Publications

OBJECTIVE: The impact of hot flashes on sleep is of great clinical interest, but results are inconsistent, especially when both hot flashes and sleep are measured objectively. Using objective and subjective measurements, we examined the impact of hot flashes on sleep by inducing hot flashes with a gonadotropin-releasing hormone agonist.

METHODS: The gonadotropin-releasing hormone agonist leuprolide was administered to 20 healthy premenopausal volunteers without hot flashes or sleep disturbances. Induced hot flashes were assessed objectively (skin conductance monitor) and subjectively (daily diary) during 1-month follow-up. Changes from baseline in objective sleep quality (actigraphy) and subjective sleep quality (Pittsburgh Sleep Quality Index) were compared between women who developed and women who did not develop objective hot flashes and, in parallel analyses, subjective hot flashes.

RESULTS: New-onset hot flashes were recorded in 14 (70%) women and reported by 14 (70%) women (80% concordance). Estradiol was universally suppressed. Objective sleep efficiency worsened in women with objective hot flashes and improved in women without objective hot flashes (median decrease, 2.6%; median increase, 4.2%; P = 0.005). Subjective sleep quality worsened more in those with subjective hot flashes than in those without subjective hot flashes (median increase in Pittsburgh Sleep Quality Index, 2.5 vs 1.0; P = 0.03). Objective hot flashes were not associated with subjective sleep quality, nor were subjective symptoms linked to objective sleep measures.

CONCLUSIONS: This experimental model of induced hot flashes demonstrates a causal relationship between hot flashes and poor sleep quality. Objective hot flashes result in worse objective sleep efficiency, whereas subjective hot flashes worsen perceived sleep quality.

OBJECTIVE: Vasomotor symptoms (VMS) recur after discontinuation of hormonal therapy. Selective serotonin reuptake inhibitors (SSRIs) are used increasingly to treat VMS, but whether VMS recur after cessation of SSRI is unknown. We hypothesized that relapse of VMS to baseline levels after SSRI cessation would be common and predicted by menopausal and psychological characteristics.

METHODS: Recurrence of VMS (frequency, severity, and bother) was measured with daily diaries for 3 weeks after cessation of escitalopram, which was administered to perimenopausal/postmenopausal women with hot flashes and night sweats in an 8-week randomized, placebo-controlled trial. Blinding of staff and participants was maintained throughout. Relapse was defined as mean daily VMS frequency, severity, or bother 20% or less lower than pretreatment levels.

RESULTS: Of 76, 57, and 51 women included in the analysis for VMS frequency, severity, and bother, 34.2%, 38.6%, and 37.3%, respectively, had relapse of VMS frequency, severity, and bother. In adjusted models, VMS frequency relapse was predicted by higher levels of pretreatment insomnia symptoms (P = 0.02) and a weaker response to escitalopram (P = 0.03).

CONCLUSIONS: Among women whose VMS improved with escitalopram, approximately one third relapsed swiftly after discontinuation of the medication. Those with pretreatment insomnia and those with a weaker response to escitalopram may be at greatest risk for VMS relapse after treatment discontinuation. Women should be educated about the likelihood of VMS symptom relapse when they discontinue SSRIs after receiving benefits from short-term treatment.

The current study characterized the temporal dynamics of ocular indicators of sleepiness during extended sleep restriction. Ten male participants (mean age ± SD = 23.3 ± 1.6 years) underwent 40 h of continuous wakefulness under constant routine (CR) conditions; they completed the Karolinska Sleepiness Scale (KSS) and a 10-min auditory psychomotor vigilance task (aPVT) hourly. Waking electroencephalography (EEG) and ocular measures were recorded continuously throughout the CR. Infrared-reflectance oculography was used to collect the ocular measures positive and negative amplitude-velocity ratio, mean blink duration, the percentage of eye closure, and a composite score of sleepiness levels (Johns Drowsiness Scale). All ocular measures, except blink duration, displayed homeostatic and circadian properties. Only circadian effects were detected in blink duration. Significant, phase-locked cross-correlations (p < 0.05) were detected between ocular measures and aPVT reaction time (RT), aPVT lapses, KSS, and EEG delta-theta (0.5-5.5 Hz), theta-alpha (5.0-9.0 Hz), and beta (13.0-20.0 Hz) activity. Receiver operating characteristic curve analysis demonstrated reasonable sensitivity and specificity of ocular measures in correctly classifying aPVT lapses above individual baseline thresholds (initial 16 h of wakefulness). Under conditions of sleep restriction, ocular indicators of sleepiness paralleled performance impairment and self-rated sleepiness levels, and demonstrated their potential to detect sleepiness-related attentional lapses. These findings, if reproduced in a larger sample, will have implications for the use of ocular-based sleepiness-warning systems in operational settings.

