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The sleep of millions has suffered during the global COVID-19 pandemic. Prevalence rates of 20-45% are reported globally for insomnia symptoms during the pandemic. Affected populations include the public and health care workers. A sleep deprived society faces the increased burden of COVID-related economic disruption, psychosocial problems, substance abuse, and suicide. Disordered sleep is not expected to disappear with control of infection, making interventions acutely necessary. The question becomes how to manage the sleep dysfunction during and after the pandemic. Depression and anxiety are prominent complaints during pandemic restrictions. Insomnia symptoms and fatigue continue even as mood improves in those who are in recovery from COVID-19 infection. Management of disturbed sleep and mental health is particularly needed in frontline health care workers. This overview describes 53 publications, as of February 2021, on disturbed sleep during the pandemic, treatment studies on COVID-related sleep disturbance, and need to rely on current treatment guidelines for common sleep disorders. The available research during the first year of COVID-19 has generally described symptoms of poor sleep rather than addressing treatment strategies. It covers digital cognitive behavioral therapy for insomnia (CBT-i) for the public and frontline workers, recognizing the need of greater acceptance and efficacy of controlled trials of CBT for affected groups. Recommendations based on a tiered public health model are discussed.

Introduction The International Restless Legs Study Group (IRLSSG) has developed the IRLS (International Restless Legs Syndrome Severity Scale) and validated it as a clinician/researcher administered scale to be used when both patient and examiner are present. The IRLSSG recognized the need for a self-completing scale that can be used economically in clinical practice and in large population-based studies. In this study the validity and the reliability of the IRLS as a self-administered scale (sIRLS) is assessed. Methods Established RLS patients were recruited by eight centers in four countries and consented to participate in this study. The validity of the sIRLS was assessed by patients completing the sIRLS before a clinician administered the IRLS. The reliability of the sIRLS was assessed by patients completing the sIRLS again, two weeks after the first one, provided no change had occurred. Results Overall, 173 patients were recruited and 164 of them were included in the analyses. The sIRLS showed satisfactory scaling assumptions and no relevant floor or ceiling effect. One factor explained 61.3% of the variance. Cronbach's alpha was 0.93 and the item homogeneity index was 0.59. Intraclass correlation coefficient between the sIRLS and the IRLS was 0.94. The sIRLS standard error of measurement was 3.61 (½ SD at baseline = 4.11). The results mostly overlapped those of the IRLS analyzed in parallel. Discussion The sIRLS is a reliable, valid and precise instrument that showed tight association with the IRLS. These findings support the use of the sIRLS for self-evaluation of RLS severity. The responses obtained on the sIRLS and the IRLS scale varied slightly. Therefore, we recommend that either the sIRLS or the IRLS scale be used as the only scale for serial measures over time.

Restless legs syndrome (RLS) is a distinct disorder, differing from chronic pain in many ways. Refractory RLS is characterized by unresponsiveness to dopamine agonists or alpha-2-delta ligands due to inadequate efficacy, augmentation, or adverse effects. This may result in severely impaired quality of life, profound insomnia, and suicidal depression. Opioid therapy is a mainstay in the management of these patients. This article summarizes the basic science and clinical evidence in support of their use, including the positive result of a large controlled multicenter study of 306 subjects, and outlines an approach to their use in clinical practice. Treatable explanations for RLS refractoriness, such as low iron stores, and other therapeutic options, such as combination therapy, should be considered before prescribing opioids. The agents most commonly used are oxycodone and methadone, but tramadol, codeine, morphine, and hydrocodone can also be considered. Controlled-release medication should be used for evening dosage and short-acting drugs, if needed, during the day. Effective doses are considerably lower than used for chronic pain (oxycodone 10-30 mg daily; methadone 5-20 mg daily) and the risk of opioid use disorder is relatively low. However, sensible precautions should be undertaken, including assessing opioid risk with standard questionnaires, using an opioid contract, using urine drug screens, consulting state prescription drug monitoring programs, and frequent reevaluation of effectiveness and side effects. Opioid use in selected patients with refractory RLS may be life-transforming with favorable risk-benefit ratio.

Hypersomnia is a symptom of disturbed sleep. Depressive disorders most commonly result in insomnia with fatigue and tiredness but not excessive sleepiness. Hypersomnia with depression is considered a feature of atypical depression and is more common in patients with bipolar disorder or the adolescent/young adult. Hypersomnia becomes clinically significant when the fight against sleepiness results in social and occupational dysfunction. The classic disorder of hypersomnia is narcolepsy with or without the emotionally triggered muscular weakness of cataplexy, although insufficient sleep, circadian misalignment, medication side effect, and sleep disorders such as sleep apnea and idiopathic hypersomnia are other reasons for excessive daytime sleepiness. What follows is a case of a man whose college career was interrupted by hypersomnia, leading to treatment of a presumed depression but subsequent diagnosis of narcolepsy, type II without cataplexy.

