Publications

Various aspects of immune response exhibit 24-h variations suggesting that infection susceptibility and treatment efficacy may vary by time of day. Whether these 24-h variations are endogenous or evoked by changes in environmental or behavioral conditions is not known. We assessed the endogenous circadian control and environmental and behavioral influences on ex-vivo lipopolysaccharide stimulation of whole blood in thirteen healthy participants under 48h of baseline conditions with standard sleep-wake schedules and 40-50h of constant environmental and behavioral (constant routine; CR) conditions. Significant 24-h rhythms were observed under baseline conditions in Monocyte Chemotactic Protein, Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin 8 but not Tumor Necrosis Factor alpha whereas significant 24-h rhythms were observed in all four immune factors under CR conditions. The rhythm amplitudes, expressed as a percentage of mean, were comparable between immune factors and across conditions. In contrast, the acrophase time (time of the fitted peak) was different between immune factors, and included daytime and nighttime peaks and changes across behavioral conditions. These results suggest that the endogenous circadian system underpins the temporal organization of immune responses in humans with additional effects of external environmental and behavioral cycles. These findings have implications for understanding the adverse effects of recurrent circadian disruption and sleep curtailment on immune function.

BACKGROUND: Women's vulnerability for a first lifetime-onset of major depressive disorder (MDD) during midlife is substantial. It is unclear whether risk factors differ for first lifetime-onset and recurrent MDD. Identifying these risk factors can provide more focused depression screening and earlier intervention. This study aims to evaluate whether lifetime psychiatric and health histories, personality traits, menopausal status and factors that vary over time, e.g. symptoms, are independent risk factors for first-onset or recurrent MDD across 13 annual follow-ups.

METHOD: Four hundred and forty-three women, aged 42-52 years, enrolled in the Study of Women's Health Across the Nation in Pittsburgh and participated in the Mental Health Study. Psychiatric interviews obtained information on lifetime psychiatric disorders at baseline and on occurrences of MDD episodes annually. Psychosocial and health-related data were collected annually. Cox multivariable analyses were conducted separately for women with and without a MDD history at baseline.

RESULTS: Women without lifetime MDD at baseline had a lower risk of developing MDD during midlife than those with a prior MDD history (28% v. 59%) and their risk profiles differed. Health conditions prior to baseline and during follow-ups perception of functioning (ps < 0.05) and vasomotor symptoms (VMS) (p = 0.08) were risk factors for first lifetime-onset MDD. Being peri- and post-menopausal, psychological symptoms and a prior anxiety disorder were predominant risk factors for MDD recurrence.

CONCLUSIONS: The menopausal transition warrants attention as a period of vulnerability to MDD recurrence, while health factors and VMS should be considered important risk factors for first lifetime-onset of MDD during midlife.

BACKGROUND: Obesity is a global public health challenge. In the US, for instance, obesity prevalence remains high at more than one-third of the adult population, while over two-thirds are obese or overweight. Obesity is associated with various health problems, such as diabetes, cardiovascular diseases (CVDs), depression, some forms of cancer, sleep apnea, osteoarthritis, among others. The body mass index (BMI) is one of the best known measures of obesity. The BMI, however, has serious limitations, for instance, its inability to capture the distribution of lean mass and adipose tissue, which is a better predictor of diabetes and CVDs, and its curved ("U-shaped") relationship with mortality hazard. Other anthropometric measures and their relation to obesity have been studied, each with its advantages and limitations. In this work, we introduce a new anthropometric measure (called Surface-based Body Shape Index, SBSI) that accounts for both body shape and body size, and evaluate its performance as a predictor of all-cause mortality.

METHODS AND FINDINGS: We analyzed data on 11,808 subjects (ages 18-85), from the National Health and Human Nutrition Examination Survey (NHANES) 1999-2004, with 8-year mortality follow up. Based on the analysis, we introduce a new body shape index constructed from four important anthropometric determinants of body shape and body size: body surface area (BSA), vertical trunk circumference (VTC), height (H) and waist circumference (WC). The surface-based body shape index (SBSI) is defined as follows: SBSI = ((H(7/4))(WC(5/6)))/(BSA VTC) (1) SBSI has negative correlation with BMI and weight respectively, no correlation with WC, and shows a generally linear relationship with age. Results on mortality hazard prediction using both the Cox proportionality model, and Kaplan-Meier curves each show that SBSI outperforms currently popular body shape indices (e.g., BMI, WC, waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), A Body Shape Index (ABSI)) in predicting all-cause mortality.

CONCLUSIONS: We combine measures of both body shape and body size to construct a novel anthropometric measure, the surface-based body shape index (SBSI). SBSI is generally linear with age, and increases with increasing mortality, when compared with other popular anthropometric indices of body shape.

