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Alterations in sleep are extremely common in patients with neuropsychiatric illness. In addition, sleep disorders such as insomnia, obstructive sleep apnea, rapid eye movement sleep behavior disorder, and circadian rhythm disorders commonly occur at a rate greater than the general population in neuropsychiatric conditions. Historically, sleep problems have been viewed as symptoms of associated neuropsychiatric disorders. However, there is increasing evidence suggesting a complex inter-relationship with possible bidirectional causality. The inter-relatedness of these conditions represents an opportunity for understanding mechanisms and improving clinical treatment. To the extent that sleep problems affect neuropsychiatric conditions, it may be possible to address sleep problems and have a positive impact on the course of neuropsychiatric illnesses. Further, some treatments for sleep disorders have direct effects on neuropsychiatric illnesses that may be unrelated to their effects on sleep disorders. Similarly, neuropsychiatric conditions and their treatments can affect sleep and sleep disorders. This article reviews available evidence on the effects of therapies for sleep disorders on neuropsychiatric conditions and also secondarily considers the impacts of therapies for neuropsychiatric conditions on sleep. Primary goals of this review are to identify gaps in current research, to determine the extent to which the cross-therapeutic effects of these treatments help to elucidate therapeutic or pathological mechanisms, and to assist clinicians in optimizing therapeutic choice in patients with sleep disorders and neuropsychiatric conditions.

Introduction: The purpose of this guideline is to establish clinical practice recommendations for the pharmacologic treatment of chronic insomnia in adults, when such treatment is clinically indicated. Unlike previous meta-analyses, which focused on broad classes of drugs, this guideline focuses on individual drugs commonly used to treat insomnia. It includes drugs that are FDA-approved for the treatment of insomnia, as well as several drugs commonly used to treat insomnia without an FDA indication for this condition. This guideline should be used in conjunction with other AASM guidelines on the evaluation and treatment of chronic insomnia in adults. Methods: The American Academy of Sleep Medicine commissioned a task force of four experts in sleep medicine. A systematic review was conducted to identify randomized controlled trials, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence. The task force developed recommendations and assigned strengths based on the quality of evidence, the balance of benefits and harms, and patient values and preferences. Literature reviews are provided for those pharmacologic agents for which sufficient evidence was available to establish recommendations. The AASM Board of Directors approved the final recommendations. Recommendations: The following recommendations are intended as a guideline for clinicians in choosing a specific pharmacological agent for treatment of chronic insomnia in adults, when such treatment is indicated. Under GRADE, a STRONG recommendation is one that clinicians should, under most circumstances, follow. A WEAK recommendation reflects a lower degree of certainty in the outcome and appropriateness of the patient-care strategy for all patients, but should not be construed as an indication of ineffectiveness. GRADE recommendation strengths do not refer to the magnitude of treatment effects in a particular patient, but rather, to the strength of evidence in published data. Downgrading the quality of evidence for these treatments is predictable in GRADE, due to the funding source for most pharmacological clinical trials and the attendant risk of publication bias; the relatively small number of eligible trials for each individual agent; and the observed heterogeneity in the data. The ultimate judgment regarding propriety of any specific care must be made by the clinician in light of the individual circumstances presented by the patient, available diagnostic tools, accessible treatment options, and resources. We suggest that clinicians use suvorexant as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use eszopiclone as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use zaleplon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use zolpidem as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use triazolam as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use temazepam as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use ramelteon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use doxepin as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians not use trazodone as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians not use tiagabine as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians not use diphenhydramine as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians not use melatonin as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians not use tryptophan as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians not use valerian as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) Citation: Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med . 2017;13(2):307–349.

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.

