In last month's Brainstorms, we discussed the actions of estrogen in the central nervous system (CNS), emphasizing its key regulatory role for monoaminergic neurons via its unique receptors known as nuclear ligand-activated transcription factors.¹ Here we update the potential antidepressant properties of estrogen, which brings us to a fork in the road²: Should a woman with depression be treated with estrogen, an antidepressant, or both? Perhaps the answer lies in the advice from folk philosopher and baseball great Yogi Berra who once said, "When you come to a fork in the road, take it." What we need are guidelines to determine which women will best respond to which treatment option so prescribers will know which fork in the road to take for individual patients.

Is Estrogen Linked to Depression?

Estrogen has long been suspected to be linked to depression in women.^3­6 A critical observation is that the incidence of depression somewhat mirrors shifts in estrogen across a woman's life cycle (Figure 1). Thus, the risk for depression is higher in women when shifts in estrogen levels are large, beginning especially after estrogen levels rise during puberty, after estrogen levels fall immediately postpartum, and while estrogen levels fluctuate in a declining manner during perimenopause (Figure 2).^3­6

By contrast, depression is not closely linked to testosterone levels in men, since the incidence of depression is essentially constant after puberty, but testosterone levels decline steadily after age 25 (Figure 3).⁶

Is Estrogen an Antidepressant?

Despite observations that estrogen can cause depression in some women, especially at high doses and when administered as oral contraceptives concomitantly with estrogen antagonist progestins, it has long been recognized that estrogen replacement therapy generally reduces mood fluctuations in perimenopausal women who have vasomotor instability.^3,4,7 On the other hand, such women do not generally suffer from a major depressive disorder (MDD). Until recently, it has been unclear from clinical trials whether physiologic doses of natural estrogens such as 17beta-estradiol showed any antidepressant properties in women with MDD.

Clinicians, on the other hand, have observed, anecdotally and in open studies of small numbers of patients, that estrogen apparently exerts antidepressant actions as a monotherapy when administered to some women who have MDD both in the postpartum period and during perimenopause.^3,4 It is somewhat astounding that controlled clinical trials of estrogen for depressed women across their life cycle are only now being published, since not only do women of child-bearing potential have the highest rates of depression, but also women on the whole consume over 70% of antidepressants.³

Two recently published, well-designed studies now suggest that 17beta-estradiol may indeed be an antidepressant for women with depression during perimenopause, including women with MDD.^8,9 In fact, estradiol treatment was associated with a robust treatment effect, including complete remission in the majority of patients studied.⁸

Which Estrogen Might Be an Antidepressant for Women With Depression?

Just as there are a wide variety of antidepressants, there are a wide variety of estrogens. Even though the 2 recent studies mentioned above^8,9 were of 17beta-estradiol, the major circulating estrogen in women, many other estrogens administered to women today have agonist actions upon CNS estrogen receptors. This includes a mixture of estrogens extracted from the urine of pregnant mare that contains estrone, equilin, and 17alpha-dihydroequilin, as well as a new class of estrogen agonists known as SERMs (selective estrogen receptor modulators), such as raloxiphene and others.^2­4 Much further research needs to be done to determine the potential antidepressant actions of these estrogens, how they should be combined with antidepressants, and which women are most likely to benefit. Hopefully, the new data emerging will rapidly lead to the development of treatment guidelines so that new insights into the CNS actions of estrogen can be applied in clinical practice.

REFERENCES

1. Stahl SM. Effects of estrogen on the central nervous system [Brainstorms]. J Clin Psychiatry 2001;62:317­318

2. Stahl SM. Sex and psychopharmacology: is natural estrogen a psychotropic drug in women? Arch Gen Psychiatry. In press

3. Jensvold MF, Halbreich U, Hamilton JA, eds. Psychopharmacology and Women: Sex, Gender and Hormones. Washington, DC: American Psychiatric Press; 1996

4. Leibenluft E, ed. Gender Differences in Mood and Anxiety: Review of Psychiatry, vol 18. Washington, DC: American Psychiatric Press; 1999

5. Weissman MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of depression and bipolar disorder. JAMA 1996;276:293­299

6. Stahl SM. Essential Psychopharmacology. 2nd ed. New York, NY: Cambridge University Press; 2000

7. Altshuler LL, Cohen LS, Moline ML, et al. Treatment of Depression in Women 2001: Expert Consensus Guideline Series. Postgraduate Medicine, March 2001. New York, NY: McGraw Hill; 2001

8. deNovaes Soares C, Almeida OP, Joffe H, et al. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double blind, randomized, placebo-controlled trial. Arch Gen Psychiatry. In press

9. Schmidt PJ, Nierman L, Danaceau MA, et al. Estrogen replacement in perimenopausal-related depression: a preliminary report. Am J Obstet Gynecol 2000;183:414­420