Eszopiclone improves insomnia and depressive and anxious symptoms in perimenopausal and postmenopausal women with hot flashes: a randomized, double-blinded, placebo-controlled crossover trial

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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

RESULTS: Of 59 women, 46 (78%) completed the study. Eszopiclone

with other symptoms (hot flashes, depression, anxiety). Given frequent symptom cooccurrence, therapies targeting sleep may provide an important approach to treatment during midlife.

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 daytime hot flashes.

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 eszopiclone 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.

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 commonly by perimenopausal and postmenopausal women than by older premenopausal 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 quality,2-4,6 and are more likely to meet criteria for insomnia,5 than those without hot flashes. Insomnia involves severe and persistent sleep disturbance that either induces marked distress or has a deleterious effect on daytime function or well-being,7,8 which commonly includes anxiety and depressive symptoms during the menopause transition.9 The risk for anx-

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. [email protected]. 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

iety and depressive symptoms is increased during the perimenopause10-14 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 nonbenzodiazepine sedative-hypnotic eszopiclone is an effective treatment of sleep-onset insomnia in peri- and early postmenopausal women.18 In the current study, we conducted a double-blind, placebo-controlled, crossover trial to examine the efficacy of eszopiclone in peri- and postmenopausal women with sleep-onset and/or sleepmaintenance insomnia. Participants also presented with cooccurring hot flashes, depressive and/or anxiety symptoms. We hypothesized that eszopiclone would treat sleep-onset and/or sleep-maintenance problems in this population and

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also improve cooccurring symptoms of nocturnal hot flashes and depressive and anxiety symptoms, thereby improving quality of life.

M ATERIALS AND M ETHODS Subjects Sixty-five perimenopausal and postmenopausal women 40-65 years old were enrolled in an 11 week randomized, double-blind, placebo-controlled, crossover study, which was approved by the Partners Healthcare Systems Institutional Review Board, with written informed consent obtained from all subjects. Subjects were either perimenopausal (early or late menopausal transition) or postmenopausal (amenorrhea ⬎12 months)19 or had bilateral oophorectomy. Women who had undergone a hysterectomy with ovaries preservation were included if their follicle-stimulating hormone level was greater than 20 IU/L. Women were eligible if they met insomnia criteria because of difficulty initiating (⬎30 minutes) and/or maintaining sleep (wake time after sleep onset ⬎30 minutes) 3 or more nights per week for 1 month or longer prior to enrollment,7,8 confirmed prospectively with a sleep diary during a 7 day run-in period. Hot flashes were assessed daily during the run-in but not required for eligibility. Eligible participants had evidence of impaired daytime function or well-being as a result of insomnia, based on a clinical interview conducted by study psychiatrists, as well as mild depressive and/or anxiety symptoms, defined by a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 10-18 and a Beck Anxiety Inventory (BAI) score of 10-18. The MADRS is a widely used clinicianrated questionnaire of depression symptoms over the past 7 days (score of 0-60, with scores ⬍10 suggesting no depression and scores ⬎18 implying clinically significant depression).20 The BAI is a widely used self-report measure of anxiety over the past 7 days (score of 0-63, with a similar interpretation of scores).21 The Mini-International Neuropsychiatric Interview structured psychiatric 171.e2

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interview was administered by study psychiatrists to exclude women with psychiatric disorders (major depression, dysthymia, panic disorder, or posttraumatic stress disorder in past 3 months) or who had current suicidal ideation, homicidal ideation, psychotic symptoms, or a suicide attempts or substance-use disorder within the past 5 years. Women who developed significant depressive symptoms (MADRS ⱖ18) or anxiety symptoms (BAI ⱖ18) during the study were withdrawn. Other exclusion criteria were previously diagnosed sleep apnea, periodic leg movement syndrome, or medical conditions affecting sleep. Use of hypnotic agents in the 4 weeks before enrollment was prohibited, but antidepressants and hormone therapy were allowed if the dose remained stable 8 weeks or longer before study entry and throughout the study.