OBJECTIVES: Sleep interruption is often reported by women with hot flashes and night sweats (or vasomotor symptoms, VMS). Although women report that VMS awaken them, polysomnography (PSG) studies have not consistently supported this contention.

DESIGN: We mimicked menopause using a gonadotropin-releasing hormone agonist (GnRHa) to investigate whether VMS increase awakenings and wake after sleep onset (WASO). VMS, serum estradiol, and at-home PSGs (two pretreatment, two posttreatment) were measured before and after 4 weeks on GnRHa. Regression models were used to determine the effect of increasing VMS frequency on awakenings and WASO, as measured objectively and subjectively.

PARTICIPANTS: Twenty-nine healthy women (mean 27.3 y).

SETTING: Academic medical center.

INTERVENTIONS: Depot GnRHa (leuprolide 3.75-mg).

RESULTS: Serum estradiol was rapidly and uniformly suppressed on GnRHa. Persistent VMS were reported by 69% of women. The number of nighttime VMS correlated directly with the degree of sleep disturbance. Each additional reported nighttime VMS was associated with a 62% increase from baseline in PSG-measured WASO (P = 0.007), a 3% increase in awakenings (P = 0.05), and 6% increase in %N1 sleep (P = 0.02). Nighttime VMS were also associated with increased perceived WASO (312%; P = 0.02), awakenings (16%; P = 0.007), Insomnia Severity Index (P = 0.03), and Pittsburgh Sleep Quality Index (P = 0.03) scores, and decreased perceived sleep efficiency (P = 0.01). Objectively recorded nighttime VMS correlated with PSG-measured WASO (rs = 0.45, P = 0.02).

CONCLUSIONS: This menopause model demonstrates that nighttime vasomotor symptoms correlate with increased sleep fragmentation. These findings are consistent with a specific contribution of vasomotor symptoms to polysomnography-measured sleep interruption suggesting that nighttime vasomotor symptoms interrupt sleep in the setting of menopause.

CONTEXT: GnRH agonists (GnRHa) are being used experimentally in an attempt to preserve fertility in young female cancer patients undergoing chemotherapy. Anti-Müllerian hormone (AMH) produced by ovarian granulosa cells may serve as a marker of ovarian reserve, but it is not clear whether this marker is useful during GnRHa treatment.

OBJECTIVE: The purpose of this study was to determine the effect of a depot GnRHa on AMH levels.

DESIGN: Depot leuprolide (3.75 mg) was administered in the midluteal phase (MLP) in healthy women. Assessments of AMH, FSH, LH, estradiol, and progesterone were performed in the early follicular phase (EFP) and MLP before GnRHa treatment and approximately 7, 14, and 30 days after GnRHa administration.

SETTING: The study was conducted in a university research center.

PATIENTS: Participants were 33 healthy, premenopausal women aged 18 to 45 years old with regular menses.

RESULTS: EFP and MLP AMH levels were similar before GnRHa administration. Relative to MLP AMH levels, AMH decreased 7 days after GnRHa administration by a median of 24% (P < .001) and then increased above pretreatment levels 14 and 30 days after GnRHa by 13% and 32%, respectively (P < .001). Changes in AMH levels did not correlate with changes in gonadotropins, estradiol, or progesterone.

CONCLUSIONS: Significant changes in AMH levels occur in the first 4 weeks after depot leuprolide administration, suggesting that AMH may not be a reliable marker of ovarian reserve during this interval. Changes in AMH occurred independent of gonadotropin levels, supporting a direct effect of GnRHa on granulosa cell expression of AMH or an indirect effect of GnRHa on the development and/or dynamics of the follicle pool.

