Morning Alertness Research Articles

Efficacy of Lemborexant in Adults ≥ 65 Years of Age with Insomnia Disorder.

Pharmacologic treatments are available to treat insomnia, a common and burdensome sleep disorder, but may be contraindicated in older adults who are prone to side effects from sleep-promoting drugs. These analyses of sleep diary data from Study E2006-G000-303 (Study 303) investigated the benefits of lemborexant 5mg (LEM5) and 10mg (LEM10) in the subgroup age ≥ 65years with insomnia. Study 303, a 12-month, double-blind study of LEM5 and LEM10 in adults (age ≥ 18years) with insomnia disorder (sleep onset and/or maintenance difficulties) assessed subject-reported (subjective) sleep-onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), and total sleep time (sTST). Morning sleepiness/alertness, insomnia severity (Insomnia Severity Index [ISI]), fatigue (Fatigue Severity Scale [FSS]), perceptions of sleep-related medication effects (Patient Global Impression-Insomnia [PGI-I] questionnaire), and safety were also evaluated. In this subgroup of older adults (≥ 65years; n = 262), there were significantly larger changes from baseline for sSOL, sSE, sTST, and sWASO with LEM5 and LEM10 versus placebo through month 6 (except sWASO month 1), indicating improvement; these improvements were sustained through month 12. Subject-reported increases in morning alertness were significantly greater with one or both LEM doses versus placebo through month 6 and sustained through month 12. There were significantly larger ISI total and daytime functioning score decreases (improvement) from baseline with LEM versus placebo at months 1, 3, and 6 (total score: both doses; daytime functioning: LEM5 month 1 and both doses months 3 and 6) and decreases from baseline FSS at months 1 and 3 (LEM5) and month 6 (both doses), sustained to month 12. Compared with placebo, more subjects reported that LEM (both doses) positively impacted ability to sleep, time to fall asleep, and TST through month 6, sustained to month 12, with no rebound after drug withdrawal. LEM was well tolerated to month 12; mild somnolence was the most common treatment-emergent adverse event. Improvements in subject-reported efficacy in LEM-treated adults age ≥ 65years with insomnia were observed as early as the first week of treatment and sustained through end of month 12. LEM was well tolerated. ClinicalTrials.gov identifier NCT02952820: E2006-G000-303; Study 303; SUNRISE-2 (First posted: October 2016); EudraCT 2015-001463-39 (First posted: November 2016).

0407 Impact of Lemborexant on Daytime Ratings of Sleepiness/Alertness in Subjects with Insomnia Disorder and Baseline Sleepiness

Abstract Introduction Since the use of sleep-promoting drugs can also lead to residual morning sleepiness, it is important to determine if a new hypnotic is associated with such a carryover effect of treatment. To this end, an assessment of sleepiness/alertness was included in lemborexant (LEM) phase 3 studies. LEM is a competitive dual orexin receptor antagonist approved in several countries for the treatment of adults with insomnia. This post-hoc analysis of Study 304 (E2006-G000-304; NCT02783729) assessed the impact of LEM on morning sleepiness/alertness in subjects who reported at least mild/moderate morning sleepiness at baseline. Methods Study 304 was a randomized controlled study in adults ≥55y with insomnia disorder (N=1006). Subjects received bedtime doses of placebo (PBO), LEM 5mg (LEM5), LEM 10mg (LEM10), or zolpidem tartrate extended release 6.25 mg (not reported here) for 1 month. A daily Sleep Diary assessed morning sleepiness, within 90 min of waketime, with the question “How alert/sleepy do you feel this morning?” rated from 1 (extremely sleepy) to 9 (extremely alert). Scores were averaged over 7-day periods for baseline (single-blind run-in) and first and last 7 days of treatment. Chi-square tests were used to compare the shift from sleepy (≤3) to more alert (>3) between PBO and treatment groups. Results At baseline, 59/203 (29.1%), 66/261 (25.3%), and 79/265 (29.8%) of the PBO, LEM5, and LEM10 subjects reported a score ≤3, indicating at least mild/moderate morning sleepiness. At the end of 1 month of treatment, 37/57 (64.9%) of the PBO subjects rated themselves as less sleepy and more alert (>3), compared with 50/64 (78.1%; P=0.11) LEM5- and 58/76 (76.3%; P=0.15) LEM10-treated subjects. Conclusion In this study, ~28% of subjects reported morning sleepiness at baseline. More subjects who reported sleepiness at baseline and received LEM reported improved morning alertness during the last week of treatment compared with PBO subjects. These data are concordant with previous findings of a lack of effect of LEM on tasks requiring alertness in the morning. Support (if any) Eisai Inc.

