Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety

<p>Background: Melatonin is extensively used in the USA in a non-regulated manner for sleep disorders. Prolonged release melatonin (PRM) is licensed in Europe and other countries for the short term treatment of primary insomnia in patients aged 55 years and over. However, a clear definition of the target patient population and well-controlled studies of long-term efficacy and safety are lacking. It is known that melatonin production declines with age. Some young insomnia patients also may have low melatonin levels. The study investigated whether older age or low melatonin excretion is a better predictor of response to PRM, whether the efficacy observed in short-term studies is sustained during continued treatment and the long term safety of such treatment.</p> <p>Methods: Adult outpatients (791, aged 18-80 years) with primary insomnia, were treated with placebo (2 weeks) and then randomized, double-blind to 3 weeks with PRM or placebo nightly. PRM patients continued whereas placebo completers were re-randomized 1:1 to PRM or placebo for 26 weeks with 2 weeks of single-blind placebo run-out. Main outcome measures were sleep latency derived from a sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of Life (World Health Organzaton-5) Clinical Global Impression of Improvement (CGI-I) and adverse effects and vital signs recorded at each visit.</p> <p>Results: On the primary efficacy variable, sleep latency, the effects of PRM (3 weeks) in patients with low endogenous melatonin (6-sulphatoxymelatonin [6-SMT] ≤8 μg/night) regardless of age did not differ from the placebo, whereas PRM significantly reduced sleep latency compared to the placebo in elderly patients regardless of melatonin levels (-19.1 versus -1.7 min; P = 0.002). The effects on sleep latency and additional sleep and daytime parameters that improved with PRM were maintained or enhanced over the 6-month period with no signs of tolerance. Most adverse events were mild in severity with no clinically relevant differences between PRM and placebo for any safety outcome.</p> <p>Conclusions: The results demonstrate short- and long-term efficacy and safety of PRM in elderly insomnia patients. Low melatonin production regardless of age is not useful in predicting responses to melatonin therapy in insomnia. The age cut-off for response warrants further investigation.</p&gt

Mobile phone text messaging intervention to improve alertness and reduce sleepiness and fatigue during shiftwork among emergency medicine clinicians: Study protocol for the SleepTrackTXT pilot randomized controlled trial

Background: Mental and physical fatigue while at work is common among emergency medical services (EMS) shift workers. Extended shifts (for example 24 hours) and excessive amounts of overtime work increase the likelihood of negative safety outcomes and pose a challenge for EMS fatigue-risk management. Text message-based interventions are a potentially high-impact, low-cost platform for sleep and fatigue assessment and distributing information to workers at risk of negative safety outcomes related to sleep behaviors and fatigue.Methods/Design: We will conduct a pilot randomized trial with a convenience sample of adult EMS workers recruited from across the United States using a single study website. Participants will be allocated to one of two possible arms for a 90-day study period. The intervention arm will involve text message assessments of sleepiness, fatigue, and difficulty with concentration at the beginning, during, and end of scheduled shifts. Intervention subjects reporting high levels of sleepiness or fatigue will receive one of four randomly selected intervention messages promoting behavior change during shiftwork. Control subjects will receive assessment only text messages. We aim to determine the performance characteristics of a text messaging tool for the delivery of a sleep and fatigue intervention. We seek to determine if a text messaging program with tailored intervention messages is effective at reducing perceived sleepiness and/or fatigue among emergency medicine clinician shift workers. Additional aims include testing whether a theory-based behavioral intervention, delivered by text message, changes 'alertness behaviors'.Discussion: The SleepTrackTXT pilot trial could provide evidence of compliance and effectiveness that would support rapid widespread expansion in one of two forms: 1) a stand-alone program in the form of a tailored/individualized sleep monitoring and fatigue reduction support service for EMS workers; or 2) an add-on to a multi-component fatigue risk management program led and maintained by employers or by safety and risk management services.Trial Registration: Clinicaltrials.gov NCT02063737, Registered on 10 January 2014. © 2014 Patterson et al

A Participatory Health Promotion Mobile App Addressing Alcohol Use Problems (The Daybreak Program): Protocol for a Randomized Controlled Trial