Restless leg syndrome, or Willis-Ekbom disease, is a neurosensorimotor disorder with significant impact that is diagnosed through 5 clinical criteria. Adherence to 5 criteria and a thorough physical examination are often sufficient for diagnosis. Associated features prove helpful in young children or the cognitively impaired. Polysomnography is not routinely required unless the patient has other sleep-related symptoms. The finding of periodic leg movements in sleep only suggests, instead of confirms, the diagnosis. It is important to arrive at appropriate diagnosis because the prevalence is in the millions and treatment significantly improves sleep quality and daytime function.

Because of proven efficacy, reduced side effects, and less concern about addiction, non-benzodiazepine receptor agonists (non-BzRA) have become the most commonly prescribed hypnotic agents to treat onset and maintenance insomnia. First-line treatment is cognitive-behavioral therapy. When pharmacologic treatment is indicated, non-BzRA are first-line agents for the short-term and long-term management of transient and chronic insomnia related to adjustment, psychophysiologic, primary, and secondary causation. In this article, the benefits and risks of non-BzRA are reviewed, and the selection of a hypnotic agent is defined, based on efficacy, pharmacologic profile, and adverse events.

Hypnosis has been used to manage insomnia and disorders of arousal. The alteration in the state of consciousness produced during hypnotic trance is more similar to relaxed reverie than sleep. Hypnosis typically occurs in a state of repose and the accomplished subject may have no recollection of the experience during a trance, 2 commonalities with sleep. Because hypnosis allows for relaxation, increased suggestibility, posthypnotic suggestion, imagery rehearsal, access to preconscious cognitions and emotions, and cognitive restructuring, disorders of sleep such as the insomnias, parasomnias, and related mood or anxiety disorders can be amenable to this therapeutic intervention.

This narrative review describes the differential diagnosis of restless legs syndrome, and provides an overview of the evidence for the associations between RLS and potential comorbidities. Secondary causes of RLS and the characteristics of pediatric RLS are also discussed. Finally, management strategies for RLS are summarized.The review began with a comprehensive PubMed search for 'restless legs syndrome/Willis-Ekbom disease' in combination with the following: anxiety, arthritis, attention-deficit hyperactivity disorder, cardiac, cardiovascular disease, comorbidities, depression, end-stage renal disease, erectile dysfunction, fibromyalgia, insomnia, kidney disease, liver disease, migraine, mood disorder, multiple sclerosis, narcolepsy, neuropathy, obesity, pain, Parkinson's disease, polyneuropathy, pregnancy, psychiatric disorder, sleep disorder, somatoform pain disorder, and uremia. Additional papers were identified by reviewing the reference lists of retrieved publications.Although clinical diagnosis of RLS can be straightforward, diagnostic challenges may arise when patients present with comorbid conditions. Comorbidities of RLS include insomnia, depressive and anxiety disorders, and pain disorders. Differential diagnosis is particularly important, as some of the medications used to treat insomnia and depression may exacerbate RLS symptoms. Appropriate diagnosis and management of RLS symptoms may benefit patient well-being and, in some cases, may lessen comorbid disease burden. Therefore, it is important that physicians are aware of the presence of RLS when treating patients with conditions that commonly co-occur with the disorder.

We aimed to evaluate the impact of a novel noninvasive oral pressure therapy (OPT) (Winx®, ApniCure) system on polysomnographic measures of sleep-disordered breathing, sleep architecture, and sleep stability in obstructive sleep apnea (OSA).A 4-week, multicenter, prospective, open-label, randomized, crossover, first-night order of control vs treatment, single-arm trial was conducted in five American Academy of Sleep Medicine (AASM) - accredited sleep clinics and one research laboratory. Sixty-three subjects (analysis cohort) were studied from a screening cohort of 367 subjects. The analysis cohort was 69.8% men, ages 53.6±8.9 years (mean±SD), body mass index of 32.3±4.5kg/m(2), with mild to severe OSA. At treatment initiation, subjects received random assignment to one night with and one without (control) treatment, and they were assessed again following 28 nights of treatment. Breathing and sleep architecture were assessed each night based on blind scoring by a single centralized scorer using AASM criteria.Average nightly usage across the take-home period was 6.0±1.4h. There were no severe or serious device-related adverse events (AEs). Median apnea-hypopnea index (AHI) was 27.5 events per hour on the control night, 13.4 events per hour on the first treatment night, and 14.8 events per hour after 28days of treatment. A clinically significant response (treatment AHI ⩽10/h and ⩽50% of control values) was seen in 20 of the 63 subjects evaluated. Rapid eye movement percentage (REM%) was significantly increased, and N1%, stage shifts to N1 sleep, overall stage shifts, total awakenings, and arousals per hour were all significantly reduced at both treatment nights compared to controls. Mean Epworth sleepiness scale (ESS) was significantly reduced from 12.1 to 8.6 (Cohen d effect size, 0.68) in those untreated for two or more weeks prior to OPT study participation and remained unchanged in subjects who directly switched from continuous positive airway pressure (CPAP) therapy to OPT.Clinically significant improvements in sleep quality and continuity, AHI, ODI, ESS, and overall clinical status were achieved in an easily identified subgroup. OPT was safe and well-tolerated and nightly usage was high.

