title: Effects of Estradiol Withdrawal on Mood in Women With Past Perimenopausal Depression: A Randomized Clinical Trial.
abstract: OBJECTIVE
  Perimenopause is accompanied by an increased risk of new and recurrent depression. The coincidence of declining ovarian function with the onset of depression led to the inference that "withdrawal" from physiologic estradiol levels underpinned depression in perimenopause. To our knowledge, this is the first controlled systematic study to directly test the estrogen withdrawal theory of perimenopausal depression (PMD).
  
  
  OBJECTIVE
  To examine the role of estradiol withdrawal in PMD.
  
  
  METHODS
  Initial open-label treatment with estradiol followed by randomized, double-blind, placebo-controlled, parallel-design evaluation of continued estradiol treatment was evaluated at an outpatient research facility at the National Institutes of Health Clinical Center. An intent-to-treat analysis was performed between October 2003 and July 2012. Participants included asymptomatic postmenopausal women with past PMD responsive to hormone therapy (n = 26) and asymptomatic postmenopausal women with no history of depression (n = 30) matched for age, body mass index, and reproductive status who served as controls. Data were analyzed between November 2012 and October 2013 by repeated-measures analysis of variance.
  
  
  METHODS
  After 3 weeks of open-label administration of transdermal estradiol (100 µg/d), participants were randomized to a parallel design to receive either estradiol (100 µg/d; 27 participants) or matched placebo skin patches (29 participants) for 3 additional weeks under double-blind conditions.
  
  
  METHODS
  Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale (completed by raters blind to diagnosis and randomization status), self-administered visual analog symptom ratings, and blood hormone levels obtained at weekly clinic visits.
  
  
  RESULTS
  None of the women reported depressive symptoms during open-label use of estradiol. Women with past PMD who were crossed over from estradiol to placebo experienced a significant increase in depression symptom severity demonstrated using the Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale, with mean (SD) scores increasing from estradiol (ie, 2.4 [2.0] and 3.0 [2.5]) to placebo (8.8 [4.9] and 6.6 [4.5], respectively [P = .0004 for both]). Women with past PMD who continued estradiol therapy and all women in the control group remained asymptomatic. Women in both groups had similar hot-flush severity and plasma estradiol levels during use of placebo.
  
  
  CONCLUSIONS
  In women with past PMD that was previously responsive to hormone therapy, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that normal changes in ovarian estradiol secretion 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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00060736.
authors.affiliation: Section on Behavioral Endocrinology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schmidt
authors.affiliation: Section on Behavioral Endocrinology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
authors.forename: Rivka
authors.initials: R
authors.lastname: Ben Dor
authors.affiliation: Section on Behavioral Endocrinology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
authors.forename: Pedro E
authors.initials: PE
authors.lastname: Martinez
authors.affiliation: Section on Behavioral Endocrinology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
authors.forename: Gioia M
authors.initials: GM
authors.lastname: Guerrieri
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville.
authors.forename: Veronica L
authors.initials: VL
authors.lastname: Harsh
authors.affiliation: Section on Behavioral Endocrinology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
authors.forename: Karla
authors.initials: K
authors.lastname: Thompson
authors.affiliation: Biostatistics and Clinical Epidemiology Service, Clinical Center, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
authors.forename: Deloris E
authors.initials: DE
authors.lastname: Koziol
authors.affiliation: Intramural Research Program on Reproductive and Adult Endocrinology, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
authors.forename: Lynnette K
authors.initials: LK
authors.lastname: Nieman
authors.affiliation: Department of Psychiatry, University of North Carolina, Chapel Hill.
authors.forename: David R
authors.initials: DR
authors.lastname: Rubinow
mesh_terms: D000368:Aged; D018592:Cross-Over Studies; D003863:Depression / Q000517:prevention & control* / Q000523:psychology; D003866:Depressive Disorder / Q000517:prevention & control* / Q000523:psychology; D004311:Double-Blind Method; D004958:Estradiol / Q000627:therapeutic use*; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000627:therapeutic use*; D005260:Female; D019584:Hot Flashes / Q000188:drug therapy; D006801:Humans; D008875:Middle Aged; D047648:Perimenopause / Q000523:psychology*; D012008:Recurrence; D055502:Secondary Prevention; D057968:Transdermal Patch; D016896:Treatment Outcome
chemical_list: D004967:Estrogens; D004958:Estradiol