0316 A Case Report: Comparing Sleep with and without blue light blockers

Abstract Introduction Blue light filtered eyewear is popular. Studies have looked at the effect of using blue light blockers in the evening but data is lacking on the effect of wearing blue light blockers (BLB) through the day. In this study we compared the effects of wearing BLB all day, on sleep and daytime sleepiness. Methods This is a single case report. A 32 year male wore an Actiwatch Pro and collected sleep diaries for 18 days. On days 1-9, non-blue light blocking eyewear (NBLB) were used all day. On days 10-18, BLB were used all day. Karolinska Sleepiness Scale (KSS) and Stanford Sleepiness Scale (SSS) during morning, afternoon and before sleep were recorded. IBM SPSS v. 29.0.0 is used for descriptive analysis, Pearson correlation and T-test comparison. Results White light exposure was not statistically different from BLB and NBLB. Data measured in minutes. Mean and standard deviation of in-bed duration with NBLB was 477.89±66.17 and with BLB was 518.06±53.06 (p=0.087). Sleep time with NBLB was 431.89±52.05 and with BLB was 471.72±48.49 (p=0.056). Wake After Sleep Onset (WASO) with NBLB was 43.78±18.63 and with BLB 46.33±14.25 (p=0.374). Percent Sleep with NBLB was 90.96±2.83% and with BLB was 91.09±2.29 (p=0.459). KSS scores for morning on NBLB was 1.75±1.035 and 1.00±0 with BLB (p= 0.023), afternoon NBLB 4.13±1.25, BLB 3.67±0.87 (p=0.194), before sleep NBLB 8.5±1.41 and 8.56±0.53 with BLB (p=0.457). SSS scores for morning on NBLB was 1.63±0.744 and 1.00±0 with BLB (p= 0.012), afternoon NBLB 3.38±1.06, BLB 3.56±0.88 (p=0.353), before sleep NBLB 7.00±1.41 and 7.89±0.60 with BLB (p=0.053). There was a strong correlation between white light exposure and increased WASO (Pearson 0.514) and strong negative correlation (Pearson -0.535) between white light exposure and percent of sleep duration. Conclusion Although there were no statistically significant differences between the sleep parameters between NBLB and BLB, we found a strong correlation between sleep time and white light exposure and negative correlation. When using BLB morning alertness was better. Support (if any)

Shine light on sleep: Morning bright light improves nocturnal sleep and next morning alertness among college students.