Background While scores ≤10 on the Epworth Sleepiness Scale (ESS) are within the normal range, the reduction in elevated ESS score that is clinically meaningful in patients with narcolepsy has not been established. Methods This post hoc analysis of a clinical trial of patients with narcolepsy evaluated correlations between Patient Global Impression of Change (PGI-C) and ESS. Data of adult patients with narcolepsy from a double-blind, 12-week placebo-controlled study of JZP-110, a wake-promoting agent, were used in this analysis. Descriptive statistics and receiver operating characteristic (ROC) analysis compared PGI-C (anchor measure) to percent change from baseline in ESS to establish the responder criterion from patients taking either placebo or JZP-110 (treatments). Results At week 12, patients ( n = 10) who reported being “very much improved” on the PGI-C had a mean 76.7% reduction in ESS score, and patients ( n = 33) who reported being “much improved” on the PGI-C had a mean 49.1% reduction in ESS score. ROC analysis showed that patients who improved were almost exclusively from JZP-110 treatment group, with an area-under-the-curve of 0.9, and revealed that a 25% reduction in ESS (sensitivity, 81.4%; specificity, 80.9%) may be an appropriate threshold for defining a meaningful patient response to JZP-110 and placebo. Conclusions A ≥25% reduction in patients' subjective ESS score may be useful as a threshold to identify patients with narcolepsy who respond to JZP-110 treatment.

This randomized, double-blinded, placebo-controlled trial (NCT00135993) assessed efficacy and safety of the dopamine agonist rotigotine in the treatment of idiopathic restless legs syndrome (RLS) over a 6-month maintenance period. A total of 505 eligible participants with moderate to severe RLS (IRLS sum score >or= 15) were randomly assigned to five groups to receive either placebo or rotigotine (0.5, 1, 2, or 3 mg/24 hr) delivered by once-daily transdermal patch (fixed-dose regimen). The two co-primary efficacy parameters decreased from baseline to end of maintenance in IRLS sum score and in clinical global impressions (CGI-1) score. On both primary measures, 2 and 3 mg/24 hr rotigotine was superior to placebo (P < 0.001). Adjusted treatment differences to placebo for the IRLS sum score were -4.5 (95% CI: -6.9, -2.2) for 2 mg/24 hr rotigotine, -5.2 (95% CI: -7.5, -2.9) for 3 mg/24 hr rotigotine, and for CGI item 1 -0.65 (95% CI: -1.0, -0.3) and -0.9 (95% CI: -1.3, -0.5) for the 2 and 3 mg/24 hr doses, respectively. Skin reactions (27%) and known dopaminergic side effects such as nausea (18.1%) and headache (11.6%) were mostly mild or moderate in rotigotine subjects. Rotigotine transdermal patches releasing 2 to 3 mg/24 hr significantly reduced the severity of RLS symptoms. Treatment efficacy was maintained throughout the 6-month double-blind period.

Patients with neurologic disorders commonly experience sleep dysfunction and psychiatric disorders. The most common sleep dysfunction is insomnia, which is a primary symptom in 30% to 90% of psychiatric disorders. Insomnia and fatigue are prominent symptoms of anxiety disorders and major depression that may occur in patients who are treated but have residual sleep dysfunction. Anxiety and depressive disorders account for 40% to 50% of all cases of chronic insomnia. It is also recognized that primary insomnia and other primary sleep disorders produce symptoms that are similar to those reported by patients with psychiatric disorders. A clinician must judge whether sleep deprivation causes mood disturbance or whether depressive or anxiety disorder represents the primary reason for sleep dysfunction. When insomnia is comorbid with mild to moderate depression, therapy should begin with bedtime dosing of sedating antidepressants such as mirtazapine, nefazodone, or tricyclic antidepressants, which are preferred because of their sedative effects. Often side effects limit their usefulness. Intervention for chronic insomnia is similar in nonpsychiatric and psychiatric patients. Behavioral therapies, particularly multicomponent cognitive-behavioral therapy, and lifestyle changes show significant long-term efficacy as treatments for chronic insomnia. The most studied pharmacologic agents to treat insomnia are sedative hypnotic agents, particularly those that are active through the benzodiazepine receptor-GABA (gamma-aminobutyric acid) complex, such as benzodiazepines, eszopiclone, zaleplon, and zolpidem. Melatonin and the melatonin-receptor agonist ramelteon have not had adequate study in psychiatric patients to define their use, but small studies suggest benefit. Prescription of adjunctive trazodone (50-150 mg) is a common clinical practice to treat comorbid insomnia during antidepressant therapy, but published data are surprisingly limited, considering its frequent use. Although there has been insufficient research on the use of atypical antipsychotic agents in severe insomnia, psychiatrists use quetiapine, olanzapine, or others to lessen agitation that disrupts sleep. When insomnia or hypersomnia continue even as mood, anxiety, or thought disorders improve with standard therapy, the physician should consider the potential presence of underlying sleep disorders.