Circadian phase resetting is sensitive to visual short wavelengths (450-480 nm). Selectively filtering this range of wavelengths may reduce circadian misalignment and sleep impairment during irregular light-dark schedules associated with shiftwork. We examined the effects of filtering short wavelengths (<480 nm) during night shifts on sleep and performance in nine nurses (five females and four males; mean age ± SD: 31.3 ± 4.6 yrs). Participants were randomized to receive filtered light (intervention) or standard indoor light (baseline) on night shifts. Nighttime sleep after two night shifts and daytime sleep in between two night shifts was assessed by polysomnography (PSG). In addition, salivary melatonin levels and alertness were assessed every 2 h on the first night shift of each study period and on the middle night of a run of three night shifts in each study period. Sleep and performance under baseline and intervention conditions were compared with daytime performance on the seventh day shift, and nighttime sleep following the seventh daytime shift (comparator). On the baseline night PSG, total sleep time (TST) (p < 0.01) and sleep efficiency (p = 0.01) were significantly decreased and intervening wake times (wake after sleep onset [WASO]) (p = 0.04) were significantly increased in relation to the comparator night sleep. In contrast, under intervention, TST was increased by a mean of 40 min compared with baseline, WASO was reduced and sleep efficiency was increased to levels similar to the comparator night. Daytime sleep was significantly impaired under both baseline and intervention conditions. Salivary melatonin levels were significantly higher on the first (p < 0.05) and middle (p < 0.01) night shifts under intervention compared with baseline. Subjective sleepiness increased throughout the night under both conditions (p < 0.01). However, reaction time and throughput on vigilance tests were similar to daytime performance under intervention but impaired under baseline on the first night shift. By the middle night shift, the difference in performance was no longer significant between day shift and either of the two night shift conditions, suggesting some adaptation to the night shift had occurred under baseline conditions. These results suggest that both daytime and nighttime sleep are adversely affected in rotating-shift workers and that filtering short wavelengths may be an approach to reduce sleep disruption and improve performance in rotating-shift workers.

OBJECTIVE: Studies have shown that patients with bipolar disorder have high rates of serious and/or untreated co-occurring general medical conditions. This case series examined reports of co-occurring medical conditions with bipolar disorder in potential clinical study participants, and in particular the percentage of these individuals who were previously unaware of their conditions.

METHOD: Patients were potential participants in 1 of 2 medication trials who met DSM-IV criteria for bipolar disorder and were excluded from those studies just prior to randomization from May 2009 through July 2011. Patients were compared with each other on a number of demographic criteria, including age, race, gender, reason for exclusion from the trial, and psychiatric diagnoses.

RESULTS: Of the patients excluded from the studies just prior to randomization, 31% (n = 10) were excluded because of medical conditions previously unreported by the patient during screening for these studies. Seventy percent of those excluded patients (n = 7) had no prior knowledge of their conditions.

CONCLUSIONS: These results suggest that patients with bipolar disorder may not only have high rates of co-occurring medical conditions but also frequently remain unaware of those conditions. These findings indicate that co-occurring general medical conditions may be a more serious problem in the treatment of bipolar disorder than previously appreciated and that more stringent monitoring and guidelines are needed regardless of medication regimen. This case series asserts that, regardless of a patient's claim of having no medical conditions, more general medical screening may be needed in outpatient psychiatric settings.

OBJECTIVE: The purpose of this post hoc analysis was to compare the treatment effect size of eszopiclone 3 mg for insomnia in patients with a diagnosis of primary insomnia and in several of the psychiatric and medical conditions that are most commonly comorbid with insomnia.

METHOD: Data were analyzed from 5 large, multicenter, randomized, double-blind, placebo-controlled studies of adult outpatients of at least 1 month duration published between 2006 and 2009. Diary-derived indices of sleep and daytime functioning and the Insomnia Severity Index were compared for patients with primary insomnia (DSM-IV-TR criteria, n = 828) and for those with insomnia comorbid with major depressive disorder (MDD, DSM-IV-TR criteria, n = 545), generalized anxiety disorder (GAD, DSM-IV-TR criteria, n = 595), perimenopause/postmenopause (Stages of Reproductive Aging Workshop criteria, n = 410), and rheumatoid arthritis (American College of Rheumatology criteria, n = 153). Cohen d effect sizes were calculated for each individual study as the between-treatment difference score divided by the pooled standard deviation.

RESULTS: Effect sizes ranged from 0.40 to 0.69 (small-medium) as early as week 1 and were maintained at 0.26-0.63 at week 4 for sleep latency, wake time after sleep onset, and total sleep time. Sleep latency and total sleep time effect sizes increased from week 1 to week 4 in the primary insomnia group. At week 4, effect sizes on all 3 parameters and the Insomnia Severity Index tended to be highest for the primary insomnia patients and tended to be lowest for patients with comorbid GAD and MDD. The effect sizes for daytime functioning were small for all insomnia patient groups.