scores were calculated for each 7 day period. Secondary measures included the following: (1) number of hot flashes/night sweats, (2) depressive symptoms, (3) anxiety symptoms, (4) menopause-related quality of life, and (5) functional impairment. The frequency of daytime and nighttime hot flashes was tabulated separately throughout the study using a diary. Menopause-related quality of life was assessed with the Menopause Quality of Life Scale (MENQOL),23 an instrument that assesses quality of life over the prior month (score 0-8, with higher scores worse).24 The MADRS was used to measure changes in depressive symptoms, and the BAI was used to measure changes in anxiety symptoms. The Sheehan Disability Scale (SDS, range 0 –30, higher score indicates greater disability) measures functional impairment related to current symptoms.25,26

Procedures The overall study design involved an 11 week randomized, double-blind, crossover period to fixed-dose eszopiclone 3 mg nightly (Food and Dug Administration–approved adult dose) and identical matching placebo patches (Figure 1), which were provided by the manufacturer. After eligibility was confirmed, subjects were randomized in a 1-to-1 ratio to 4 weeks of treatment with eszopiclone first (es¡plb) or placebo first (plb¡esz), followed by a 2 week washout during which no medications were administered, and then crossed over to the other treatment for another 4 weeks. Treatment effects on sleep parameters were assessed with the Insomnia Severity Index (ISI)22 and a sleep diary. The ISI is a widely used, 7 item self-report questionnaire addressing insomnia symptoms (scores 0-7 indicating no clinically significant insomnia; 8-14, subthreshold insomnia; 15-28, clinical insomnia) with good reliability and validity for insomnia.22 Sleep parameters calculated from the sleep diary were wake time after sleep onset (WASO), sleep efficiency (percent of time between bedtime and wake-up time spent asleep), sleep-onset latency (minutes), total sleep time (TST), and number of awakenings. Average daily

Statistical analysis The primary analysis was conducted using an intent-to-treat, repeated-measure, linear mixed model, with change in the ISI score from the beginning to end of each treatment period as the dependent measure, treatment and time as main effects, and a time-by-treatment interaction term to account for potential carryover effects between treatment periods. The study was powered (90%) based on the ISI, assuming a true difference between groups of 3.6 and an SD of the difference of 8.3 (2 sided ␣ ⫽ 0.05). The same analytic approach was used to evaluate the efficacy of eszopiclone on secondary outcome measures, including changes in sleep parameters (WASO, sleep efficiency, sleep-onset latency, TST) and changes in depressive symptoms (MADRS), anxiety symptoms (BAI), daytime and nighttime hot flashes, quality-of-life (MENQOL), and functional impairment (SDS). All regression models included a timeby-treatment interaction term (significant if P ⬍ .10). There was no significant interaction between time and treatment for the primary outcome measure. For those secondary outcome measures with significant interactions (TST, WASO, sleep efficiency, MADRS scores, night-

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FIGURE 1

Flow of subjects through study protocol

Joffe. Eszopiclone and hot flashes. Am J Obstet Gynecol 2010.

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TABLE 1

Baseline characteristics by treatment assignmenta Demographic

Eszopiclone then placebo (n ⴝ 30)

Placebo then eszopiclone (n ⴝ 29)

Age, mean ⫾ SD

51.8 ⫾ 4.7

52.6 ⫾ 4.5

White, n (%)

20 (66.7)

22 (75.9)

9 (30.0)

15 (51.7)

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

College degree, n (%)

................................................................................................................................................................................................................................................................................................................................................................................

Marital status, n (%)

.......................................................................................................................................................................................................................................................................................................................................................................

Never married/single

8 (26.7)

5 (17.2)

.......................................................................................................................................................................................................................................................................................................................................................................

Married/living with partner

14 (47.6)

10 (34.5)

8 (26.7)

14 (48.3)

.......................................................................................................................................................................................................................................................................................................................................................................

Separated/divorced/widowed

................................................................................................................................................................................................................................................................................................................................................................................ 2

27.4 ⫾ 6.8

Body mass index, kg/m

27.8 ⫾ 7.0

................................................................................................................................................................................................................................................................................................................................................................................

Menopause status, n (%)

.......................................................................................................................................................................................................................................................................................................................................................................

Perimenopausal

8 (26.60)

10 (34.5)

.......................................................................................................................................................................................................................................................................................................................................................................

