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Effects of estradiol withdrawal on mood in women with past perimenopausal depression

29 June 2015

Peter Schmidt and his team have published some much needed research comparing the effects of the withdrawal of estrogen from women who have perimenopausal depression (PMD) with those who have continued the therapy [1]. After 3 weeks of open-label administration of transdermal estradiol (100 µg/day), participants were randomized to a parallel design to receive either estradiol (100 µg/day; 27 participants) or matched placebo skin patches (29 participants) for 3 additional weeks under double-blind conditions. The women completed the Center for Epidemiologic Studies-Depression Scale, the 17-item Hamilton Depression Rating Scale (completed by raters blinded to diagnosis and randomization status), and self-administered visual analog symptom ratings, and blood hormone levels were obtained at weekly clinic visits. The results showed that none of the 29 patients who received estradiol reported depressive symptoms but those who crossed over from estradiol to placebo experienced a significant increase in depressive symptoms. The conclusion was that, in women with a past history of PMD who had previous responded to hormone therapy, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that changes in estradiol can trigger an abnormal behavioral state in these susceptible women. Women with a history of PMD should be alert to the risk of recurrent depression when discontinuing hormone therapy and psychiatrists should be aware that there is more appropriate treatment than antidepressants and mood stabilizing drugs.


Dr Schmidt, almost alone in the world of psychiatry, is studying the effects of estrogen therapy on premenopausal depression, postnatal depression and perimenopausal depression, the components of Reproductive Depression [2]. The fact that estrogen will help depression in these three disorders has been known for more than 20 years but has not been picked up by psychiatrists, and women with hormone-responsive depression continue to be treated inappropriately with antidepressants [3]. The many gynecologists who treat depression in women with hormones despair at the failure of psychiatrists to treat this endocrine depression with the appropriate therapy. Perhaps more randomized trials are needed, but I am reminded of Sir Richard Doll’s comment when, after showing that lung cancer was ten times more common in smokers than non-smokers, was criticized for not doing a randomized controlled trial. His comment, that there was no point doing a randomized trial to prove the very obvious, is a benchmark of medical history.

We can only hope this paper goes a little way to convince psychiatrists that there is another more logical treatment for this commonplace depression in women.

John Studd
London PMS and Menopause Centre, London, UK


1. Schmidt PJ, Ben Dor R, Martinez PE, et al. Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry 2015 May 27. Epub ahead of print
2. Studd J, Nappi RE. Reproductive depression. Gynecol Endocrinol 2012;28(Suppl 1):42-5
3. Studd JW. A guide to the treatment of depression in women by estrogens. Climacteric 2011;14:637-42


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