STUDY OBJECTIVES: Previous studies have demonstrated short-wavelength sensitivity for the acute alerting response to nocturnal light exposure. We assessed daytime spectral sensitivity in alertness, performance, and waking electroencephalogram (EEG).

DESIGN: Between-subjects (n = 8 per group).

SETTING: Inpatient intensive physiologic monitoring unit.

PARTICIPANTS: Sixteen healthy young adults (mean age ± standard deviation = 23.8 ± 2.7 y).

INTERVENTIONS: Equal photon density exposure (2.8 × 10(13) photons/cm(2)/s) to monochromatic 460 nm (blue) or 555 nm (green) light for 6.5 h centered in the middle of the 16-h episode of wakefulness during the biological day. Results were compared retrospectively to 16 individuals who were administered the same light exposure during the night.

MEASUREMENTS AND RESULTS: Daytime and nighttime 460-nm light exposure significantly improved auditory reaction time (P < 0.01 and P < 0.05, respectively) and reduced attentional lapses (P < 0.05), and improved EEG correlates of alertness compared to 555-nm exposure. Whereas subjective sleepiness ratings did not differ between the two spectral conditions during the daytime (P > 0.05), 460-nm light exposure at night significantly reduced subjective sleepiness compared to 555-nm light exposure at night (P < 0.05). Moreover, nighttime 460-nm exposure improved alertness to near-daytime levels.

CONCLUSIONS: The alerting effects of short-wavelength 460-nm light are mediated by counteracting both the circadian drive for sleepiness and homeostatic sleep pressure at night, but only via reducing the effects of homeostatic sleep pressure during the day.

BACKGROUND: Psychotropic medications, particularly select antipsychotics, are a common cause of drug-induced hyperprolactinemia. As high prolactin may be associated with hypogonadism, reproductive dysfunction, and bone loss, it is important to recognize this condition and understand its management.

OBJECTIVE: The aim of this review is to evaluate the causes, signs, and symptoms associated with hyperprolactinemia, to describe mechanisms through which psychotropic medications elevate prolactin, and to suggest an evidence-based management approach for patients with psychotropic drug-induced hyperprolactinemia.

METHODS: A PubMed/MEDLINE search was conducted on the topic of psychotropic agents as a cause of hyperprolactinemia. The material with most relevance to current psychiatric practice and of highest level of evidence was included in this review.

CONCLUSION: Hyperprolactinemia should be evaluated in adult patients receiving psychotropic agents if signs and symptoms associated with hyperprolactinemia are present. It is also important to exclude pituitary and hypothalamic disease by magnetic resonance imaging if hyperprolactinemia is not definitely caused by psychotropic medications. As bone loss may occur because of hyperprolactinemia-mediated hypogonadism, bone mineral density (BMD) should be evaluated in patients with persistent high prolactin and reproductive dysfunction. Aripiprazole or other prolactin-sparing atypical antipsychotics may be alternatives or aripiprazole can be considered as adjunctive therapy in select cases of psychotropic-induced hyperprolactinemia.

OBJECTIVE: This report describes the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health network and methodological issues addressed in designing and implementing vasomotor symptom trials.

METHODS: Established in response to a National Institutes of Health request for applications, the network was charged with conducting rapid throughput randomized trials of novel and understudied available interventions postulated to alleviate vasomotor and other menopausal symptoms. Included are descriptions of and rationale for criteria used for interventions and study selection, common eligibility and exclusion criteria, common primary and secondary outcome measures, consideration of placebo response, establishment of a biorepository, trial duration, screening and recruitment, statistical methods, and quality control. All trial designs are presented, including the following: (1) a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effectiveness of the selective serotonin reuptake inhibitor escitalopram in reducing vasomotor symptom frequency and severity; (2) a two-by-three factorial design trial to test three different interventions (yoga, exercise, and ω-3 supplementation) for the improvement of vasomotor symptom frequency and bother; and (3) a three-arm comparative efficacy trial of the serotonin-norepinephrine reuptake inhibitor venlafaxine and low-dose oral estradiol versus placebo for reducing vasomotor symptom frequency. The network's structure and governance are also discussed.

CONCLUSIONS: The methods used in and the lessons learned from the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health trials are shared to encourage and support the conduct of similar trials and to encourage collaborations with other researchers.

OBJECTIVE: The purpose of this study was to determine the efficacy of 3 nonhormonal therapies for the improvement of menopause-related quality of life in women with vasomotor symptoms.

STUDY DESIGN: We conducted a 12-week 3 × 2 randomized, controlled, factorial design trial. Peri- and postmenopausal women, 40-62 years old, were assigned randomly to yoga (n = 107), exercise (n = 106), or usual activity (n = 142) and also assigned randomly to a double-blind comparison of omega-3 (n = 177) or placebo (n = 178) capsules. We performed the following interventions: (1) weekly 90-minute yoga classes with daily at-home practice, (2) individualized facility-based aerobic exercise training 3 times/week, and (3) 0.615 g omega-3 supplement, 3 times/day. The outcomes were assessed with the following scores: Menopausal Quality of Life Questionnaire (MENQOL) total and domain (vasomotor symptoms, psychosocial, physical and sexual).