Natural postmenopause

17 (56.7)

14 (48.3)

Surgical postmenopause

0 (0.0)

1 (3.5)

Hysterectomy only

5 (16.7)

4 (13.8)

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

FSH levels, mean ⫾ SD

67.3 ⫾ 41.5

63.4 ⫾ 35.9

................................................................................................................................................................................................................................................................................................................................................................................

Concurrent medication use

.......................................................................................................................................................................................................................................................................................................................................................................

Antidepressant

6 (20.0)

3 (10.3)

Hormonal therapy

4 (13.3)

1 (3.4)

....................................................................................................................................................................................................................................................................................................................................................................... b ................................................................................................................................................................................................................................................................................................................................................................................

Sleep problems meeting eligibility criteria, n (%)

.......................................................................................................................................................................................................................................................................................................................................................................

Difficulty initiating sleep

6 (20.0)

2 (6.9)

Difficulty maintaining sleep

5 (16.7)

6 (20.7)

19 (63.3)

21 (72.4)

....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Difficulty initiating and maintaining sleep

................................................................................................................................................................................................................................................................................................................................................................................

Vasomotor symptoms, mean ⫾ SD

.......................................................................................................................................................................................................................................................................................................................................................................

Number of nighttime hot flashes

2.0 ⫾ 1.5

2.2 ⫾ 1.6

Number of daytime hot flashes

2.68 ⫾ 2.2

2.25 ⫾ 1.8

....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................

Mood characteristics meeting eligibility criteria

.......................................................................................................................................................................................................................................................................................................................................................................

Significant depressive symptoms only, n (%)

18 (60.0)

13 (44.8)

11.8 ⫾ 2.3

11.7 ⫾ 2.4

..............................................................................................................................................................................................................................................................................................................................................................

MADRS score for the subgroup

.......................................................................................................................................................................................................................................................................................................................................................................

Significant anxiety symptoms only, n (%)

2 (6.7)

2 (6.9)

..............................................................................................................................................................................................................................................................................................................................................................

11.0 ⫾ 1.1

BAI score for the subgroup

14.5 ⫾ 4.9

.......................................................................................................................................................................................................................................................................................................................................................................

Both depressive and anxiety symptoms, n (%)

10 (33.3)

14 (48.3)

MADRS score for the subgroup

13.3 ⫾ 3.3

13.6 ⫾ 2.6

BAI score for the subgroup

12.9 ⫾ 2.9

14.6 ⫾ 2.7

.............................................................................................................................................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................................................................................................................................

................................................................................................................................................................................................................................................................................................................................................................................

Joffe. Eszopiclone and hot flashes. Am J Obstet Gynecol 2010.

time hot flashes), separate analyses for each treatment period were conducted using Student t tests. Mixed-effect linear regression models were built to determine the association between improvement in sleep parameters and other menopause-related symp171.e4

(continued )

toms after adjusting for treatment assignment, treatment period, and their interaction. Analyses were conducted using SAS statistical software version 9.1 (SAS Institute Inc, Cary, NC) with statistical significance at the 2-sided ␣ ⫽ 0.05 level.

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R ESULTS Fifty-nine of 65 women who completed the run-in (91%) were eligible to be randomized and 6 (9%) were excluded (Figure 1), with 30 (50.8%) assigned to the esz¡plb group and 29 (49.2%) to the plb¡esz group. Overall, 46 of 59 women

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TABLE 1

Baseline characteristics by treatment assignmenta (continued) Demographic

Eszopiclone then placebo (n ⴝ 30)

Placebo then eszopiclone (n ⴝ 29)

BASELINE MEASURES PRIOR TO PERIOD 1, MEAN ⫾ SD Sleep measures

.......................................................................................................................................................................................................................................................................................................................................................................

ISI

15.6 ⫾ 3.4

15.3 ⫾ 5.0

Wake time after sleep onset, min

68.8 ⫾ 48.7

88.3 ⫾ 45.5

2.2 ⫾ 1.4

2.5 ⫾ 1.3

56.9 ⫾ 45.7

48.0 ⫾ 36.6

....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Number of awakenings

.......................................................................................................................................................................................................................................................................................................................................................................

