PHQ‐2) is composed of two questions that assess for sad mood and loss of interest but not for bipolar disorder. Each question is scored from 0 to 3 for a total possible score of 0 to 6. The scale is reported to have 83% sensitivity and 92% specificity.19
The Menopausal Rating Scale (MRS) is an 11‐item, 5‐point Likert scale that assesses for somatic, urogenital, and mood symptoms in women experiencing the menopausal transition. Scores range from 0 to 44, with higher scores indicating greater symptom severity.20,21 Clinicians caring for women with major depression during the menopausal transition should always assess for active suicidality.
Laboratory studies Laboratory tests that can serve as a useful screen for metabolic causes of depression and confirm menopausal status include a thyroid profile, CBC, complete metabolic profile (CMP), urinalysis, and estradiol and folliclestimulating hormone (FSH) determinations. Newly available genetic assays can identify genetic polymorphisms and CYP‐450 enzyme abnormalities to aid clinicians in choosing the most efficacious psychotropic medication.
Nonpharmacologic treatments Cognitive behavior therapy (CBT), psychoeducation, exercise, and sleep hygiene can be beneficial for depression during the menopausal transition.22–24 Psychoeducation aimed at reducing smoking, alcohol intake, and psychological stress may decrease depressive symptoms, as can eating a balanced diet.25 Limited data support the use of black cohosh and St. John's wort in treating depressive symptoms related to the menopausal transition, but further research is needed. A randomized controlled trial of 301 perimenopausal women found that a combination of black cohosh and St. John's wort reduced psychological symptoms by 41.8% in the treatment group compared to 12.7% in the control group over a 16‐week period.26 In a large‐scale study of 6,141 menopausal women in Germany, a combination of black cohosh and St. John's wort was more effective in reducing menopausal mood symptoms than black cohosh alone.27 Clinicians should exercise caution, however, when advising patients about herbal therapies since they may be associated with significant side effects at high doses and may interact with medications; for example, St. John's wort may result in serotonin syndrome when taken with an antidepressant medication.28
Pharmacologic treatments Selective serotonin reuptake inhibitors (SSRIs) and serotonin‐norepinephrine reuptake inhibitors (SNRIs) (Table 1, available online) comprise first‐line therapy for depression during the menopausal transition.29–34 Hypnotics and benzodiazepines can be added to promote sleep and further decrease depressive symptoms.35 Second‐line pharmacologic agents used as adjunctive therapy in treatment resistance include atypical antipsychotics, anticonvulsants, lithium, tetracyclic antidepressants, L‐methylfolate, testosterone, and thyroid supplementation.10,36–41 While primary care clinicians can start women on SSRIs and SNRIs, consultation with or referral to psychiatric specialists for second‐line treatments is warranted in cases of treatment resistance. In addition, women suspected of having bipolar disorder based on the results of a PRIME‐MD evaluation can experience mania when taking an SSRI or SNRI without an accompanying mood stabilizer;42 these patients should also be referred to a psychiatric specialist for management.