BACKGROUND: At-risk patterns of alcohol use are prevalent in many countries with significant costs to individuals, families, and society. Screening and brief interventions, including with Web delivery, are effective but with limited translation into practice to date. Previous observational studies of the Hello Sunday Morning approach have found that their unique Web-based participatory health communication method has resulted in a reduction of at-risk alcohol use between baseline and 3 months. The Hello Sunday Morning blog program asks participants to publicly set a personal goal to stop drinking or reduce their consumption for a set period of time, and to record their reflections and progress on blogs and social networks. Daybreak is Hello Sunday Morning's evidence-based behavior change program, which is designed to support people looking to change their relationship with alcohol. OBJECTIVE: This study aims to systematically evaluate different versions of Hello Sunday Morning's Daybreak program (with and without coaching support) in reducing at-risk alcohol use. METHODS: We will use a between groups randomized control design. New participants enrolling in the Daybreak program will be eligible to be randomized to receive either (1) the Daybreak program, including peer support plus behavioral experiments (these encourage and guide participants in developing new skills in the areas of mindfulness, connectedness, resilience, situational strategies, and health), or (2) the Daybreak program, including the same peer support plus behavioral experiments, but with online coaching support. We will recruit 467 people per group to detect an effect size of f=0.10. To be eligible, participants must be resident in Australia, aged =18 years, score =8 on the alcohol use disorders identification test (AUDIT), and not report prior treatment for cardiovascular disease. RESULTS: The primary outcome measure will be reduction in the AUDIT-Consumption (AUDIT-C) scores. Secondary outcomes include mental health (Kessler's K-10), days out of role (Kessler), alcohol consumed (measured with a 7-day drinking diary in standard 10 g drinks), and alcohol-related harms (CORE alcohol and drug survey). We will collect data at baseline and 1, 3, and 6 months and analyze them with random effects models, given the correlated data structure. CONCLUSIONS: A randomized trial is required to provide robust evidence of the impact of the online coaching component of the Daybreak program, including over an extended period

Sequential psychological and pharmacological therapies for comorbid and primary insomnia: Study protocol for a randomized controlled trial

Background: Chronic insomnia is a prevalent disorder associated with significant psychosocial, health, and economic impacts. Cognitive behavioral therapies (CBTs) and benzodiazepine receptor agonist (BzRA) medications are the most widely supported therapeutic approaches for insomnia management. However, few investigations have directly compared their relative and combined benefits, and even fewer have tested the benefits of sequential treatment for those who do not respond to initial insomnia therapy. Moreover, insomnia treatment studies have been limited by small, highly screened study samples, fixed-dose, and fixed-agent pharmacotherapy strategies that do not represent usual clinical practices. This study will address these limitations. Methods/design: This is a two-site randomized controlled trial, which will enroll 224 adults who meet the criteria for a chronic insomnia disorder with or without comorbid psychiatric disorders. Prospective participants will complete clinical assessments and polysomnography and then will be randomly assigned to first-stage therapy involving either behavioral therapy (BT) or zolpidem. Treatment outcomes will be assessed after 6 weeks, and treatment remitters will be followed for the next 12 months on maintenance therapy. Those not achieving remission will be offered randomization to a second, 6-week treatment, again involving either pharmacotherapy (zolpidem or trazodone) or psychological therapy (BT or cognitive therapy (CT)). All participants will be re-evaluated 12 weeks after the protocol initiation and at 3-, 6-, 9-, and 12-month follow-ups. Insomnia remission, defined categorically as a score < 8 on the Insomnia Severity Index, a patient-reported outcome, will serve as the primary endpoint for treatment comparisons. Secondary outcomes will include sleep parameters derived from daily sleep diaries and from polysomnography, subjective measures of fatigue, mood, quality of life, and functional impairments; and measures of adverse events; dropout rates; and treatment acceptability. Centrally trained therapists will administer therapies according to manualized, albeit flexible, treatment algorithms. Discussion: This clinical trial will provide new information about optimal treatment sequencing and will have direct implication for the development of clinical guidelines for managing chronic insomnia with and without comorbid psychiatric conditions