Sleep latency, min

.......................................................................................................................................................................................................................................................................................................................................................................

Sleep efficiency, %

74.3 ⫾ 14.6

70.0 ⫾ 12.3

356.8 ⫾ 70.6

325.8 ⫾ 75.0

.......................................................................................................................................................................................................................................................................................................................................................................

Total sleep time, min

................................................................................................................................................................................................................................................................................................................................................................................

Mood measures

.......................................................................................................................................................................................................................................................................................................................................................................

MADRS score

11.4 ⫾ 3.9

10.6 ⫾ 3.8

6.6 ⫾ 4.5

7.3 ⫾ 4.6

.......................................................................................................................................................................................................................................................................................................................................................................

BAI score

................................................................................................................................................................................................................................................................................................................................................................................

Vasomotor symptoms

.......................................................................................................................................................................................................................................................................................................................................................................

Number of nighttime hot flashes

2.0 ⫾ 1.5

2.2 ⫾ 1.6

Number of daytime hot flashes

2.68 ⫾ 2.2

2.25 ⫾ 1.8

....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................

Quality of life and functional disability

.......................................................................................................................................................................................................................................................................................................................................................................

Functional disability (SDS)

9.6 ⫾ 5.7

8.4 ⫾ 4.8

Quality of life (MENQOL)

4.4 ⫾ 1.3

4.1 ⫾ 1.4

....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................

BASELINE MEASURES PRIOR TO PERIOD 2, MEAN ⫾ SD

Sleep measures

.......................................................................................................................................................................................................................................................................................................................................................................

ISI

12.2 ⫾ 4.6

14.2 ⫾ 5.2

Wake time after sleep onset, min

43.5 ⫾ 46.0

60.6 ⫾ 42.3

....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

1.4 ⫾ 1.3

1.7 ⫾ 1.4

Sleep latency, min

48.8 ⫾ 49.7

47.4 ⫾ 38.7

Sleep efficiency, %

82.0 ⫾ 14.5

76.0 ⫾ 15.5

385.9 ⫾ 81.2

345.0 ⫾ 73.6

Number of awakenings

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Total sleep time, min

................................................................................................................................................................................................................................................................................................................................................................................

Mood measures

.......................................................................................................................................................................................................................................................................................................................................................................

MADRS score

8.3 ⫾ 4.2

10.5 ⫾ 6.1

BAI score

4.1 ⫾ 2.8

6.2 ⫾ 4.5

....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................

Vasomotor symptoms

.......................................................................................................................................................................................................................................................................................................................................................................

Number of nighttime hot flashes

1.8 ⫾ 1.7

1.9 ⫾ 1.8

Number of daytime hot flashes

2.4 ⫾ 2.1

1.6 ⫾ 1.8

....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Quality of life and functional disability

.......................................................................................................................................................................................................................................................................................................................................................................

Functional disability (SDS)

7.3 ⫾ 6.9

7.5 ⫾ 6.7

Quality of life (MENQOL)

3.6 ⫾ 1.0

3.3 ⫾ 1.3

....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................

BAI, Beck Anxiety Inventory; FSH, follicle-stimulating hormone; ISI, Insomnia Severity Index; MADRS, Montgomery-Åsberg Depression Rating Scale; MENQOL, Menopause Quality of Life Scale; SDS, Sheehan Disability Scale. a

No significant differences between groups for any characteristics; b Three (60%) were using estrogen and progesterone and 2 (40%) were using estrogen only; duration of use ranged from 3 months to 10 years (median, 2 years).

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TABLE 2

Treatment effects of eszopiclone and placebo Difference between eszopiclone and placebo

