Effects of melatonin on sleep disturbances in multiple sclerosis: A randomized, controlled pilot study.

BACKGROUND: Sleep disturbances are commonly reported by people with multiple sclerosis (PwMS). However, optimal management of sleep disturbances is uncertain, and objective studies of sleep quality in PwMS are scarce. OBJECTIVES: To determine the effect of exogenous melatonin on sleep quality and sleep disturbances in PwMS. METHODS: Thirty adult PwMS reporting sleep difficulties were recruited in a randomized, controlled, double-blind cross-over study. They took either melatonin or placebo for 2 weeks, and the opposite for the following 2 weeks. During weeks 2 and 4, an actigraph was used to capture mean total sleep time and sleep efficiency. Patient-reported outcomes (PROs) were collected at weeks 0, 2 and 4. RESULTS: Melatonin use significantly improved mean total sleep time (p = 0.03), with a trend towards higher sleep efficiency (p = 0.06). No PROs were significantly different; there was a trend for melatonin use to decrease mean Insomnia Severity Index score (p = 0.07), improve Pittsburgh Sleep Quality Index sleep quality component (p = 0.07), and improve NeuroQoL-Fatigue (p = 0.06). No other PROs showed differences between melatonin and placebo; nor did step count measured by actigraphy (all p > 0.45). CONCLUSION: These results provide preliminary evidence that melatonin, a low-cost, over-the-counter supplement, could improve objective measures of sleep quality in PwMS.

Human circadian variations.

Circadian rhythms, present in most phyla across life, are biological oscillations occurring on a daily cycle. Since the discovery of their molecular foundations in model organisms, many inputs that modify this tightly controlled system in humans have been identified. Polygenic variations and environmental factors influence each person's circadian rhythm, contributing to the trait known as chronotype, which manifests as the degree of morning or evening preference in an individual. Despite normal variation in chronotype, much of society operates on a "one size fits all" schedule that can be difficult to adjust to, especially for certain individuals whose endogenous circadian phase is extremely advanced or delayed. This is a public health concern, as phase misalignment in humans is associated with a number of adverse health outcomes. Additionally, modern technology (such as electric lights and computer, tablet, and phone screens that emit blue light) and lifestyles (such as shift or irregular work schedules) are disrupting circadian consistency in an increasing number of people. Though medical and lifestyle interventions can alleviate some of these issues, growing research on endogenous circadian variability and sensitivity suggests that broader social changes may be necessary to minimize the impact of circadian misalignment on health.

Mutations in Metabotropic Glutamate Receptor 1 Contribute to Natural Short Sleep Trait.

Sufficient and efficient sleep is crucial for our health. Natural short sleepers can sleep significantly shorter than the average population without a desire for more sleep and without any obvious negative health consequences. In searching for genetic variants underlying the short sleep trait, we found two different mutations in the same gene (metabotropic glutamate receptor 1) from two independent natural short sleep families. In vitro, both of the mutations exhibited loss of function in receptor-mediated signaling. In vivo, the mice carrying the individual mutations both demonstrated short sleep behavior. In brain slices, both of the mutations changed the electrical properties and increased excitatory synaptic transmission. These results highlight the important role of metabotropic glutamate receptor 1 in modulating sleep duration.

Genetics of the human circadian clock and sleep homeostat.

Timing and duration of sleep are controlled by the circadian system, which keeps an ~24-h internal rhythm that entrains to environmental stimuli, and the sleep homeostat, which rises as a function of time awake. There is a normal distribution across the population in how the circadian system aligns with typical day and night resulting in varying circadian preferences called chronotypes. A portion of the variation in the population is controlled by genetics as shown by the single-gene mutations that confer extreme early or late chronotypes. Similarly, there is a normal distribution across the population in sleep duration. Genetic variations have been identified that lead to a short sleep phenotype in which individuals sleep only 4-6.5 h nightly. Negative health consequences have been identified when individuals do not sleep at their ideal circadian timing or are sleep deprived relative to intrinsic sleep need. Whether familial natural short sleepers are at risk of the health consequences associated with a short sleep duration based on population data is not known. More work needs to be done to better assess for an individual's chronotype and degree of sleep deprivation to answer these questions.