Objective and subjective sleep disorders in automated peritoneal dialysis

Background: Automated peritoneal dialysis (APD) is one of the fastest growing dialysis modalities. It is unknown whether sleep and mood are disturbed while performing repeated overnight exchanges. Objectives: In this report, we aim to describe and compare the prevalence of sleep-disordered breathing (SDB), periodic limb movements (PLMS), poor sleep quality (SQ), and depression among APD patients compared with stages 3b-5 (estimated glomerular filtration rate ≤44 ml/min/1.73 m2) chronic kidney disease (CKD) and hemodialysis (HD) patients. Design: This is a cross-sectional, descriptive study. Setting: Study participants were recruited from outpatient nephrology clinics, local dialysis centers, and the Thomas E. Starzl Transplant Institute in Western Pennsylvania between April 2004 and July 2009. Patients: There were 186 participants in this study including 22 APD patients, 89 CKD patients, and 75 HD patients. Measurements: In-home polysomnography was performed and two questionnaires were completed, the Pittsburgh Sleep Quality Index (PSQI) and the Patient Health Questionnaire-9 (PHQ-9). Methods: SDB and PLMS were quantified by in-home unattended polysomnography; poor SQ was defined by a score >5 on the PSQI, and the presence of moderate to severe depression was defined by a score >5 on the PHQ-9. Results: The APD patients had a median age of 37.5 years, were predominantly female (72.7 %), and had a median body mass index (BMI) of 23.8 kg/m2. In univariate analyses, APD patients had significantly lower apnea-hypopnea index compared to HD patients by 12.2 points (likelihood ratio test p = 0.008) and revealed the least percent of TST with nocturnal hypoxemia compared to CKD patients by 2.7 points, respectively (likelihood ratio test p = 0.01). The APD group had also significantly greater stages 3 to 4 sleep compared to the CKD patients by 8.6 points (likelihood ratio test p = 0.009). In multivariate analyses and after adjustment for age, gender, race, and BMI, both APD and HD patients had higher average PSQI scores than CKD patients by 2.54 and 2.22 points, respectively (likelihood ratio test p = 0.005). No other comparisons of sleep parameters among groups reached statistical significance. Limitations: The limitations of this study are the small sample size of the APD population and the demographic and clinical differences among the three study groups. Conclusions: Despite differences in univariate analyses, after multivariate adjustment, APD patients had similar sleep parameters and sleep architecture and as poor SQ and symptoms of depression as HD patients. Future studies with larger APD cohorts are needed

Ecological momentary assessment of fatigue, sleepiness, and exhaustion in ESKD

Background: Many patients on maintenance dialysis experience significant sleepiness and fatigue. However, the influence of the hemodialysis (HD) day and circadian rhythms on patients' symptoms have not been well characterized. We sought to use ecological momentary assessment to evaluate day-to-day and diurnal variability of fatigue, sleepiness, exhaustion and related symptoms in thrice-weekly maintenance HD patients. Methods. Subjects used a modified cellular phone to access an interactive voice response system that administered the Daytime Insomnia Symptom Scale (DISS). The DISS assessed subjective vitality, mood, and alertness through 19 questions using 7- point Likert scales. Subjects completed the DISS 4 times daily for 7 consecutive days. Factor analysis was conducted and a mean composite score of fatigue-sleepiness- exhaustion was created. Linear mixed regression models (LMM) were used to examine the association of time of day, dialysis day and fatigue, sleepiness, and exhaustion composite scores. Results: The 55 participants completed 1,252 of 1,540 (81%) possible assessments over the 7 day period. Multiple symptoms related to mood (e.g., feeling sad, feeling tense), cognition (e.g., difficulty concentrating), and fatigue (e.g., exhaustion, feeling sleepy) demonstrated significant daily and diurnal variation, with higher overall symptom scores noted on hemodialysis days and later in the day. In factor analysis, 4 factors explained the majority of the observed variance for DISS symptoms. Fatigue, sleepiness, and exhaustion loaded onto the same factor and were highly intercorrelated. In LMM, mean composite fatigue-sleepiness-exhaustion scores were associated with dialysis day (coefficient and 95% confidence interval [CI] 0.21 [0.02 - 0.39]) and time of day (coefficient and 95% CI 0.33 [0.25 - 0.41]. Observed associations were minimally affected by adjustment for demographics and common confounders. Conclusions: Maintenance HD patients experience fatigue-sleepiness-exhaustion symptoms that demonstrate significant daily and diurnal variation. The variability in symptoms may contribute to poor symptom awareness by providers and greater misclassification bias of fatigue related symptoms in clinical studies. © 2014 Abdel-Kader et al.; licensee BioMed Central Ltd

Prenatal muscle development in a mouse model for the secondary dystroglycanopathies

The defective glycosylation of α-dystroglycan is associated with a group of muscular dystrophies that are collectively referred to as the secondary dystroglycanopathies. Mutations in the gene encoding fukutin-related protein (FKRP) are one of the most common causes of secondary dystroglycanopathy in the UK and are associated with a wide spectrum of disease. Whilst central nervous system involvement has a prenatal onset, no studies have addressed prenatal muscle development in any of the mouse models for this group of diseases. In view of the pivotal role of α-dystroglycan in early basement membrane formation, we sought to determine if the muscle formation was altered in a mouse model of FKRP-related dystrophy

