title: Increased estradiol and improved sleep, but not hot flashes, predict enhanced mood during the menopausal transition.
abstract: BACKGROUND
  The antidepressant effect of estrogen in women undergoing the menopause transition is hypothesized to be mediated by central nervous system effects of increasing estradiol on mood or through a pathway involving suppression of hot flashes and associated sleep disturbance. Estrogen therapy (ET) and the hypnotic agent zolpidem were selected as interventions in a three-arm, double-blind, placebo-controlled trial to distinguish the effects of estradiol, sleep, and hot flashes on depression.
  
  
  METHODS
  Women with depressive disorders, hot flashes, and sleep disturbance were randomly assigned to transdermal 17β-estradiol 0.05 mg/d, zolpidem 10 mg/d, or placebo for 8 wk. Changes in serum estradiol, perceived sleep quality, objectively measured sleep, and hot flashes were examined as predictors of depression improvement [Montgomery-Åsberg Depression Rating Scale (MADRS)] using multivariate linear regression.
  
  
  RESULTS
  Seventy-two peri/postmenopausal women with depression disorders were randomized to 17β-estradiol (n = 27), zolpidem (n = 31), or placebo (n = 14). There was no significant difference between groups in depression improvement (overall MADRS decrease 11.8 ± 8.6). Increasing estradiol (P = 0.009) and improved sleep quality (P < 0.001) predicted improved mood in adjusted models but reduced hot flashes (P = 0.99) did not. Post hoc subgroup analyses revealed that the therapeutic effect of increasing estradiol levels on mood was seen in perimenopausal (P = 0.009), but not postmenopausal, women.
  
  
  CONCLUSIONS
  For women with menopause-associated depression, improvement in depression is predicted by improved sleep, and among perimenopausal women, by increasing estradiol levels. These results suggest that changes in estradiol and sleep quality, rather than hot flashes, mediate depression during the menopause transition. Therapies targeting insomnia may be valuable in treating menopause-associated depression.
authors.affiliation: Center for Women’s Mental Health, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. hjoffe@partners.org
authors.forename: Hadine
authors.initials: H
authors.lastname: Joffe
authors.forename: Laura Fagioli
authors.initials: LF
authors.lastname: Petrillo
authors.forename: Alexia
authors.initials: A
authors.lastname: Koukopoulos
authors.forename: Adele C
authors.initials: AC
authors.lastname: Viguera
authors.forename: April
authors.initials: A
authors.lastname: Hirschberg
authors.forename: Ruta
authors.initials: R
authors.lastname: Nonacs
authors.forename: Brittny
authors.initials: B
authors.lastname: Somley
authors.forename: Erica
authors.initials: E
authors.lastname: Pasciullo
authors.forename: David P
authors.initials: DP
authors.lastname: White
authors.forename: Janet E
authors.initials: JE
authors.lastname: Hall
authors.forename: Lee S
authors.initials: LS
authors.lastname: Cohen
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D000339:Affect / Q000502:physiology*; D003866:Depressive Disorder / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology; D004311:Double-Blind Method; D004958:Estradiol / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D019584:Hot Flashes; D006801:Humans; D006993:Hypnotics and Sedatives / Q000627:therapeutic use; D008875:Middle Aged; D047648:Perimenopause / Q000502:physiology* / Q000523:psychology*; D011569:Psychiatric Status Rating Scales; D011725:Pyridines / Q000627:therapeutic use; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D012893:Sleep Wake Disorders / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology; D016896:Treatment Outcome; D000077334:Zolpidem
chemical_list: D006993:Hypnotics and Sedatives; D011725:Pyridines; D004958:Estradiol; D000077334:Zolpidem; D005640:Follicle Stimulating Hormone