RESULTS: Among 355 randomly assigned women who average age was 54.7 years, 338 women (95%) completed 12-week assessments. Mean baseline vasomotor symptoms frequency was 7.6/day, and the mean baseline total MENQOL score was 3.8 (range, 1-8 from better to worse) with no between-group differences. For yoga compared to usual activity, baseline to 12-week improvements were seen for MENQOL total -0.3 (95% confidence interval, -0.6 to 0; P = .02), vasomotor symptom domain (P = .02), and sexuality domain (P = .03) scores. For women who underwent exercise and omega-3 therapy compared with control subjects, improvements in baseline to 12-week total MENQOL scores were not observed. Exercise showed benefit in the MENQOL physical domain score at 12 weeks (P = .02).

CONCLUSION: All women become menopausal, and many of them seek medical advice on ways to improve quality of life; little evidence-based information exists. We found that, among healthy sedentary menopausal women, yoga appears to improve menopausal quality of life; the clinical significance of our finding is uncertain because of the modest effect.

IMPORTANCE: Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride is used widely as a nonhormonal treatment. While the clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial to date.

OBJECTIVE: To determine the efficacy and tolerability of low-dose oral 17β-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS).

DESIGN, SETTING, AND PARTICIPANTS: In total, 339 perimenopausal and postmenopausal women with at least 2 bothersome VMS per day (mean, 8.1 per day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites between December 5, 2011, and October 15, 2012.

INTERVENTIONS: Participants were randomized to double-blind treatment with low-dose oral 17β-estradiol (0.5 mg/d) (n = 97), low-dose venlafaxine hydrochloride extended release (75 mg/d) (n = 96), or placebo (n = 146) for 8 weeks.

MAIN OUTCOMES AND MEASURES: The primary outcome was the mean daily frequency of VMS after 8 weeks of treatment. Secondary outcomes were VMS severity, bother, and interference with daily life. Intent-to-treat analyses compared the change in VMS frequency between each active intervention and placebo and between the 2 active treatments.

RESULTS: Compared with baseline, the mean VMS frequency at week 8 decreased to 3.9 (95% CI, 2.9-4.9) VMS per day (52.9% reduction) in the estradiol group, to 4.4 (95% CI, 3.5-5.3) VMS per day (47.6% reduction) in the venlafaxine group, and to 5.5 (95% CI, 4.7-6.3) VMS per day (28.6% reduction) in the placebo group. Estradiol reduced the frequency of symptoms by 2.3 more per day than placebo (P < .001), and venlafaxine reduced the frequency of symptoms by 1.8 more per day than placebo (P = .005). The results were consistent for VMS severity, bother, and interference. Low-dose estradiol reduced the frequency of symptoms by 0.6 more per day than venlafaxine (P = .09). Treatment satisfaction was highest (70.3%) for estradiol (P < .001 vs placebo), lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine (P = .06 vs placebo). Both interventions were well tolerated.

CONCLUSIONS AND RELEVANCE: Low-dose oral estradiol and venlafaxine are effective treatments for VMS in women during midlife. While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01418209.

OBJECTIVES: Women report greater sleep disturbance during the premenstrual phase of the menstrual cycle and during menses. However, the putative hormonal basis of perceived menstrual cycle-related sleep disturbance has not been investigated directly. We examined associations of objective measures of sleep fragmentation with reproductive hormone levels in healthy, premenopausal women.

METHODS: Twenty-seven women with monthly menses had hormone levels measured at two time points during a single menstrual cycle: the follicular phase and the peri-ovulatory to mid-luteal phase. A single night of home polysomnography (PSG) was recorded on the day of the peri-ovulatory/mid-luteal-phase blood draw. Serum progesterone, estradiol, and estrone levels concurrent with PSG and rate of change in progesterone (PROGslope) from the follicular blood draw to PSG were correlated with log-transformed wake after sleep onset (lnWASO%) and number of wakes/hour of sleep (lnWake-Index) using linear regression.

RESULTS: Sleep was more fragmented in association with a steeper PROGslope (lnWASO% p=0.016; lnWake-Index p=0.08) and higher concurrent estrone level (lnWASO% p=0.03; lnWake-Index p=0.01), but the effect of estrone on WASO was lost after accounting for PROGslope. WASO% and Wake-Index were not associated with concomitant progesterone or estradiol levels.

CONCLUSIONS: A steeper rate of rise in progesterone levels from the follicular phase through the mid-luteal phase was associated with significantly greater WASO, establishing a link between reproductive hormone dynamics and sleep fragmentation in the luteal phase of the menstrual cycle.