The relationship between daytime light, especially morning light and sleep, has not been well documented. People who work in an office spend most of their time indoors and thus have less access to high-level daylight. The current study employed a field intervention approach to investigate whether exposure to 1.5h of bright electric light in the early morning for 1 workweek would benefit sleep among students who spent most of their time in an office at the university. Twelve students (24.92 ± 1.78 years) underwent a 2 workday baseline measurement and two inconsecutive 5 workday interventions (with 1 week washout) with morning bright light and regular office light (1000 lx, 6500 K vs. 300 lx, 4000 K, at eye level). The sleep outcomes were recorded with actigraphy and a sleep diary. In addition, self-ratings of daytime sleepiness, mood, mental fatigue, perceived effort, and next morning sleepiness were measured each workday. The results showed that exposure to morning bright light versus regular office light yielded a higher sleep efficiency (83.82% ± 1.60 vs. 80.35% ± 1.57, p=0.02), a smaller fragmentation index (15.26% ± 1.31 vs. 17.18% ± 1.28, p=0.05), and a shorter time in bed (7.12 ± 0.13 vs. 7.51 ± 0.12, p=0.03). Meanwhile, an earlier sleep onset time, shorter sleep latency, and lower morning sleepiness were observed after a 5 workday morning bright light intervention compared with the baseline (ps <0.05), no such benefit was found for self-ratings (ps >0.05). These findings support existing evidence that morning bright light could function as an enhancer of sleep and alertness for office occupants.

Effectivines of drugs for insomnia treatment

IntroductionUp to 10% of the US adult population will experience chronic insomnia, with women and elderly individuals at particularly high risk. Cognitive behavioral therapy is the core treatment for insomnia. When cognitive behavioral therapy is not enough, medications can help patients overcome the barriers and learned behaviors that prevent a good night’s sleep.ObjectivesThrough this research we aimed to investigate the effectiveness and safety of new drugs in the treatment of insomnia.MethodsWe try to do a Bibliographic Review in PubMed using keywords like “insomnia” “new hypnotic drugs” and “effectiveness”ResultsPatients receiving trazodone perceived better sleep quality than those receiving the placebo with a non-significantly moderate heterogeneity. As to secondary efficacy outcomes, we only found a significant reduction for trazodone in the number of awakenings compared to the placebo. Trazodone was effective in sleep maintenance by decreasing the number of early awakenings and it could significantly improve perceived sleep quality, although there were no significant improvements in sleep efficiency or other objective measures. Importantly, lemborexant improves latency to sleep onset and sleep maintenance and is able to help people who experience early morning awakenings. Safety data reveal that lemborexant has minimal residual effects on morning alertness or next day function.ConclusionsUnfortunately, treatment of insomnia is not always that simple. The disorder’s complex underlying pathophysiology warrants consideration of different nonpharmacologic and pharmacologic treatment options. Indeed, recent insights gained from research into the pathophysiology of insomnia have facilitated development of newer treatment approaches with more efficacious outcomes.DisclosureNo significant relationships.

No Association Between the 5-HTTLPR Polymorphism and Diurnal Preference in Koreans

Objective: Recent studies have extended the study of diurnal preferences to the genetic level. Most studies have focused on clock genes, but some studies have searched for the possibilities of other genes associated with the circadian rhythm. Considering that the circadian rhythm is associated with the serotonergic system, investigating the association between major genes of the serotonin system and the diurnal preference phenotype is essential. In this study, we evaluated whether the 5-HTTLPR polymorphism is associated with diurnal preference in a Korean population.Methods: In total, 509 healthy subjects were genotyped for the 5-HTTLPR polymorphism. The Korean version of the Composite Scale of Morningness (CSM) was used to measure the phenotype patterns of diurnal preference. In addition, scores of three subscales—morningness, activity planning, and morning alertness—were extracted from the CSM.Results: No significant associations were observed between CSM scores and the 5-HTTLPR genotype or allele carrier status.Conclusion: The results of this study suggests that 5-HTTLPR has no effect on diurnal preference in a healthy Korean population. Further studies with a large number of subjects from multiple ethnicities are necessary to fully evaluate the association between 5-HTTLPR and diurnal preference.