Suvorexant (MK-4305) is an orexin receptor antagonist shown to be efficacious for insomnia over 3 months. We aimed to assess its clinical profile during and after 1 year of treatment. We did a randomised, placebo-controlled, parallel-group trial at 106 investigational centres in the Americas, Australia, Europe, and South Africa from December, 2009, to August, 2011. Patients aged 18 years or older with primary insomnia by DSM-IV-TR criteria were assigned using a computer-generated randomised allocation schedule to receive nightly suvorexant (40 mg for patients younger than 65 years, 30 mg for patients aged 65 years or older) or placebo at a 2:1 ratio for 1 year with a subsequent 2-month randomised discontinuation phase in which patients on suvorexant either continued suvorexant or were abruptly switched to placebo while patients on placebo remained on placebo. Treatment assignment was masked from patients and investigators. The primary objective was to assess the safety and tolerability of suvorexant for up to 1 year. Secondary objectives were to assess the efficacy of suvorexant for improving patient-reported subjective total sleep time (sTST) and time to sleep onset (sTSO) over the first month of treatment. Efficacy endpoints over the first month were assessed with a mixed model with terms for baseline value of the response variable, age, sex, region, treatment, time, and treatment by time interaction. This trial is registered with ClinicalTrials.gov, number NCT01021813. 322 (62%) of 522 patients randomly assigned to receive suvorexant and 162 (63%) of 259 assigned to receive placebo completed the 1-year phase. Over 1 year, 362 (69%) of 521 patients treated with suvorexant experienced any adverse events compared with 164 (64%) of 258 treated with placebo. Serious adverse events were recorded in 27 patients (5%) who received suvorexant and 17 (7%) who received placebo. The most common adverse event, somnolence, was reported for 69 patients (13%) who received suvorexant and seven (3%) who received placebo. At month 1, suvorexant (517 patients in the efficacy population) showed greater efficacy than placebo (254 in the efficacy population) in improving sTST (38·7 min vs 16·0 min; difference 22·7, 95% CI 16·4 to 29·0; p<0·0001) and sTSO (–18·0 min vs −8·4 min, difference −9·5, −14·6 to −4·5; p=0·0002). Our findings show that suvorexant was generally safe and well tolerated over 1 year of nightly treatment in patients with insomnia, with efficacy noted for subjective measures of sleep onset and maintenance. Merck & Co Inc.

Determining the most effective insomnia medication for patients may require therapeutic trials of different medications. In addition, medication side effects, interactions with co-administered medications, and declining therapeutic efficacy can necessitate switching between different insomnia medications or deprescribing altogether. Currently, little guidance exists regarding the safest and most effective way to transition from one medication to another. Thus, we developed evidence-based guidelines to inform clinicians regarding best practices when deprescribing or transitioning between insomnia medications. Five U.S.-based sleep experts reviewed the literature involving insomnia medication deprescribing, tapering, and switching and rated the quality of evidence. They used this evidence to generate recommendations through discussion and consensus. When switching or discontinuing insomnia medications, we recommend benzodiazepine hypnotic drugs be tapered while additional CBT-I is provided. For Z-drugs zolpidem and eszopiclone (and not zaleplon), especially when prescribed at supratherapeutic doses, tapering is recommended with a 1–2-day delay in administration of the next insomnia therapy when applicable. There is no need to taper DORAs, doxepin, and ramelteon. Lastly, off-label antidepressants and antipsychotics used to treat insomnia should be gradually reduced when discontinuing. In general, offering individuals a rationale for deprescribing or switching and involving them in the decision-making process can facilitate the change and enhance treatment success.

Deep brain stimulation (DBS) is well suited to target disorders with network dysregulation, as is the case in many neuropsychiatric diseases. While DBS is a well-established therapy for Parkinson’s disease, essential tremor, dystonia, and medically refractory epilepsy, it is actively being studied in clinical trials for neuropsychiatric disorders including treatment-refractory major depressive disorder (MDD). Due to the nature of symptomology and participant characteristics, special care must be taken in the design and implementation of clinical trials testing DBS for neuropsychiatric disorders. In particular, these studies typically include multi-year relationships between participants and study staff with frequent interactions, high burden of study activities on participants, and disclosure by participants of sensitive information related to symptoms and disease state. Through our experience with six participants across more than 5 years of the Presidio clinical trial assessing personalized closed-loop DBS for treatment-refractory MDD, we have gathered experience and evidence to inform best practices for conducting these interaction-intensive clinical studies in a vulnerable population. Here, we present these Key Practices along with discussion, informed by multiple fundamental principles: The Belmont Report; emotional and physical safety for study participants and staff; and integrity and validity of scientific outcomes.

Background Eligibility criteria are a critical component of a well-designed clinical trial, enhancing trial safety and internal validity. Yet, data suggest that exclusion rates based on these criteria often vary by participant race/ethnicity. Method This study compared the proportion of participants ( n  = 4235) from seven racial/ethnic groups, who were included versus excluded from participation in a randomized controlled trial (RCT) testing two digital sleep interventions for the prevention of perinatal depression. Eight 2 × 7 chi-squared tests were conducted to compare the proportion of each racial/ethnic group excluded due to each eligibility criterion. Logistic regressions were fitted to estimate the magnitude of the relationship between racial/ethnic group and exclusion based on each eligibility criterion. Results The proportion of excluded participants differed by race/ethnicity across all eight eligibility criteria. For example, Black participants were more likely to be excluded due to comorbid conditions such as sleep apnea X 2  (6,  N  = 4151) = 20.94,  p  = .002, and Asian participants were more likely to be excluded for reporting subclinical insomnia symptoms X 2  (6,  N  = 4151) = 85.99,  p  < .001. Logistic regressions showed that compared to White participants, Black participants had significantly higher odds (odds ratios ranging from 1.70 to 6.86) of study exclusion for three of the eight eligibility criteria. Conclusions Eligibility criteria excluded prospective study participants at different rates dependent on their race/ethnicity. Differences in trial exclusion can contribute to the under-enrollment of minoritized pregnant people in RCTs for behavioral health. Quantifying and reporting eligibility disparities enables investigators to more precisely evaluate the trade-offs of specific inclusion criteria against the generalizability of findings to diverse populations.