Objective: The study evaluated the Time of Day Sleepiness Scale (ToDSS) to determine subjective estimates of sleepiness in the morning, afternoon, and evening. Scores on the ToDSS were compared to the Epworth Sleepiness Scale (ESS). The ToDSS was evaluated on three cohorts of patients at a sleep medicine clinic. Method: The items of the ToDSS are modified from the ESS to enable subjective assessment in the morning (before noon), afternoon (noon to 1800 h), and evening (after 1800 h). The scale takes about 5 min to complete. For each item, patients provide an estimate of their level of sleepiness in three separate columns, each indicating the time of day (morning, afternoon, and evening). Results: Each ToDSS score evidenced a one factor structure. The ToDSS enabled the assessment of differential levels of sleepiness across the day among several cohorts, with scores increasing in the afternoon and evening. The ESS and each score of the ToDSS demonstrated high correlations. Lower subjective estimates of sleepiness were documented after treatment with continuous positive airway pressure. Conclusions: The ToDSS was shown to have comparable psychometric features to the ESS and provided perceived sleepiness levels across the day in an efficient and cost-effective manner. It also enabled characterization of treatment response among a cohort of patients with obstructive sleep apnea.

TWO TO 3 PERCENT OF THE US POPULATION EXPERIENCE CLINICALLY RELEVANT SYMPTOMS OF PRIMARY RESTLESS LEGS SYNDROME (RLS) SEVERE enough to warrant treatment.1–3 Patients with RLS report difficulty falling asleep and exhibit abnormal sleep architecture,1,4 with a clinically significant decrease in sleep efficiency due to their symptoms. Consequently, RLS often impacts patients' daytime functioning and is a major source of morbidity and lost productivity.5 Dopaminergic agents provide important benefits for many RLS patients.5–7 However, neither ropinirole nor pramipexole has demonstrated efficacy in improving sleep architecture (eg, the time or percentage of total sleep time spent in slow wave sleep is either unchanged or reduced in these studies).6–8 Up to 30% of patients with RLS report symptoms that worsen with long-term dopaminergic treatment (augmentation).9,10 Recurrence of early-morning RLS symptoms, or rebound, may occur with short-term dopamine agonist treatment. Early clinical studies suggested that gabapentin, approved in the United States for the treatment of postherpetic neuralgia11–13 and partial seizures,13–15 is effective in improving RLS symptoms.16–20 Gabapentin has also been shown to reduce the frequency of periodic leg movements (PLMs)21–23 and to improve sleep23 in patients with RLS. However, gabapentin is not approved for the treatment of RLS and has inherent pharmacokinetic deficiencies that may limit effectiveness. Plasma exposure to gabapentin is highly variable due to saturation of its absorption pathway in the upper intestine24 and gabapentin requires frequent dosing due to its short plasma half-life. XP13512/GSK1838262 was developed to overcome the pharmacokinetic deficiencies of gabapentin.25 XP13512 is absorbed by high-capacity nutrient transporters throughout the gastrointestinal tract and is rapidly and extensively converted by nonspecific esterases to gabapentin. The pharmacokinetics of XP13512 provide dose-proportional gabapentin exposure. XP13512 is formulated as an extended-release tablet that allows for reduced dosing frequency.26 This study explored the efficacy and tolerability of XP13512 in subjects with moderate-to-severe primary RLS. An 1800 mg/day dose was chosen to produce maximum gabapentin levels of approximately 6–12 μg/mL in the late evening and night.26 Exploratory secondary analyses examined the effects of XP13512 on sleep quality and sleep architecture.

Low-dose doxepin hydrochloride (1, 3 and 6 mg) is a tricyclic antidepressant currently being investigated for the treatment of primary insomnia in adult and geriatric patients. Although it has been used at much higher doses to treat depression effectively for a number of decades, it offers a unique potency and selectivity for antagonizing the H1 (histamine) receptor at low doses. This mechanism of action may prove to be advantageous compared with other medications currently approved for the treatment of insomnia. This article reviews previous clinical studies using doxepin for insomnia and the recent clinical trial data, and briefly discusses other potential roles of this compound in clinical practice.

The symptoms of restless legs syndrome (RLS) are associated with reductions in patients' quality of life (QoL) and mental heath. Sleep disturbance, which is often the most troublesome symptom of RLS, may have a negative impact on patients' daytime cognitive abilities. Research has established a relationship between the symptoms of RLS and mood symptoms, but causality is unclear. Some studies have indicated that the symptoms of RLS precede those of depression or anxiety, and others relate the severity of mood symptoms to the severity of RLS symptoms. Associations between the sleep disturbance produced by RLS and patients' mood symptoms have also been demonstrated. The impact of RLS symptoms and their treatment on QoL, mental health, and cognition are reviewed herein.

