REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY Eszopiclone improves insomnia and depressive and anxious symptoms in perimenopausal and postmenopausal women with hot flashes: a randomized, double-blinded, placebo-controlled crossover trial Hadine Joffe, MD, MSc; Laura Petrillo, MD; Adele Viguera, MD; Alexia Koukopoulos, MD; Kate Silver-Heilman, BA; Adriann Farrell, BA; Gary Yu, MPH; Michael Silver, MS; Lee S. Cohen, MD OBJECTIVE: Menopause-associated insomnia is commonly associated with other symptoms (hot flashes, depression, anxiety). Given frequent symptom cooccurrence, therapies targeting sleep may provide an im- portant approach to treatment during midlife. STUDY DESIGN: Peri/postmenopausal women (40-65 years old) with sleep-onset and/or sleep-maintenance insomnia cooccurring with hot flashes and depressive and/or anxiety symptoms were randomized to eszo- piclone 3 mg orally or placebo in a double-blinded, crossover 11 week trial. Changes in the Insomnia Severity Index (ISI) scale and secondary outcomes (diary-based sleep parameters, depression/anxiety, hot flashes, quality of life) were analyzed using repeated-measure linear models. RESULTS: Of 59 women, 46 (78%) completed the study. Eszopiclone reduced ISI scores by 8.7  1.4 more points than placebo (P  .0001). Eszopiclone improved (P  .05) all sleep parameters, depressive symptoms, anxiety symptoms, quality of life, and nighttime but not day- time hot flashes. CONCLUSION: Eszopiclone treats insomnia and cooccurring meno- pause-related symptoms. Our results provide evidence that hypnotic therapies may improve multiple domains of well-being during midlife. Key words: eszopiclone, insomnia, menopause, randomized clinical trial, vasomotor symptoms Cite this article as: Joffe H, Petrillo L, Viguera A, et al. Eszopiclone improves insomnia and depressive and anxious symptoms in perimenopausal and postmenopausal women with hot flashes: a randomized, double-blinded, placebo-controlled crossover trial. Am J Obstet Gynecol 2010;202:171.e1-11. S leep disturbance is a core symptom of the menopause transition, 1 with poor sleep quality reported more com- monly by perimenopausal and post- menopausal women than by older pre- menopausal women. 2-4 The prevalence of an insomnia disorder increases from 13% in older premenopausal women to 26% in peri- and postmenopausal women. 5 Hot flashes are the primary symptom of the menopause transition, 1 and women with nocturnal hot flashes report repeated awakenings. Women with hot flashes report worse sleep qual- ity, 2-4,6 and are more likely to meet crite- ria for insomnia, 5 than those without hot flashes. Insomnia involves severe and persis- tent sleep disturbance that either induces marked distress or has a deleterious ef- fect on daytime function or well-be- ing, 7,8 which commonly includes anxiety and depressive symptoms during the menopause transition. 9 The risk for anx- iety and depressive symptoms is in- creased during the perimenopause 10-14 and postmenopause. 11,15 Menopausal symptoms of hot flashes, insomnia, depression, and anxiety are all associated with worse quality of life among midlife women. 16 Given that insomnia commonly cooccurs with these other menopause-associated symptoms, 17 therapies targeting sleep disturbance may improve quality of life overall. We have previously shown that the nonbenzodiaz- epine sedative-hypnotic eszopiclone is an effective treatment of sleep-onset insom- nia in peri- and early postmenopausal women. 18 In the current study, we conducted a double-blind, placebo-controlled, cross- over trial to examine the efficacy of eszo- piclone in peri- and postmenopausal women with sleep-onset and/or sleep- maintenance insomnia. Participants also presented with cooccurring hot flashes, depressive and/or anxiety symptoms. We hypothesized that eszopiclone would treat sleep-onset and/or sleep-mainte- nance problems in this population and From the Perinatal and Reproductive Psychiatry Clinical Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Presented at the 46th Annual Meeting of the American College of Neuropsychopharmacology, Boca Raton, FL, Dec. 11, 2007, and the 48th Annual Meeting of the New Clinical Drug Evaluation Unit, Phoenix, AZ, May 27, 2008. Received March 24, 2009; revised Aug. 13, 2009; accepted Oct. 19, 2009. Reprints: Hadine Joffe, MD, MSc, Director of Research, Perinatal and Reproductive Psychiatry Program, Massachusetts General Hospital, 185 Cambridge St, 2nd Floor, Boston, MA 02114. hjoffe@partners.org. This study was supported in part by Sepracor Inc, Marlborough, MA. Drs Joffe, Petrillo, Viguera, and Cohen received research support from Sepracor Inc. Drs Joffe and Cohen were advisors/consultants to Sepracor Inc. 0002-9378/$36.00 • © 2010 Mosby, Inc. All rights reserved. • doi: 10.1016/j.ajog.2009.10.868 Research www. AJOG.org FEBRUARY 2010 American Journal of Obstetrics & Gynecology 171.e1