The assessment and management of insomnia: an update.

Insomnia poses significant challenges to public health. It is a common condition associated with marked impairment in function and quality of life, psychiatric and physical morbidity, and accidents. As such, it is important that effective treatment is provided in clinical practice. To this end, this paper reviews critical aspects of the assessment of insomnia and the available treatment options. These options include both non-medication treatments, most notably cognitive behavioral therapy for insomnia, and a variety of pharmacologic therapies such as benzodiazepines, "z-drugs", melatonin receptor agonists, selective histamine H1 antagonists, orexin antagonists, antidepressants, antipsychotics, anticonvulsants, and non-selective antihistamines. A review of the available research indicates that rigorous double-blind, randomized, controlled trials are lacking for some of the most commonly administered insomnia therapies. However, there are an array of interventions which have been demonstrated to have therapeutic effects in insomnia in trials with the above features, and whose risk/benefit profiles have been well characterized. These interventions can form the basis for systematic, evidence-based treatment of insomnia in clinical practice. We review this evidence base and highlight areas where more studies are needed, with the aim of providing a resource for improving the clinical management of the many patients with insomnia.

Extreme morning chronotypes are often familial and not exceedingly rare: the estimated prevalence of advanced sleep phase, familial advanced sleep phase, and advanced sleep-wake phase disorder in a sleep clinic population.

STUDY OBJECTIVES: Report the first prevalence estimates of advanced sleep phase (ASP), familial advanced sleep phase (FASP), and advanced sleep-wake phase disorder (ASWPD). This can guide clinicians on the utility of screening for extreme chronotypes both for clinical decision-making and to flag prospective participants in the study of the genetics and biology of FASP. METHODS: Data on morning or evening sleep schedule preference (chronotype) were collected from 2422 new patients presenting to a North American sleep center over 9.8 years. FASP was determined using a severity criterion that has previously identified dominant circadian mutations in humans. All patients were personally seen and evaluated by one of the authors (C.R.J.). RESULTS: Our results demonstrate an ASP prevalence of 0.33%, an FASP prevalence of 0.21%, and an ASWPD prevalence of at least 0.04%. Most cases of young-onset ASP were familial. CONCLUSIONS: Among patients presenting to a sleep clinic, conservatively 1 out of every 300 patients will have ASP, 1 out of every 475 will have FASP, and 1 out of every 2500 will have ASWPD. This supports obtaining a routine circadian history and, for those with extreme chronotypes, obtaining a family history of circadian preference. This can optimize treatment for evening sleepiness and early morning awakening and lead to additional circadian gene discovery. We hope these findings will lead to improved treatment options for a wide range of sleep and medical disorders in the future.

Influence of verbal recall of a recent stress experience on anxiety and desire for cocaine in non-treatment seeking, cocaine-addicted volunteers.

It has long been postulated that stress increases the risk of drug abuse and relapse. The principal goal of this project was to evaluate the effects of verbal recall of a recent stress experience (specifically meaningful to each individual) on physiological and subjective measures in cocaine-addicted participants. Subjects described a recent stressful non-drug-related experience and a neutral non-stressful experience, and then completed mood and drug effect questionnaires, while heart rate and blood pressure were recorded. Participants (N = 25) were predominantly African American and male. As a group, participants used cocaine for more than 15 years and approximately 18 of the last 30 days, and a majority reported use of nicotine and/or alcohol. All participants were evaluated during a time in which they tested positive for cocaine metabolite. On a scale of 1-10, participants reported their verbal recall of a recent stress event as highly stressful and their verbal recall of a recent neutral event as non-stressful (p < 0.0001). The self-reported vividness of this recall was high (>8 out of 10) for both the stress and neutral events. Heart rate and systolic and diastolic blood pressure did not differ after verbal recall of either stress or neutral events. Similarly, self-reported subjective effects (including ratings of anxiety and craving for cocaine) did not differ after verbal recall of either stress or neutral events. In summary, despite the fact that participants recounted highly stressful and vivid memories, this experience did not elicit significant changes in cardiovascular or subjective effects. These data suggest that simply recalling a stressful event may not be a sufficient enough stimulus to contribute to craving or relapse in cocaine-addicted individuals.