Variable

Effect of eszopiclone compared with placebo

Interactiona F

F

P value

8.7 ⫾ 1.4

40.8

⬍ .0001

2.7

.11

Sleep latency, min

17.8 ⫾ 14.4

4.4

.04

0.1

.76

Total sleep time, min

66.5 ⫾ 17.6

6.7

.01

5.6

.02

Wake time after sleep onset, min

37.7 ⫾ 8.6

4.0

.05

6.8

.01

Sleep efficiency, %

14.6 ⫾ 3.7

7.2

.01

7.7

.008

Montgomery-Åsberg Depression Rating Scale

8.9 ⫾ 2.3

15.8

.0004

4.9

.03

Beck Anxiety Inventory

1.5 ⫾ 1.1

7.2

.03

1.8

.20

Menopause-Specific Quality of Life Questionnaire

0.93 ⫾ 0.27

.0002

0.5

.48

Sheehan Disability Scale

3.2 ⫾ 1.8

2.8

.09

1.0

.31

Nighttime hot flashes

1.5 ⫾ 0.3

4.2

.047

18.4

⬍ .0001

Daytime hot flashes

0.7 ⫾ 0.3

1.8

.18

1.4

.25

Insomnia Severity Index

P value

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

16.4

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ a

Interaction between treatment period and treatment assignment.

Joffe. Eszopiclone and hot flashes. Am J Obstet Gynecol 2010.

initiating treatment (78%) completed the study (90% of the esz¡plb group and 65.5% of the plb¡esz group). More women in the plb¡esz group than the esz¡plb group withdrew from the study (Fisher’s exact, P ⫽ .03), although there was no difference in the proportion withdrawing early because of side effects. For the esz¡plb group, study noncompleters withdrew because of side effects (n ⫽ 2) and logistical reasons (n ⫽ 1). Reasons for early withdrawal in the plb¡esz group were side effects (n ⫽ 1), logistical reasons (n ⫽ 3), initiation of disallowed medications (n ⫽ 2), loss to follow-up (n ⫽ 3), and increase in depressive symptoms (n ⫽ 1).

Subject characteristics Demographic and menopause characteristics did not differ between groups (Table 1). The mean (⫾SD) age overall was 52.2 ⫾ 4.6 years and the mean body mass index was 27.5 ⫾ 6.6 kg/m2. The majority were white (71.2%) and naturally postmenopausal (52.5%), 40.7% were married, and 40.7% had at least a college education. Only a small minority of participants was using hormonal therapy (8.5%) or antidepressants (15.3%). Whereas hot flashes were not an eligibil171.e6

ity criterion, all women reported them during the run-in (2.4 ⫾ 2.0 daytime hot flashes, 2.1 ⫾ 1.5 nighttime hot flashes). At baseline, there was no significant difference between groups in sleep parameters (Table 1), with the proportion of women having problems initiating sleep (13.6%), maintaining sleep (18.6%), or both (67.8%) not differing between groups. The mean ISI score at study entry was 15.6 ⫾ 3.4 in the esz¡plb group and 15.3 ⫾ 5.0 in the plb¡esz group. There were no significant differences between groups in the proportion that had depressive and/or anxiety symptoms or in MADRS and BAI scores for those subgroups at study entry (Table 1), with the majority of participants having depressive symptoms alone (52.5%) or both depressive and anxiety symptoms (40.7%), and a minority (6.8%) with only anxiety symptoms.

Treatment effects Compared with placebo, eszopiclone had a beneficial effect on insomnia (Table 2 and Figure 2). The ISI score was reduced by 8.7 ⫾ 1.4 more points on eszopiclone than on placebo (P ⬍ .0001), without a significant time-by-treatment

American Journal of Obstetrics & Gynecology FEBRUARY 2010

interaction. The ISI score was 7 or less after 4 weeks of treatment in 87% of women on eszopiclone and in 34% of women on placebo, consistent with resolution of insomnia.22 Eszopiclone had a significant effect on sleep latency, which was reduced by 17.8 ⫾ 14.4 more minutes on eszopiclone than on placebo (P ⫽ .04; Table 2 and Figure 3, A), with no significant time-bytreatment interaction. Analysis of other secondary sleep outcomes (WASO, sleep efficiency, TST) revealed greater improvement on eszopiclone than on placebo, with significant time-by-treatment interactions (Table 2). For both treatment periods together, WASO was reduced by 37.7 ⫾ 8.6 minutes more on eszopiclone than on placebo (P ⫽ .05; Figure 3, B), sleep efficiency improved by 14.6% ⫾ 3.7 more on eszopiclone than on placebo (P ⫽ .01; Figure 3, C), and TST increased by 66.5 ⫾ 17.6 minutes more on eszopiclone than on placebo (P ⫽ .01; Figure 3, D). Whereas eszopiclone improved WASO, sleep efficiency, and TST during both the first and second treatment period, the placebo effect was more marked in the first treatment period and analyses con-