When patients report problems sleeping, a psychiatrist must determine their significance based on frequency, duration, and daytime impairment. Because up to 50% of adults report sleep problems in any year, it is necessary to define when insomnia becomes long-standing, severe, and a complication to daytime function. Psychiatrists must determine if a sleep disturbance reduces mood, motor performance, or cognitive function. If insomnia syndrome is present, major depression, dysthymia, and anxiety disorders commonly are comorbid. To assist in evaluating insomnia, psychiatrists are urged to use the 6 Ps + M of insomnia model to conceptualize the characteristics of the insomnia and coordinate therapeutic intervention.

To evaluate the efficacy and safety of pramipexole in patients with moderate to severe restless legs syndrome (RLS) METHODS: The authors conducted a 12-week, double-blind, randomized, placebo-controlled trial of fixed doses of pramipexole (0.25, 0.50, and 0.75 mg/day). Patients (N = 344) were up-titrated to their randomized dose over 3 weeks. The primary efficacy endpoints were patient ratings of symptom severity on the International RLS Study Group Rating Scale (IRLS) and clinician ratings of improvement on the Clinical Global Impressions-Improvement (CGI-I) scale. Secondary efficacy endpoints included visual analogue ratings of sleep and quality of life (QOL) RESULTS: By both primary measures, pramipexole was superior to placebo. For IRLS, the adjusted mean (SE) change from baseline to week 12 was -9.3 (1.0) for placebo, -12.8 (1.0) for 0.25 mg/day, -13.8 (1.0) for 0.50 mg/day, and -14.0 (1.0) for 0.75 mg/day (all p0.01). Similarly, pramipexole increased the percentage of patients with a CGI-I rating of "very much improved" or "much improved" at the end of the trial (51.2% for placebo and 74.7%, 67.9%, and 72.9% for pramipexole; all p0.05). Pramipexole significantly improved ratings of symptom severity, day and night, and also ratings of sleep satisfaction and QOL. Pramipexole was well tolerated: The most frequent adverse events with higher occurrence in the pramipexole group were nausea (19.0% vs 4.7%) and somnolence (10.1% vs 4.7%)As rated by patients and by clinicians, pramipexole was efficacious and safe in reducing the symptoms of restless legs syndrome.

In addition to excessive sleepiness, patients with narcolepsy often have significant fatigue, depressed mood, and decreased quality of life.To determine whether treatment with modafinil for excessive sleepiness improves fatigue, mood, and health-related quality of life (HRQOL) in patients with narcolepsy.Outpatients with narcolepsy underwent a 14-day washout of psychostimulants and then were enrolled in this 6-week, open-label, multicenter study. Patients received modafinil starting at 200 mg once daily for week 1, and then 200 or 400 mg daily for weeks 2 through 6. Efficacy was evaluated using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the Profile of Mood States (POMS). Safety was assessed by monitoring adverse events (AE).At baseline, 151 patients had moderate to severe excessive sleepiness (mean Epworth Sleepiness Scale score=17.8+/-4.4). Most patients (or =70% of 123 who completed the study) received 400 mg modafinil once daily during weeks 2 through 6. Modafinil significantly improved HRQOL, based on SF-36 measures of mental and physical component summary scores and subdomain scores of role-physical, social functioning, and vitality (each P0.001). Modafinil treatment was also associated with significantly reduced fatigue and significantly improved vigor and cognition as assessed by the POMS (each P0.001) from weeks 1 through 6. The most frequent AE with modafinil treatment were headache, nausea, and insomnia; most AE were mild or moderate in nature. Only seven patients (5%) withdrew from the study because of AE.In narcolepsy patients who were switched from psychostimulants, modafinil therapy improved HRQOL and subjective feelings of vigor and cognitive functioning and reduced fatigue.

STUDY OBJECTIVES To compare pregabalin versus placebo and pramipexole for reducing restless legs syndrome (RLS)-related sleep disturbance. DESIGN Randomized, double-blinded, crossover trial. SETTING Twenty-three US sleep centers. PARTICIPANTS Eighty-five individuals with moderate to severe idiopathic RLS and associated sleep disturbance. INTERVENTIONS Participants were randomized across 6 treatment sequences comprising three 4-week periods on pregabalin 300 mg/day (n = 75), pramipexole 0.5 mg/day (n = 76), or placebo (n = 73). MEASUREMENTS AND RESULTS Polysomnography was conducted over 2 nights at the end of each period. Primary (wake after sleep onset [WASO], pregabalin vs placebo) and key secondary endpoints were analyzed for statistical significance, with descriptive statistics for other endpoints. Pregabalin improved sleep maintenance, demonstrated by reductions in WASO (-27.1 min vs placebo [P < 0.0001]; -26.9 vs pramipexole) and number of awakenings after sleep onset (-2.7 vs placebo; -7.9 vs pramipexole [P < 0.0001]) by polysomnography, and an increase in subjective total sleep time (30.8 min vs placebo [P < 0.0001]; 26.8 vs pramipexole). Pregabalin also increased slow wave sleep duration (20.9 min vs placebo; 32.1 vs pramipexole [P < 0.0001]). Reduction in periodic limb movement arousal index (PLMAI) with pregabalin was similar to pramipexole and greater than placebo (-3.7 PLMA/h [P < 0.0001]), although reduction in total PLM in sleep was less than for pramipexole. CONCLUSIONS This study demonstrated improvements in objective and subjective measures of sleep maintenance and sleep architecture with pregabalin compared with placebo and pramipexole. Effects of pregabalin on periodic limb movement arousal index were comparable to pramipexole. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT00991276; http://clinicaltrials.gov/show/NCT00991276.