Research findings suggest that both SSRIs, eg, citalopram and escitalopram, and SNRIs are efficacious in treating vasomotor and depressive symptoms.30,36 One study found a remission rate of 86.6% with citalopram,36 and another study found a remission rate of 75% for escitalopram.33 While SSRIs tend to work best in the presence of estrogen in perimenopausal women or in women who take estrogen supplementation, SNRIs tend to be efficacious for women in menopausal transition regardless of estrogen levels.30,43 Individualized approaches are best, however, because some women will respond to SSRIs even with low estrogen levels. SSRIs may decrease bone mineral density (BMD) and increase the risk for osteoporosis; therefore, BMD assessment should be considered.44 Efforts to improve sleep with the use of hypnotics or benzodiazepines may also decrease depression during the menopausal transition. The hypnotic eszopiclone was found to be efficacious among 410 perimenopausal and postmenopausal women in reducing both sleep disruption and depressive symptoms.45
In a study assessing efficacy of a tetracyclic antidepressant and an SSRI as an adjunct to estrogen supplementation, remission rates were 87.5% with mirtazapine.41 Atypical antipsychotics may also be beneficial as a secondline adjunct in the treatment of depression during the menopausal transition. In a small study of 24 midlife women with major depression who were treated with the atypical antipsychotic quetiapine, 17 women responded with a 50% decrease in depressive symptoms and 15 achieved full remission.37 Women taking atypical antipsychotics may experience metabolic syndrome, weight gain, dry mouth, and drowsiness. Monthly monitoring of fasting blood sugar levels, lipids, weight, waist circumference, and BMI is recommended during the initiation of atypical antipsychotics, with yearly screening thereafter.46
Although no hormonal therapies are FDA‐approved for treating depression during the menopausal transition, study findings suggest that off‐label use of estrogen replacement therapy (ERT) may be beneficial. Results from a recent study of 72 women suggest that estrogen supplementation may be effective in ameliorating depression among perimenopausal but not postmenopausal women.47 Findings from another study found that although estrogen was not effective for later postmenopausal depression, discontinuing therapy might increase the risk of depression onset.48 ERT has also been shown to improve sleep quality during the menopausal transition by reducing time to sleep onset, decreasing frequency of nighttime awakenings, and improving REM sleep.17
Although the Women's Health Initiative reported that ERT may increase the risk for cardiovascular events overall, further examination of the subgroup of women aged 50 to 59 years in early menopause found a cardioprotective effect.49 Thus, women in early menopause who take ERT may experience reduction in depressive symptoms as well as gain cardiovascular benefits compared with women in later menopause. Progesterone must be prescribed to women with an intact uterus taking estrogen in order to counteract the possibility of endometrial hyperplasia and uterine cancer. Women who are using ERT should be followed for adverse changes in the breasts and endometrium and to monitor their cardiovascular status.
L‐Methylfolate has been the subject of intense investigation in the treatment of depression. Low folate levels within the brain have been linked to depressive symptoms because folate is a critical factor in forming tetrahydrobiopterin (BH4), which in turn is necessary for formation of the monoamines serotonin, norepinephrine, and dopamine.10,38 L‐Methylfolate is the only folate formulation that crosses the blood‐brain barrier to enhance BH4 production. In addition, L‐methylfolate is useful for women who have a C677T polymorphism that prevents conversion of folate into its active form. Women who have folate deficiency as a result of taking mood stabilizers may benefit from the addition of L‐methylfolate as an adjunct for treatment of resistant depression.7
In women who are sensitive to decline in circulating testosterone, supplementation may be helpful in increasing libido and reducing depressive and vasomotor symptoms.50 Among 300 perimenopausal and postmenopausal women who received a subcutaneous testosterone implant, findings suggest significant improvement in psychological, somatic, and urogenital functioning.20 While testosterone has been prescribed for these indications, no testosterone preparation has been approved for use in women, and side effects may include virilization, hirsutism, acne, and increased cardiovascular risk.
Thyroid supplementation with triiodothyronine (T3) in amounts ranging from 25 mcg to 150 mcg may be helpful.51,52 Findings from a study of 17 premenopausal and 22 menopausal women with normal thyroid function found that subclinical hypothyroidism significantly contributed to symptoms of major depression.39 In a pooled synthesis of 444 patients with major depression, thyroid supplementation with T3 in conjunction with an SSRI was efficacious, particularly for those who have atypical depression, treatment‐resistant depression, or a polymorphism in the D‐1 deiodinase gene.52
Treatment and assessment of depression during the menopausal transition requires a multidisciplinary approach that includes primary care clinicians and psychiatric and gynecologic specialists. In order to provide the best patient outcomes, the treatment team should consider the interplay of depression and vasomotor symptoms; effects and levels of estrogen, testosterone, and thyroid hormones and low folate levels, which adversely affect the production of serotonin, norepinephrine, and dopamine in the brain; and genetic polymorphisms specific to women that inform treatment options.
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