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www.AJOG.org ducted separately by treatment period demonstrated a significant effect of eszopiclone relative to placebo on WASO (P ⫽ .0001), sleep efficiency (P ⫽ .003), and TST (P ⫽ .002) during the second, but not first, period. Analyses of other secondary endpoints revealed that eszopiclone had a beneficial effect on anxiety symptoms and quality of life and a trend toward statistical significance for greater improvement in functional disability, with no significant time-by-treatment interactions. Among those with anxiety symptoms at baseline, BAI scores were reduced by a mean of 1.5 ⫾ 1.1 on eszopiclone more than on placebo (P ⫽ .03; Figure 4, A). Quality of life (P ⫽ .0002) and functional disability (P ⫽ .09) improved more on eszopiclone than on placebo. Among those with depressive symptoms at baseline, there was a significant effect of eszopiclone on depressive symptoms (P ⫽ .0004; Figure 4, B), with MADRS scores reduced by a mean of 7.4 ⫾ 1.6 more points on eszopiclone than on placebo. Because of a significant timeby-treatment interaction, the effect of eszopiclone on mood was analyzed separately by treatment period. Compared with placebo, eszopiclone had a significant effect on depressive symptoms during the second (P ⫽ .003), but not first, treatment period. The effect of treatment on hot flashes was analyzed separately for daytime and nighttime symptoms (Table 2). There was a significant effect of eszopiclone on nighttime hot flashes (reduction by 1.5 ⫾ 0.3 nighttime hot flashes more on eszopiclone than on placebo, P ⫽ .047), with a significant time-by-treatment interaction, but the effect on daytime symptoms was not different (Figure 4, C and D). In separate analyses by treatment period, eszopiclone had a significant effect on nighttime hot flashes during the second (P ⫽ .0006), but not first, treatment period relative to placebo. Further analyses conducted to determine the impact of treating sleep disturbance on other menopause-related symptoms (Table 3) revealed the following significant (P ⬍ .05) associations: improvement in mood was predicted by

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FIGURE 2

Effect of eszopiclone on insomnia

Effect of eszopiclone vs placebo on the severity of insomnia symptoms was measured by the ISI. Joffe. Eszopiclone and hot flashes. Am J Obstet Gynecol 2010.

improvement in insomnia, WASO, sleep efficiency, and TST; improvement in anxiety was predicted by improvement in the ISI; improvements in quality of life and functional disability were predicted by a reduction in the ISI; and improvement in nighttime hot flashes was predicted by an increased TST.

Medication tolerability Overall, the treatment was well tolerated. Three women withdrew because of side effects while on eszopiclone (jitteriness and heart palpitations, n ⫽ 1; metallic taste, n ⫽ 1; dizziness, n ⫽ 1), and none withdrew because of side effects on placebo. The only side effect occurring in more than 5% of the population was metallic taste on eszopiclone (n ⫽ 15, 25%).

C OMMENT Results of this double-blind, placebocontrolled, crossover study indicated that eszopiclone is an effective treatment of insomnia in peri- and postmenopausal women who have sleep-onset and/or sleep-maintenance insomnia cooccurring with hot flashes, depression, and/or anxiety symptoms. In addition to

reducing the severity of insomnia, eszopiclone improved time to sleep onset, anxiety, quality of life, and functional disability. Analyses of other secondary outcomes that involved a significant time-by-treatment interaction revealed a significant effect of eszopiclone on TST, WASO, sleep efficiency, and depressive symptoms during the second, but not first, treatment period. Eszopiclone reduced nocturnal, but not daytime, hot flashes. These findings suggest that use of a nonbenzodiazepine hypnotic agent to target sleep disturbance in symptomatic midlife women improves insomnia and multiple other domains, resulting in improved quality of life. Consistent with standard approaches to analyzing crossover studies,27 we included a time-by-treatment interaction term to evaluate a possible carryover effect between treatment periods. There was no significant time-by-treatment interaction for the primary outcome measure assessing insomnia (ISI), indicating that the effect of eszopiclone on insomnia was independent of whether the