OBJECTIVE Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensorimotor disorder that can result in considerable sleep disruption. This narrative review provides an overview of RLS diagnosis and reports epidemiologic evidence for an association between RLS and mood disorders. Possible links between RLS, sleep disturbances, and mood disorders are considered, and theoretical pathophysiologic pathways are discussed. Finally, pharmacologic therapies for RLS are summarized. DATA SOURCES A PubMed search was performed using the search term restless legs syndrome in combination with affective/anxiety, antidepressants, anxiety/anxiety disorder, attention deficit hyperactivity disorder, depression/depressive disorder, mood/mood disorder, neuropsychiatric, panic/panic disorder, psychiatric disorder, and psychosis. English-language articles published between January 1993 and May 2013 were retrieved. Additional studies were identified from the reference lists of relevant publications. STUDY SELECTION 173 publications were retrieved. Articles related to the association between idiopathic RLS and depression, anxiety, and mood disorders were reviewed. In total, 32 epidemiologic studies were identified. These studies were reviewed in detail and ranked according to quality. DATA EXTRACTION Data were extracted on the basis of relevance to the topic. Epidemiologic studies were assessed using 3 parameters: methodology, data quality, and generalizability of the results. Each factor was scored from 1 (high quality) to 4 (low quality), giving a total score of between 3 and 12 for each study. RESULTS AND CONCLUSIONS RLS and mood disorders are frequently comorbid. Recognition and appropriate treatment of comorbid RLS are particularly important in patients with psychiatric disorders, as RLS is a common medical reason for insomnia, and antidepressant use may exacerbate sensory symptoms.

Richard K Bogan,1 Aaron Ellenbogen,2 Philip M Becker,3 Clete Kushida,4 Eric Ball,5 William G Ondo,6 Christine K Caivano,7 Sarah Kavanagh71SleepMed, Columbia, SC, 2Quest Research Institute, Farmington Hills, MI, 3Sleep Medicine Associates of Texas, Dallas, TX, 4Division of Sleep Medicine, Department of Psychiatry and Behavioral Sciences, Stanford Center for Human Sleep Research, Stanford, CA, 5Walla Walla Clinic, Walla Walla, WA, 6University of Texas Health Science Center, Houston, TX, 7Global Regulatory Affairs (CKC)* and Neurosciences MDC (SK), GlaxoSmithKline, Research Triangle Park, NC, USA*Development Sciences department at the time of the analysisPurpose: The aim of the study reported here was assessment of subjective and novel sleep endpoints, according to sleep disturbance severity at baseline, in adult subjects with moderate to severe primary restless legs syndrome (RLS) treated with gabapentin enacarbil (GEn) 1200 mg or placebo.Methods: Integrated analysis of two 12-week randomized trials in subjects with RLS was undertaken. Sleep outcomes from the Medical Outcomes Study (MOS) Sleep Scale and the Post Sleep Questionnaire were evaluated. Novel sleep endpoints derived from the 24-Hour RLS Symptom Diary were compared with similar endpoints derived from the Pittsburgh Sleep Diary (PghSD). Subjects were divided into two subgroups based on their level of sleep disturbance (responses to item 4 of the International Restless Legs Scale) at baseline. Data were analyzed using a last observation carried forward approach.Results: The modified intent-to-treat population comprised 427 subjects (GEn 1200 mg, n = 223; placebo, n = 204). GEn significantly improved all MOS Sleep Scale domain scores from baseline compared with placebo (P < 0.05) in both subgroups. Compared with placebo, GEn-treated subjects with very severe to severe sleep disturbance reported higher overall sleep quality, fewer nighttime awakenings, and fewer hours awake per night due to RLS symptoms at Week 12 on the Post Sleep Questionnaire (all P < 0.001, distribution of responses); sleep quality was the only significant item in those with moderate to no sleep disturbance (P < 0.0001). Evaluation of sleep endpoints derived from the 24-Hour RLS Symptom Diary and PghSD yielded similar results.Conclusion: Once-daily GEn 1200 mg significantly improves subjective sleep outcomes compared with placebo in subjects with RLS, regardless of the severity of sleep disturbance at baseline, although a greater improvement in sleep assessments may be observed in subjects with very severe to severe sleep disturbance than in those with moderate to no disturbance. Similar patterns were observed between treatment groups when comparing sleep endpoints derived from the PghSD and the novel sleep endpoints derived from the 24-Hour RLS Symptom Diary.Keywords: 24-Hour RLS Symptom Diary, Pittsburgh Sleep Diary, Medical Outcomes Study Sleep Scale, Post Sleep Questionnaire

Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is a common disorder, occurring at least twice a week and causing at least moderate distress in 1.5% to 2.7% of the population. It is important for primary care physicians to be familiar with this disorder and its management. Much has changed in its management since our previous algorithm was published in 2004, including the availability of several new drugs. This revised algorithm was written by members of the Medical Advisory Board of the Willis-Ekbom Disease Syndrome Foundation based on scientific evidence and expert opinion. It considers the management of RLS/WED under intermittent RLS/WED, chronic persistent RLS/WED, and refractory RLS/WED. Nonpharmacological approaches, including mental alerting activities, avoiding substances or medications that may exacerbate RLS, and the role of iron supplementation, are outlined. Chronic persistent RLS/WED should be treated with either a nonergot dopamine agonist or a calcium channel α-2-δ ligand. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS/WED and describe management approaches, including combination therapy and the use of high-potency opioids.

OBJECTIVES This open-label, multicenter, 52-week extension study (NCT00333359) assessed the long-term safety and efficacy of gabapentin enacarbil in subjects with moderate-to-severe primary restless legs syndrome (RLS). METHODS Subjects had completed one of 4 randomized, double-blind parent studies (XP052/XP053/XP081/XP083). Gabapentin enacarbil 1200 mg was administered once daily at 5 pm; dose adjustments to 600 or 1800 mg were permitted based on investigator judgment. Safety assessments included adverse events (AEs), vital signs, clinical laboratory tests, and electrocardiograms. Efficacy evaluations included the International Restless Legs Scale total score and the investigator-rated Clinical Global Impression-Improvement scale, at week 52 last observation carried forward. RESULTS The safety population comprised 573 subjects; 386 (67.4%) completed the study. Treatment-emergent AEs were reported by 80.1% of subjects and led to withdrawal in 10.3% of subjects; most (67.7%) were mild or moderate in intensity. The most common AEs were somnolence and dizziness (19.7% and 11.5% of subjects). Twenty subjects (3.5%) reported serious AEs; one subject died (fall, 25 days after stopping gabapentin enacarbil, judged not treatment related). No serious AE occurred in more than 1 subject. No clinically relevant changes were reported in vital signs, laboratory parameters, or electrocardiograms. At week 52 last observation carried forward, the mean (SD) change from parent study baseline in International Restless Legs Scale total score was -15.2 (8.85 [parent study baseline score, 23.2 (5.03)]), and 84.8% of subjects were Clinical Global Impression-Improvement responders ("much improved" or "very much improved"). CONCLUSIONS Gabapentin enacarbil was generally safe and well tolerated and improved RLS symptoms in subjects with moderate-to-severe primary RLS for up to 64 weeks of treatment.

Restless legs syndrome (RLS) is a common condition that results in uncomfortable sensations and an urge to move the limbs. Two centers tested a new dopamine agonist, pramipexole, in 23 patients with RLS in a time-limited, open-label, clinical trial. After 4 weeks or more, 19 patients reported significant improvement as assessed by the short International Restless Legs Syndrome Study Group questionnaire (p < 0.0001). These encouraging preliminary results justify larger, controlled trials for pramipexole in patients with RLS.

Insomnia in its chronic form is present in high numbers of patients presenting to physicians. As older women who have medical problems have the highest rates of chronic insomnia, physicians must have a high index of suspicion and be prepared to explore various etiologic factors that might be operative. Treatment should focus on setting specific goals, with patients using strategies that combine lifestyle changes, behavioral interventions, and appropriate medications. OTC agents, sedating antidepressants at low dosages (trazodone, doxepin, amitriptyline, and others), and nonhypnotic benzodiazepines are insufficiently studied to provide evidence-based support for their use to treat chronic insomnia. Particularly in the elderly, close monitoring is needed to prevent falls, accidents, and cognitive impairment from these agents. FDA-labeled hypnotic agents are efficacious, but long-term studies have not been available until the recent release of eszopiclone in the United States. Recent work encourages the use of CBT even in patients who have used sleeping pills for several years, although the success of CBT has been less encouraging when applied to chronic insomnia sufferers who have concurrent psychiatric disorders and who have taken hypnotics for years.

