Psychosomatics 40:304-308, August 1999
© 1999 The Academy of Psychosomatic Medine
Iatrogenic Acute Estrogen Deficiency and Psychiatric Syndromes in Breast Cancer Patients
Laura Sheingold Duffy, M.D.,
Donna B. Greenberg, M.D.,
Jerry Younger, M.D., and
Marie G. Ferraro, B.A.
Received July 7, 1998; revised September 21, 1998; accepted September 21, 1999. From the Departments of Psychiatry and Medical Oncology, The Massachusetts General Hospital Cancer Center, and Harvard Medical School, Boston, Massachusetts. Address correspondence and reprint requests to Dr. Greenberg, WRN 605, Massachusetts General Hospital, Fruit Street, Boston, MA 02114; e-mail: dgreenberg{at}partners.org
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ABSTRACT
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The change of estrogen function, represented by amenorrhea or hot flashes, that results from breast cancer treatment may increase the risk of major depressive disorder in those women undergoing treatment for breast cancer. This pilot study describes the course of menopausal symptoms and the incidence of depression in 21 patients who were likely to become acutely estrogen deficient during treatment for breast cancer. These included women who lost menses during chemotherapy, who suddenly stopped estrogen replacement therapy (ERT), or who started tamoxifen. Eight patients (38%) developed major depressive disorder, the majority within 6 months of starting treatment. Twenty patients (95%) had dysphoria and/or insomnia. Fourteen patients (66%) had hot flashes. While this is only pilot data, these data suggest that breast cancer patients whose treatment precipitates menopausal symptoms should be targeted for diagnosis of depression and treated if diagnosed.
Key Words: Breast Cancer • Estrogen • Depression
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INTRODUCTION
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Breast cancer diagnosis and treatment with chemotherapy are tough challenges that call upon the coping strategies of any woman. As clinicians, we wondered whether the hormonal modulation embedded in breast cancer treatment raised the risk of major depressive disorder soon after diagnosis. We began a prospective pilot study of the subset of women with breast cancer who were likely to have acute changes in physiological estrogen due to the influence of chemotherapy on ovaries in premenopausal women or due to tamoxifen's anti-estrogen effect in postmenopausal women. Hot flashes, amenorrhea, and the discontinuation of estrogen replacement treatment (ERT) were markers for acute changes in estrogen effect.
Premenopausal women diagnosed with breast cancer often undergo adjuvant chemotherapy, which affects ovarian function leading to temporary or permanent amenorrhea, depending on the woman's age.1 In the setting of adjuvant chemotherapy, the drop in estrogen occurs more rapidly than would occur with the evolution of natural menopause. When a postmenopausal woman is diagnosed with breast cancer, estrogen replacement is discontinued abruptly. Treatment with tamoxifen brings some anti-estrogen effects and the risk of hot flashes. The likelihood of estrogen deficiency has increased as the dose and potency of anti-cancer regimens have increased and as estrogen antagonists have been used in more regimens. Symptoms of acute estrogen deficiency correlated with the severity of psychiatric symptoms reported by 44% of 222 breast cancer patients in a questionnaire study by Couzi.2
Newly diagnosed breast cancer patients who received chemotherapy had a higher risk of depressive symptoms in a multicenter prospective study than those who had not received chemotherapy.3 Certainly, the morbidity of chemotherapy adds to patient discomfort, but the symptoms of estrogen insufficiency, like hot flashes, which may add affective risk, were not evaluated. Estrogen insufficiency might be a critical factor in the tendency for chemotherapy to precipitate a persistent major depressive disorder.
Tamoxifen itself may increase the risk of depression.4 Tamoxifen was more often associated with depressive symptoms in a prospective study of node-negative breast cancer patients. One oncologist serially questioned the node-negative patients for symptoms of depression in the 6–12 months after completion of initial treatment with surgery, radiation, or chemotherapy. Tamoxifen was prescribed if estrogen or progesterone receptors were positive. Twenty-six of 257 (15%) patients treated with tamoxifen (alone or with doxorubicin and cyclophosphamide) had symptoms of depression, compared with 3 (3%) in the group who had chemotherapy or surgery but no tamoxifen. The researcher asked about mood, fatigue, sleep disturbance, early morning awakening, unprovoked tearfulness, emotional outbursts, and (if necessary) suicidal thinking. The diagnosis was made in the first 3 to 6 months of visits after completion of the initial treatment. Eight of 23 on tamoxifen had mild depression that remitted without any change in treatment. Three with moderate depression improved with reduction of the tamoxifen dose; five required an antidepressant to continue tamoxifen. Seven had severe depression that improved with discontinuation of tamoxifen. Hot flashes were not systematically recorded, but the authors generally felt that the presence of hot flashes did not correlate with depression severity. One of three depressed patients in the group without tamoxifen required antidepressant treatment. The group that took tamoxifen was older than the control group, but the onset of depression appeared temporally related to tamoxifen treatment and appeared to remit within 2 to 4 weeks when tamoxifen was discontinued.