Voluntary exercise can strengthen the circadian system in aged mice

Consistent daily rhythms are important to healthy aging according to studies linking disrupted circadian rhythms with negative health impacts. We studied the effects of age and exercise on baseline circadian rhythms and on the circadian system's ability to respond to the perturbation induced by an 8 h advance of the light:dark (LD) cycle as a test of the system's robustness. Mice (male, mPer2luc/C57BL/6) were studied at one of two ages: 3.5 months (n = 39) and &gt;18 months (n = 72). We examined activity records of these mice under entrained and shifted conditions as well as mPER2::LUC measures ex vivo to assess circadian function in the suprachiasmatic nuclei (SCN) and important target organs. Age was associated with reduced running wheel use, fragmentation of activity, and slowed resetting in both behavioral and molecular measures. Furthermore, we observed that for aged mice, the presence of a running wheel altered the amplitude of the spontaneous firing rate rhythm in the SCN in vitro. Following a shift of the LD cycle, both young and aged mice showed a change in rhythmicity properties of the mPER2::LUC oscillation of the SCN in vitro, and aged mice exhibited longer lasting internal desynchrony. Access to a running wheel alleviated some age-related changes in the circadian system. In an additional experiment, we replicated the effect of the running wheel, comparing behavioral and in vitro results from aged mice housed with or without a running wheel (&gt;21 months, n = 8 per group, all examined 4 days after the shift). The impact of voluntary exercise on circadian rhythm properties in an aged animal is a novel finding and has implications for the health of older people living with environmentally induced circadian disruption

Nap sleep spindle correlates of intelligence

Contains fulltext : 152518.pdf (publisher's version ) (Open Access)Sleep spindles are thalamocortical oscillations in non-rapid eye movement (NREM) sleep, that play an important role in sleep-related neuroplasticity and offline information processing. Several studies with full-night sleep recordings have reported a positive association between sleep spindles and fluid intelligence scores, however more recently it has been shown that only few sleep spindle measures correlate with intelligence in females, and none in males. Sleep spindle regulation underlies a circadian rhythm, however the association between spindles and intelligence has not been investigated in daytime nap sleep so far. In a sample of 86 healthy male human subjects, we investigated the correlation between fluid intelligence and sleep spindle parameters in an afternoon nap of 100 minutes. Mean sleep spindle length, amplitude and density were computed for each subject and for each derivation for both slow and fast spindles. A positive association was found between intelligence and slow spindle duration, but not any other sleep spindle parameter. As a positive correlation between intelligence and slow sleep spindle duration in full-night polysomnography has only been reported in females but not males, our results suggest that the association between intelligence and sleep spindles is more complex than previously assumed

Effectiveness and cost-effectiveness of an educational intervention for practice teams to deliver problem focused therapy for insomnia: rationale and design of a pilot cluster randomised trial

Background: Sleep problems are common, affecting over a third of adults in the United Kingdom and leading to reduced productivity and impaired health-related quality of life. Many of those whose lives are affected seek medical help from primary care. Drug treatment is ineffective long term. Psychological methods for managing sleep problems, including cognitive behavioural therapy for insomnia (CBTi) have been shown to be effective and cost effective but have not been widely implemented or evaluated in a general practice setting where they are most likely to be needed and most appropriately delivered. This paper outlines the protocol for a pilot study designed to evaluate the effectiveness and cost-effectiveness of an educational intervention for general practitioners, primary care nurses and other members of the primary care team to deliver problem focused therapy to adult patients presenting with sleep problems due to lifestyle causes, pain or mild to moderate depression or anxiety. Methods and design: This will be a pilot cluster randomised controlled trial of a complex intervention. General practices will be randomised to an educational intervention for problem focused therapy which includes a consultation approach comprising careful assessment (using assessment of secondary causes, sleep diaries and severity) and use of modified CBTi for insomnia in the consultation compared with usual care (general advice on sleep hygiene and pharmacotherapy with hypnotic drugs). Clinicians randomised to the intervention will receive an educational intervention (2 × 2 hours) to implement a complex intervention of problem focused therapy. Clinicians randomised to the control group will receive reinforcement of usual care with sleep hygiene advice. Outcomes will be assessed via self-completion questionnaires and telephone interviews of patients and staff as well as clinical records for interventions and prescribing. Discussion: Previous studies in adults have shown that psychological treatments for insomnia administered by specialist nurses to groups of patients can be effective within a primary care setting. This will be a pilot study to determine whether an educational intervention aimed at primary care teams to deliver problem focused therapy for insomnia can improve sleep management and outcomes for individual adult patients presenting to general practice. The study will also test procedures and collect information in preparation for a larger definitive cluster-randomised trial. The study is funded by The Health Foundation