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FIGURE 3

Effect of eszopiclone on sleep parameters

Effect of eszopiclone vs placebo on A, sleep-onset latency (min), B, wake-time after sleep onset (min), C, sleep efficiency (%), and D, total sleep time (min) was measured. Joffe. Eszopiclone and hot flashes. Am J Obstet Gynecol 2010.

medication was administered before or after placebo (Figure 2). There was also no significant time-bytreatment interaction for secondary outcome measures (time to sleep onset, anxiety, quality of life, functional disability), indicating no period effect. However, a significant interaction was observed for other secondary measures (TST, WASO, sleep efficiency, depressive symptoms, nighttime hot flashes). We therefore analyzed the effect of eszopiclone on these endpoints separately by treatment period, which revealed that eszopiclone was more effective than placebo during the second, but not first, treatment period. 171.e8

These analyses reflect our finding that, although the effect of placebo was more marked during the first period, eszopiclone had a beneficial effect on secondary measures during both treatment periods (Figures 3, B-D, and 4, B and C). These findings suggest that, after initial treatment with eszopiclone, there is an attenuated response to placebo in the subsequent treatment period, which may be attributed to a dramatic shift in perception of treatment at the crossover point. Our results are consistent with placebo-controlled trials in adults with primary insomnia showing that eszopiclone improves sleep-onset and sleep-mainte-

American Journal of Obstetrics & Gynecology FEBRUARY 2010

nance symptoms28-30 and polysomnographic measures.30-32 Previous trials similarly found that eszopiclone improves sleep parameters (time to sleeponset, number of awakenings, sleep efficiency, TST). Like other studies,18,28-30 we found that eszopiclone improves daytime function and quality-of-life. Reflecting these benefits of eszopiclone, a greater proportion of our participants who were randomized to eszopiclone first completed the study, raising the possibility that early benefit increased their willingness to complete study procedures. Our findings are consistent with other studies demonstrating the benefit of es-

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FIGURE 4

Effect of eszopiclone on mood and hot flashes

Effect of eszopiclone vs placebo on A, anxious symptoms, as measured by the Beck Anxiety Inventory, B, depressive symptoms, as measured by the Montgomery-Åsberg Depression Rating Scale, C, number of nighttime hot flashes, and D, number of daytime hot flashes. Joffe. Eszopiclone and hot flashes. Am J Obstet Gynecol 2010.

zopiclone for depression and anxiety symptoms in patients with insomnia cooccurring with major depression33 and generalized anxiety disorder.34 Although our participants had mild mood symptoms not meeting criteria for psychiatric illness and received eszopiclone as monotherapy, rather than in combination with a selective serotonin reuptake inhibitor,33,34 there was a significant therapeutic benefit of eszopiclone for depressive and anxious symptoms. These findings suggest that eszopiclone may improve mood symptoms either as an indirect consequence of improving sleep or because of a direct effect of the medication on psychological symptoms.

Our study design precludes differentiation of these 2 explanations. Our findings are also consistent with previous placebo-controlled trials using hypnotic agents to treat insomnia in peri- and postmenopausal women, which showed the benefits of eszopiclone for women with sleep-onset insomnia18 and zolpidem for women with sleep-maintenance insomnia and hot flashes.35 Our study population differed from previous trials18,35 because their sleep-onset and/or sleep-maintenance disturbances cooccurred with other common menopause-associated symptoms of depressive, anxiety, and vasomotor symptoms.

Whereas hot flashes were not required, they were universal in our participants. Women who experience hot flashes during the menopause transition report worse sleep quality2-4,6 and are more likely to meet insomnia criteria5 than those without hot flashes. Treatment with eszopiclone reduced nocturnal, but not daytime, hot flashes relative to placebo, a selective effect that suggests that eszopiclone either suppresses hot flashes at peak serum levels (half-life 6 hours) or reduces reports of nighttime hot flashes because women sleep through them. A direct effect of eszopiclone on hot flashes is not expected because it modulates ␥-aminobutyric acid

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TABLE 3

Effect of sleep changes on menopause-associated symptomsa ␤a

Variable

SE

F

P value

Change in Montgomery-Åsberg Depression Rating Scale score

.....................................................................................................................................................................................................................................