While evidence supports the benefits of medications for the treatment of chronic insomnia, there is ongoing debate regarding their appropriate duration of use. A panel of sleep experts conducted a clinical appraisal regarding the use of insomnia medications, as it relates to the evidence supporting the focus statement, “No insomnia medication should be used on a daily basis for durations longer than 3 weeks at a time”. The panelists’ assessment was also compared to findings from a national survey of practicing physicians, psychiatrists, and sleep specialists. Survey respondents revealed a wide range of opinions regarding the appropriateness of using the US Food and Drug Administration (FDA)-approved medications for the treatment of insomnia lasting more than 3 weeks. After discussion of the literature, the panel unanimously agreed that some classes of insomnia medications, such as non-benzodiazepines hypnotics, have been shown to be effective and safe for long-term use in the appropriate clinical setting. For eszopiclone, doxepin, ramelteon and the newer class of dual orexin receptor antagonists, the FDA label does not specify that their use should be of a limited duration. Thus, an evaluation of evidence supporting the long-term safety and efficacy of newer non-benzodiazepine hypnotics is timely and should be considered in practice recommendations for the duration of pharmacologic treatment of chronic insomnia.

Background Sleep disturbance symptoms (SDS) are common among US adults. Given the number of affected individuals, it is not surprising that there is a wide range of available remedies. These include prescription medicines, over the counter (OTC) options such as medications and dietary supplements, as well as the repurposing of recreational substances. Methods A cross-sectional survey was developed and deployed via the Ipsos KnowledgePanel® platform to generate a sample representative of the US adult population. Qualified subjects were those that reported at least 2 nights of SDS per month or less than 2 nights of difficulty due to the use of an active treatment. The primary purpose was to identify subjects with recent SDS to assess how they manage their symptoms. Results A total of 2,223 individuals entered the survey, with 1,299 qualifying for participation as per the qualification criteria (58% frequency rate). 1,244 participants completed the entire survey (53% female; mean age 52.5 years). Among those reporting recent sleep treatment use (60%), the most used treatments in descending order were vitamin/supplement-based products, OTC allergy/cold medicines, OTC pain relief/sleep combinations, cannabis products, off-label prescription medicines, OTC sleep medicines, or alcohol. 74% of survey completers indicated that they are not currently seeking help from a qualified health care professional (HCP). Conclusion More than half of American adults reported experiencing two or more nights per month of impaired sleep or are actively treating their symptoms. A substantial number were repurposing medications or turning to marijuana/THC and alcohol in an attempt to treat these symptoms. Despite the high frequency of SDS and drug/substance use, few reported seeking input from an HCP. These results emphasize the widespread nature of sleep difficulties and the common nature of self-treatment. A safe and effective OTC sleep aid or other accessible intervention could potentially play an important public health role given these circumstances.

Sleep is essential to cognitive function and health in humans, yet the ultimate reasons for sleep—i.e. ‘why’ sleep evolved—remain mysterious. We integrate findings from human sleep studies, the ethnographic record, and the ecology and evolution of mammalian sleep to better understand sleep along the human lineage and in the modern world. Compared to other primates, sleep in great apes has undergone substantial evolutionary change, with all great apes building a sleeping platform or ‘nest’. Further evolutionary change characterizes human sleep, with humans having the shortest sleep duration, yet the highest proportion of rapid eye movement sleep among primates. These changes likely reflect that our ancestors experienced fitness benefits from being active for a greater portion of the 24-h cycle than other primates, potentially related to advantages arising from learning, socializing and defending against predators and hostile conspecifics. Perspectives from evolutionary medicine have implications for understanding sleep disorders; we consider these perspectives in the context of insomnia, narcolepsy, seasonal affective disorder, circadian rhythm disorders and sleep apnea. We also identify how human sleep today differs from sleep through most of human evolution, and the implications of these changes for global health and health disparities. More generally, our review highlights the importance of phylogenetic comparisons in understanding human health, including well-known links between sleep, cognitive performance and health in humans.