Freeman and colleagues9 found that PMS was a predictor of menopausal symptoms and that women in the menopausal transition were up to 3 times more likely than premenopausal women to report depressive symptoms. A history of depression was the strongest predictor of these changes.10 In interviews of 347 women aged 35 to 55 years in the Seattle Midlife Women’s Health Study, Woods and Mitchell11 found that a history of either premenstrual or postpartum affective symptoms distinguished women with consistently depressed mood.
Evidence supports the contention that the perimenopause increases susceptibility to depression, particularly, but not necessarily, among women with lifelong susceptibility to MDD. This includes those whose MDEs were induced by reproductive endocrine change (eg, during the premenstruum, during pregnancy, or postpartum).
Risks of untreated depression
A risk to benefit ratio of treatment must be established to determine the optimal treatment for perimenopausal depression. Untreated depression during the perimenopause exacerbates heart disease, diabetes, and osteoporosis. More specifically, with regard to cardiovascular disease, a higher prevalence of depressive disorders was associated with more severe atherosclerosis.12 Recurrent depressive, but not anxiety, disorders were associated with a 2-fold increase for the risk of carotid atherosclerosis in middle-aged women. However, a history of a single depressive episode was not associated with increased risk of plaque, suggesting that prevention of recurrent depressive episodes may prevent further progression of atherosclerosis.
Symptoms of depression are significantly related to increased risk of cardiovascular events in women in whom myocardial ischemia is suspected; to death from cardiovascular disease; and, on the basis of the findings from the Women’s Health Initiative Observational Study, to all-cause mortality, even after controlling for established cardiovascular disease risk factors.13,14 Major depression increases the risk of first heart attack (odds ratio [OR] = 3.9), stroke (OR = 2.7), and diabetes (OR = 2.23).15 Although the effects of treatment of depression on medical outcomes has not been systematically studied, remission of maternal depression symptoms after 3 months of pharmacotherapy was associated with reductions in the children’s diagnoses and symptoms of medical and psychiatric illness.16
The effects of hormone replacement therapy (HRT) on mood in menopausal depression vary depending on the diagnosis (eg, MDD), the menopausal status (whether there are hot flashes), the dose and preparation of estrogen and progesterone, and the duration of treatment.17
In women with treatment-resistant MDD, estrogen supplementation in replacement dosages may have important additive effects. In initial studies not confined to menopausal women, 25 μg of ethinyl estradiol added to imipramine was superior to 50 mg of ethinyl estradiol plus imipramine or imipramine alone in women with primary depression.18 The higher dosage of estrogen, although associated with less insomnia, was associated with significant adverse effects (lethargy, hypotension, tremor, depersonalization). These findings suggest that there may be a therapeutic window for estrogen treatment; if endogenous levels are already high, additional estrogen supplementation may lead to toxic reactions.
In a 6-week nonrandomized trial in primarily postmenopausal women (older than 60 years) with unipolar depression, the 72 women who received fluoxetine (20 mg/d) and estrogen replacement therapy had a greater improvement in depression ratings than the 286 women who received estrogen replacement therapy alone (40% vs 17%, respectively). Fluoxetine-treated patients who did not receive estrogen replacement therapy did not show benefit greater than placebo. Thus, estrogen enhanced the efficacy of fluoxetine.19
Liu and colleagues20 also found that HRT with 0.625 mg of conjugated estrogen and 5 mg of progesterone combined with 20 mg of fluoxetine for 2 months was more effective in reducing symptoms than HRT alone in 123 women with menopausal depression. In a study of sertraline (50 to 150 mg), women older than 60 who received estrogen replacement therapy (without progesterone) had greater global improvement, better quality of life, and less anxiety than women who received sertraline but not estrogen replacement therapy; these women also had modest improvements in cognitive functioning.21
In contrast, we found that oral (1 to 2 mg) or transdermal (0.1 to 0.2 mg) 17β-estradiol enhanced the antidepressant effects of fluoxetine (10 to 40 mg) in an 8-week pilot study of women with perimenopausal or postmenopausal MDD.22 In a follow-up randomized clinical trial, the combination of antidepressant plus estrogen was not superior to antidepressant alone; in fact, patients who received an antidepressant plus estrogen showed smaller (nonsignificant) reductions in interview-based depression ratings than those who received an antidepressant alone.17 Estrogen treatment alone did not significantly reduce symptoms of MDD. Estrogen treatment, however, may accelerate the antidepressant response.23
In an open-label pilot study, Freeman and colleagues24 found that escitalopram alone for 8 weeks significantly improved psychological, vasomotor, and somatic symptoms. Escitalopram was more efficacious for the treatment of depression than ethinyl estradiol and norethindrone acetate.25 Soares and colleagues26 found that after 4 weeks of estrogen therapy, perimenopausal and postmenopausal women with recalcitrant depression benefited from adjunctive treatment with 20 to 60 mg of citalopram for 8 weeks.
Dr Parry is Professor of Psychiatry at the University of California, San Diego. She reports no conflicts of interest concerning the subject matter of this article.
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