CONCLUSIONS: Eszopiclone 3 mg is an effective treatment for insomnia across 5 clinically diverse patient populations; however, magnitude of effect is mediated by underlying comorbidity and their treatments, with largest measures of effect seen in primary insomnia and lowest in MDD and GAD. These consistent results, and the fact that clinical trials were conducted in patients being treated as appropriate for their comorbid clinical conditions, support the results' real-world generalizability and utility to clinical practice.

OBJECTIVE: To examine associations between vasomotor symptoms and lipids over 8 years, controlling for other cardiovascular risk factors, estradiol, and follicle-stimulating hormone.

METHODS: Study of Women's Health Across the Nation participants (N=3,201), aged 42-52 years at entry, completed interviews on frequency of hot flushes and night sweats (none, 1-5 days, 6 days or more, in the past 2 weeks) physical measures (blood pressure, height, weight), and blood draws (low-density lipoprotein [LDL], high-density lipoprotein [HDL], apolipoprotein A-1, apolipoprotein B, lipoprotein[a], triglycerides, serum estradiol, follicle-stimulating hormone) yearly for 8 years. Relations between symptoms and lipids were examined in linear mixed models adjusting for cardiovascular risk factors, medications, and hormones.

RESULTS: Compared with no flushes, experiencing hot flushes was associated with significantly higher LDL (1-5 days: β [standard error]=1.48 [0.47], P<.01; 6 days or more: β [standard error]=2.13 [0.62], P<.001), HDL (1-5 days: β [standard error]=0.30 [0.18]; 6 days or more: β [standard error]=0.77 [0.24], P<.01), apolipoprotein A-1 (1-5 days: β [standard error]=0.92 [0.47], P<.10; 6 days or more: β [standard error]=1.97 [0.62], P<.01), apolipoprotein B (1-5 days: β [standard error]=1.41 [0.41], P<.001; 6 days or more: β [standard error]=2.51 [0.54], P<.001), and triglycerides (1-5 days: percent change [95% confidence interval]=2.91 [1.41-4.43], P<.001; 6 days or more: percent change [95% confidence interval[=5.90 [3.86-7.97], P<.001) in multivariable models. Findings largely persisted adjusting for hormones. Estimated mean differences in lipid levels between hot flushes 6 days or more compared with no days ranged from less than 1 (for HDL) to 10 mg/dL (for triglycerides). Night sweats were similar. Associations were strongest for lean women.

CONCLUSION: Vasomotor symptoms were associated with higher LDL, HDL, apolipoprotein A-1, apolipoprotein B, and triglycerides. Lipids should be considered in links between hot flushes and cardiovascular risk.

LEVEL OF EVIDENCE: II.

OBJECTIVE: Concern about adverse effects of progestins on mood has influenced the use of medroxyprogesterone (MPA) and other progestins. In this brief report, we examined whether the administration of MPA leads to depressive symptoms in two groups of perimenopausal and postmenopausal women randomly assigned to treatment with estrogen: one currently experiencing clinical depression and another without depression.

METHODS: Open-label MPA 10 mg/day was administered for 14 days for endometrial protection after completion of double-blinded treatment with 17β-estradiol 0.1 mg/day for 8 to 12 weeks in 40- to 60-year-old perimenopausal and postmenopausal women enrolled in two separate randomized placebo-controlled trials for treatment of cognitive problems ("nondepressed group") or clinical depression ("depressed group"). Nonparametric tests were used to compare changes in depressive symptoms on the Beck Depression Inventory (BDI) within each group and between groups during MPA therapy.

RESULTS: Of the 24 nondepressed (median BDI at baseline, 5.5; interquartile range [IQR], 2.5-8.5) and 14 depressed (median BDI at baseline, 17; IQR, 15-21) women treated with MPA, the BDI scores did not change during MPA treatment in either group (median change, 0; IQR, -2 to 0.5 and median, 0; IQR, -0.5 to 1.5, P = 0.28 and P = 0.50, respectively). Changes in BDI scores during treatment with MPA did not differ between groups (P = 0.25).

CONCLUSIONS: Among women receiving MPA for 2 weeks after discontinuation of estradiol, depressive symptoms did not emerge on MPA. These findings were consistent for both depressed and nondepressed women, suggesting that, even among women who are currently experiencing depression, brief treatment with MPA is unlikely to disrupt mood.