Clinical depression has been noted as an infrequent side effect of tamoxifen. In a meta-analysis of 75,000 breast cancer patients taking tamoxifen, depression was associated with tamoxifen in 1% of patients. These patients were not systematically evaluated for depression, so it is likely that only major manifestations of depressive disease would have brought this condition to attention.5
If the hormonal effects of breast cancer treatment do increase the risk of depression, ERT could be used to manage estrogen deficiency, but its use is controversial.6,7 Estrogen can promote growth of breast cancer cells, and estrogen withdrawal has been a key strategy in breast cancer treatment.8–10 Furthermore, estrogen can augment serotonergic activity and some norepinephrine-related processes in postmenopausal women and may decrease vulnerability to depression.11 Benefits of estrogen replacement have been widely publicized, and patients feel that the loss of estrogen replacement is one of the many losses that comes with the diagnosis of breast cancer.
The relation between mood and sex hormones likely varies among women. Schmidt et al.12 showed that premenstrual syndrome, a deterioration in mood state, was an abnormal response to normal hormonal changes in susceptible women. The serotonin reuptake inhibitors fluoxetine and sertraline have been used to treat premenstrual depressive syndromes.13,14 We suspect that the tendency to develop major depressive disorder in settings of estrogen change would similarly occur in a susceptible subset of women but could be treated by an antidepressant.
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METHODS
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We conducted our study in 1995–1998. Subjects came from the practice of medical oncologists at Massachusetts General Hospital. Premenopausal women treated with chemotherapy and/or tamoxifen and postmenopausal women treated with tamoxifen were eligible subjects. All women who agreed to participate signed informed consent forms. A research psychiatrist interviewed each subject and recorded the frequency and severity of hot flashes, as well as current and lifetime psychiatric diagnoses defined by the Structured Clinical Interview for the Diagnostic Statistical Manual (SCID). Menstrual history, evidence of premenstrual dysphoric disorder, and history of postpartum depression were also recorded. Every 2 months over 2 years, each subject was interviewed to record acute menopausal symptoms, meaning of menopause to the woman, and presence of major depressive or panic disorder based on SCID modules.
Menopausal symptoms were defined by hot flashes and amenorrhea. Sudden waking, jitteriness, and dysphoria that did not persist were often associated symptoms.
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RESULTS
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Of 38 women contacted, 21 (55%) agreed to participate. Characteristics of the sample are shown in Table 1. Patients were followed from the beginning of chemotherapy and/or tamoxifen treatment (an average of 18.5 months, range: 11 to 30). Eight (38%) of the 21 women developed a major depressive episode, the majority within the first 6 months of treatment; the time of onset is shown in Figure 1. Of 15 premenopausal women, 14 became estrogen deficient, developing hot flashes or amenorrhea. Fourteen had received chemotherapy; two tamoxifen. Four (38%) became depressed. One of these was taking tamoxifen with chemotherapy.
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TABLE 1. Demographic data of subjects, including menopausal status, psychiatric history, and type of breast cancer treatment (N=21)
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Of six postmenopausal women, four (66%) became depressed. Of these, two had abruptly stopped ERT at cancer diagnosis, one had used estrogen briefly; the remaining one had no history of ERT but had had a previous postpartum depression. Both postmenopausal women who did not become depressed took tamoxifen, and neither had been receiving ERT prior to diagnosis.
A history of depression was found in 50% of the depressed group and 61% of the non-depressed group. Clinical variables for both groups are shown in Table 2.
Of the eight depressed subjects, three had full resolution of depression with antidepressants (nefazodone: 150 mg bid, setraline: 50 mg, and fluoxetine: 40 mg, respectively). One did not fully improve on sertraline (75 mg), but the dose was not increased. One improved with psychotherapy alone. The two with depression, mild panic attacks, and hot flashes were not treated with antidepressants but improved over time. The last subject became depressed in the setting of severe hot flashes, with little improvement over the next 11 months, even though the hot flashes resolved. She did not use any antidepressant or treatment for her hot flashes.
Although only 8 met criteria for major depressive disorder, the vast majority of the 21 subjects (95%) had mild-to-moderate dysphoria and/or insomnia during the course of treatment. Fourteen women (67%) developed hot flashes. Of seven with hot flashes of severe intensity, six improved with either vitamin E or low-dose megestrol; one improved with time alone.
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DISCUSSION
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We would like to call attention to a subset of estrogen-deficient breast cancer patients who may be at greater risk for major depressive disorder. Furthermore, major depressive disorder, once identified, may be responsive to therapeutic psychopharmacologic treatment, despite the lack of estrogen. In this preliminary study from a small sample, full-blown major depressive episodes were common among the women who became estrogen deficient during breast cancer treatment.
Even in those patients who did not develop major depressive disorder, the clinician's attention to and clarification of menopausal symptoms seemed to be an important therapeutic strategy. Dysphoria, insomnia, and hot flashes were almost universal in women whose breast cancer treatment induced estrogen deficiency. Estrogen deficiency adds to other adverse side effects of adjuvant chemotherapy and presents another difficulty for these patients. Individual variations existed in onset, severity, and symptomatology of menopausal symptoms. Worse hot flashes occurred in two subgroups: women who were near menopause at diagnosis and women who were postmenopausal and stopped ERT precipitously at diagnosis. Most improved over time. They also had options for symptomatic treatment, which often led to improvement.
Since none of the patients who had depressive symptoms but did not meet criteria for major depressive disorder were treated with antidepressants, we do not know if those drugs would have been helpful for dysphoria and minor depression.
This study was limited by the small sample, lack of controls, and the fact that all women eligible did not agree to participate. A larger prospective sample of women treated for breast cancer would be necessary to confirm an increased rate of major depressive disorder in those who become estrogen deficient, compared with those who do not.
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ABSTRACT
INTRODUCTION