⬍ .0001

Insomnia Severity Index

0.46

0.09

28.31

Wake after sleep onset, min

0.04

0.01

13.99

.001

Sleep efficiency, %

–0.11

0.04

9.76

.003

Total sleep time, min

–0.03

0.01

15.18

⬍ .001

0.01

0.01

1.18

..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................

Sleep latency, min

.28

..............................................................................................................................................................................................................................................

Change in Beck Anxiety Inventory score

.....................................................................................................................................................................................................................................

⬍ .001

Insomnia Severity Index

0.26

0.07

15.21

Wake after sleep onset, min

0.01

0.01

1.11

.30

..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................

Sleep efficiency, %

0.01

0.02

0.05

.82

Total sleep time, min

–0.002

0.01

0.20

.65

Sleep latency, min

–0.01

0.01

1.44

.24

..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

Change in nighttime hot flashes

.....................................................................................................................................................................................................................................

Insomnia Severity Index

0.03

0.03

0.96

.33

Wake after sleep onset, min

0.005

0.003

1.93

.17

.....................................................................................................................................................................................................................................

line.37 Finally, because our study population was primarily white and nonobese and had relatively few hot flashes, generalizability to women with different profiles is unknown. In summary, results of this randomized placebo-controlled crossover study indicate that targeting sleep disturbance in peri- and postmenopausal women who present with sleep-onset and/or sleep-maintenance insomnia in combination with other menopause-associated symptoms has beneficial effects on multiple symptom domains, including sleep disturbance, mood, anxiety, and nighttime hot flashes. Because multiple symptoms commonly cooccur in this population of midlife women, our findings suggest that eszopiclone may serve an important therapeutic role in the management of women with this symptom array. f

.....................................................................................................................................................................................................................................

Sleep efficiency, %

–0.01

0.01

2.25

.14

ACKNOWLEDGMENT

Total sleep time, min

–0.004

0.002

4.55

.04

0.001

0.003

0.11

.74

The authors would like to acknowledge David Schoenfeld, PhD, for statistical guidance and Stephanie Connors, BS, for technical and administrative assistance.

..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................

Sleep latency, min

..............................................................................................................................................................................................................................................

Change in Menopause Quality of Life Scale score

.....................................................................................................................................................................................................................................

Insomnia Severity Index

0.12

0.02

29.59

⬍ .0001

Wake after sleep onset, min

0.004

0.003

2.42

.13

..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................

Sleep efficiency, %

–0.01

0.01

0.99

.33

Total sleep time, min

–0.003

0.002

3.02

.09

Sleep latency, min

–0.003

0.003

1.39

.24

..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

Change in Sheehan Disability Scale score

.....................................................................................................................................................................................................................................

Insomnia Severity Index

0.58

0.12

23.64

⬍ .0001

Wake after sleep onset, min

0.02

0.02

1.21

.28

Sleep efficiency, %

–0.08

0.05

2.48

.12

Total sleep time, min

–0.02

0.01

3.84

.06

0.03

0.016

3.05

.09

..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................

Sleep latency, min

.............................................................................................................................................................................................................................................. a

Represents the effect of each sleep parameter after adjusting for treatment assignment (eszopiclone vs placebo), treatment period, and the interaction between treatment assignment and period in adjusted regression models.

Joffe. Eszopiclone and hot flashes. Am J Obstet Gynecol 2010.

receptors, which is not a core mechanism for other hot flash treatments. Regardless, this beneficial effect suggests that hypnotic therapy may be an important treatment consideration for women with nighttime hot flashes. In addition to its strengths, this study is limited by the lack of polysomnography evaluation to exclude women with sleep apnea, which can contribute to in171.e10

somnia in some peri- and postmenopausal women.36 Another limitation is that the 2 week washout between treatment periods may have been too short and therefore contribute to residual carryover effects that could not be fully evaluated by the statistical methods used to assess carryover, as evidenced by symptom levels prior to the second treatment period not always returning to base-

American Journal of Obstetrics & Gynecology FEBRUARY 2010

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