STUDY OBJECTIVES: Polysomnographic study evaluating the efficacy of ropinirole for the treatment of patients with restless legs syndrome (RLS) suffering from periodic leg movements in sleep (PLMS). DESIGN: Double-blinded, placebo-controlled, parallel-group study. SETTING: 15 tertiary referral centers in the USA. PARTICIPANTS: 65 patients with RLS and PLMS. INTERVENTIONS: Ropinirole (0.25-4.0 mg per day) or placebo for 12 weeks. MEASUREMENTS AND RESULTS: Data from 59 patients were included in the primary endpoint analysis. PLMS per hour decreased more with ropinirole (48.5 to 11.8), compared with placebo (35.7 to 34.2; adjusted treatment difference: -27.2; 95% confidence interval [CI]: -39.1, -15.4; P < .0001). Periodic limb movements with arousal per hour decreased from 7.0 to 2.5 with ropinirole but increased from 4.2 to 6.0 with placebo (adjusted treatment difference: -4.3, 95% CI: -7.6, -1.1; P = .0096). Periodic limb movements while awake per hour decreased from 56.5 to 23.6 with ropinirole but increased from 46.6 to 56.1 with placebo (adjusted treatment difference: -39.5; 95% CI: -56.9, -22.1; P < .0001). Ropinirole treatment significantly improved patients' ability to initiate sleep (P < .05) and the amount of Stage 2 sleep compared with placebo (P < .001). There were also non-significant trends toward increases in total sleep time and sleep efficiency. Sleep adequacy (measured on the subjective Medical Outcomes Study sleep scale) was significantly improved with ropinirole treatment (adjusted treatment difference: 12.1; 95% CI: 1.1, 23.1; P = .0316). In contrast, the placebo group showed a greater increase in Stage 3/4 sleep (P < .01). No serious adverse events occurred in either group. CONCLUSIONS: Ropinirole is effective in the treatment of both the sleep and waking symptoms of RLS.

Chronic dyssomnia is highly prevalent and has multiple etiologies. Hypnotherapy has been reported as beneficial for insomnia, but the description of the subject populations has been limited. A group of patients was evaluated at a sleep disorders center for a dyssomnia that occurred on at least 3 nights per week for 6 months or more. Six patients accepted hypnotherapy for their persistent psychophysiological insomnia and other sleep disorder diagnoses. Three patients responded to two sessions of structured hypnotherapy. The three responders remained improved at 16-month follow-up. Factors that seemed to contribute to long-term response in this small group of patients included a report of sleeping at least half of the time while in bed, increased hypnotic susceptibility, no history of major depression, and a lack of secondary gain.

Insomnia, a remarkably common disturbance in a basic biologic function, arises from multiple psychological, physiologic, and environmental factors. Transient insomnia usually resolves spontaneously. Short-term insomnia is usually normalized by coping with acute changes in a medical condition or a relationship. In patients with insomnia caused by stressful life events, a short (ie, 10 days or less) course of a short- or intermediate-acting benzodiazepine hypnotic may be indicated. Long-term insomnia deserves comprehensive evaluation. Psychiatric disorders are common in patients with long-term insomnia. In patients over age 50, intrinsic sleep disorders are more prevalent. Behavioral therapy, including improved sleep hygiene, stimulus-control techniques, and sleep-restriction therapy, is preferred in the management of long-term insomnia. Pharmacotherapy (eg, low-dose antidepressant or benzodiazepine) is best used as an adjunct.

Pulsed mass‐spectrometric studies of the bimolecular formation of Ar2+ show that the reaction proceeds via three excited states of argon which have excitation functions that peak at 18, 28, and 65 eV. In kinetic studies, effective radiative lifetimes and specific reaction rates have been determined at these electron energies. The rather large rate constants observed (1.3–2.0×10−9 cm3 molecule−1·sec−1) yield collision diameters in good agreement with those predicted by simple theoretical considerations of the radii of argon atoms in the 3p5 4d and 3p5 5p configurations, such configurations being of the lowest energy compatible with the smallest reported appearance potential of 14.7 eV for Ar2+.

The extinction of opposed-jet diffusion flames is studied under an applied electric field of varying intensity and polarity. Experiment reveals that at any particular flame composition, an electric field enables one to support flames with greater apparent flame strengths than without a field. The overall order of reaction varies with both intensity and polarity of the electric field. It is suggested that, below discharge intensity, an electric field may affect combustion kinetics by altering gas concentration gradients, or by contributing new electron molecule reactions.

A computer simulation of an opposed-jet methane/oxygen/nitrogen diffusion flame is presented which includes a realistic set of chemical reactions and realistic transport properties. The overall continuity equation and momentum balance are modeled in an approximate manner. The predicted concentration and temperature profiles agree satisfactorily with the available experimental information. It is shown that replacing the differential equations by their finite difference forms is a convenient way to handle this kind of two point boundary condition problem. An electric field is imposed on the flame by introducing a simplified model of the “ionic wind” which neglects any effects of electrons. Under these circumstances the concentration and temperature profiles are predicted to shift toward the cathode, but most do not change appreciably in magnitude. Flames at two temperatures are studied, with concentrations of NO predicted to be much higher in the higher temperature flame. Several reactions involving NO 2 did not affect the concentration of NO calculated using only the Zeldovich mechanism.

The behavior of ducted laminar and turbulent diffusion flames is influenced by de electric fields. The geometry, luminosity, velocity field, and heat transfer are examined.

The cross section for electron impact excitation of He to the doubly excited (2p)/sup 2/ /sup 3/P/sub 3/ state was calculated. This state is the lowest lying, doubly excited state that is stable to autoionization. The differential cross sectlon results indicate that the scattered beam has an intensity maximunm at right angles to the incident beam. The total cross section shows the fairly sharp peak and rapid decay with increased electron energy characteristic of exchange reactions. The transition cross section is compared with others. (D.C.W.)