Estrogen and Depression

ABSTRACT & COMMENTARY

Source: Schmidt PJ, et al. Estrogen replacement in perimenopause-related depression: A preliminary report. Am J Obstet Gynecol 2000;183:414-420.

For more than a hundred years, a potential role of estrogen in the treatment of depression has been suggested. Estrogen has been hypothesized to improve mood in perimenopausal and postmenopausal women reporting depressive symptoms; postmenopausal women with depression unresponsive to traditional antidepressant therapy; nondepressed menopausal women not experiencing hot flushes; and women with postpartum depression. Results from these various studies have resulted in mixed findings. However, methodology may be partly to blame. For example, many studies have not systematically confirmed a diagnosis of depression with a structured clinical interview; others have not separated women with hot flushes from those without hot flushes. In the present study, Schmidt and colleagues hypothesized that perimenopausal women with either major or minor depression who received short-term estradiol replacement would show significant improvements in their mood, regardless of the presence of hot flushes.

Women between the ages of 44 and 55 years who met diagnostic criteria for perimenopausal-related depression and who met inclusion and exclusion criteria were eligible for the study. Before study entry, all women participated in an eight-week screening phase consisting of four clinic visits at two-week intervals, during which mood ratings were completed and blood samples were obtained to measure plasma follicle-stimulating hormone (FSH). In addition, subjects completed daily self-ratings of the severity of a variety of mood symptoms and hot flushes. Inclusion criteria consisted of: 1) self-report of the onset of depression associated with menstrual cycle irregularity of at least six months’ duration but with less than one year of amenorrhea; 2) the diagnosis of major or minor depression determined by a structured diagnostic interview, the Structured Clinical Interview for the Diagnostic and Statistical Manual III Revised; 3) scores on the Center for Epidemiologic Studies Depression Scale ³ 10 during three of four screening visits; and 4) plasma FSH ³ 20 IU/L on three of four screening visits. Women were excluded if they had medical illness, were taking medication, had abnormal results of a gynecologic examination or a mammogram, or had any medical contraindication to estrogen replacement therapy. Women were also excluded if they had a history of psychiatric illness during the two years before the onset of the current episode of depression.

Thirty-four women were admitted into this study. In a double-blind manner, 16 received estradiol (Estraderm skin patch, 0.05 mg/d) first and 18 received placebo (placebo skin patches) first. After three weeks, those women who received placebo were crossed over to receive estradiol for an additional three weeks. Those women who were receiving estradiol continued to receive estradiol for an additional three weeks. A traditional crossover study was not performed because of the potential compromise of the blind that could occur if women who received estradiol first experienced menstrual bleeding caused by estrogen withdrawal. Blood samples and symptom rating scales were completed weekly (9 visits) on all patients. Subjects were rated with the Center for Epidemiologic Studies Depression Scale (CES-D), the 21-item Hamilton Rating Scale for Depression (HAM-D), and a 23-item visual analog scale self-rating instrument assessing the severity of mood symptoms.

Of the 34 women who participated in the study, eight had a current diagnosis of major depressive episode, and the remainder met criteria for current minor depression. Baseline characteristics were comparable between the groups. Only three women dropped out of the study (all receiving placebo).

After three weeks of estradiol, the CES-D scores, the 21-item HAM-D and the visual analog scales symptoms scores were significantly improved when compared to baseline scores and significantly lower than scores in women receiving placebo. No significant effect of the presence of hot flushes was observed for the majority of symptoms. Secondary analysis (baseline vs 3 weeks vs 6 weeks) of scores on the standardized cross-sectional ratings demonstrated the following: a significant improvement after three weeks of estradiol compared with three weeks of placebo in the same subjects; no significant difference between women who had received six weeks of estradiol compared to those women who had received three weeks of estradiol or between the scores at three weeks and six weeks in women receiving six weeks of estradiol; and no significant interactions of hot flush group with drug condition and time.

When response rate (defined as a 50% reduction in CES-D scores—full responders and 25-50% reduction in CES-D scores—partial responders) was studied, 80% of subjects receiving estradiol had a full or partial response compared to 22% of subjects receiving placebo.

COMMENT BY CLAUDIA A. ORENGO, MD, PhD

Schmidt et al present a well-designed, placebo-controlled, randomized study of 34 perimenopausal women with major or minor depressive syndrome. They demonstrate that a dose of estradiol 0.05 mg/d administered by skin patch is associated with a significant improvement in mood in depressed perimenopausal women with or without hot flushes. Interestingly, they find that estradiol improves mood in the absence of hot flushes, which suggests the efficacy of estradiol is not solely a product of its ability to reduce the distress of hot flushes.

The response to estradiol occurred within three weeks and no further improvement in mood was noted after six weeks of estradiol replacement. Side effects of estradiol were minor and well tolerated, with the only dropouts occurring during placebo administration. However, the study does not permit the speculation about the consequences or side effects of long-term estrogen administration.

Of clinical importance is that the presence of a history of major or minor depression did not discriminate responders to estradiol. These data suggest that the beneficial effects of hormone replacement on mood in perimenopausal women are not unique to those with a history of depression. Strengths of this study include the use of standardized diagnostic criteria for depression, the use of standardized scales measuring the severity of depression, and the use of hot flushes as a control.

A sample of self-selected, well-educated, motivated and compliant women limit the generalizability of the study. Nevertheless, this study provides useful, clinically relevant information on mood and estrogen replacement in depressed perimenopausal women.