Alertness-Grundmessung als stärkster Prädiktor für den Erwerbsstatus bei Patienten mit MS sechs Monate nach der Rehabilitation

Baseline alertness as the strongest predictor of employment status in patients with MS 6 months after rehabilitationS. Marchione, C. Dettmers, A. Weimer-Jaekel, B. Godde, M. JoebgesAbstractIntroduction: Fatigue is a dominant impairment in multiple sclerosis, which often also limits the professional performance of patients with MS (PwMS). In clini-cal practice fatigue is often difficult to assess. The question of our study was whether the objective cognitive fatigability – measured as reaction time or tonic alertness – or the subjective self-assessment of the patient – recorded by the Fatigue Scale for Motor and Cognitive Functions (FSMC) – predicts employment status 6 months after discharge from rehabilitation.Methods: PwMS whose rehabilitation measures were paid for by the government pension fund, and who had doubts about maintaining their professional per-formance in terms of their workload, underwent further testing. Tonic alertness from the test battery TAP-M was used as an indicator of cognitive fatigability. Participants were tested in the morning at 8:00 a.m., after standardized exer-cise at 11:00 a.m., and in the afternoon at 2:00 p.m. In addition, fatigue was determined using a self-assessment questionnaire (FSMC). Six months after discharge from neurological rehabilitation, their employment status was classi-fied through a telephone interview and also compared with our socio-medical performance assessment. Results: A complete data set was collected from 64 patients (43 female; age 48.9 ± 8.7 years; duration of illness 14.7 ± 9.5 years; EDSS 3.8 ± 1.3; 67 % relapsing remitting, 16 % secondary progressive, 17 % primary progressive). According to the International Standard Classification of Occupations (ISCO) code, 86 % were “white collar” workers, for example, in service, office and non-manual jobs. Six months after discharge from the rehabilitation clinic, 15 (23 %) out of 64 PwMS reported working less than 3 hours per day, 35 (55 %) PwMS reported 3 to 6 hours, and the remaining 14 (22 %) PwMS were full-time employees. The mean total value of the FSMC questionnaire for cognition was 38.9 ± 7.4, which was equivalent to severe cognitive fatigue. Eleven of the 14 full-time employees had severe fatigue. The morning alert-ness measurement (alertness1) (β = -.985; p= .003) and, the decline in alert-ness from morning to noon (alertness difference21; β = -.590; p= .033) and from noon to afternoon (alertness difference32; β =-.709; p= .020) were sig-nificant predictors for employment status. A reduction in alertness (increase in reaction time) by 1 SD on the alertness scale increases the probability of not working full-time by a factor of 2.67. Likewise, the probability of not working full-time increases by a factor of 1.80 if fatigability is increased by 1 SD from morning to noon. If fatigability increases by 1 SD from noon to eve-ning, the probability of not working full-time increases by a factor of 2.03. Discussion: The FSMC has no prognostic value for employment status 6 months after discharge from rehabilitation. The morning alertness measurement has the highest predictive value. However, an above average decline in alertness over the course of the day also reduces the probability of working full-time. Keywords: fatigue, fatigability, MS, alertness, employment status, prognostic factor

Study on the effect of awakening daylight in dormitories on morning alertness, mood, fatigue and sleep quality of college students

Awakening lighting has an important influence on circadian rhythm, alertness, mood and other physiological and psychological indexes. In a real situation with no electric awakening light, psychological suggestion or interference, the influencing mechanism of awakening daylight on human physiology and psychology is explored from the awakening data of dynamic daylight. This data can further guide the application of electric awakening lighting. The effects of daylight exposure at eye level on sleep quality, morning alertness, mood and fatigue of college students in dormitories in Beijing were studied. The subjects were 8 male and 8 female students from 4 dormitories in two adjacent apartments, and field experiments were conducted for 36 days in winter and 30 days in summer. The real-time illuminance of daylight before awakening was recorded by a wireless illuminance sensor, and the amount of light exposure and the maximum illuminance before awakening were calculated. The evaluation data of physiological and psychological indexes such as sleep quality, morning alertness, mood and fatigue were obtained by using sleep monitoring equipment—Jawbone UP3, PSQI, KSS, positive and negative semantic scales. The results showed that the lighting exposure accumulation before awakening in summer were significantly correlated with morning alertness, mood and deep sleep duration and there was a significant correlation between the Emax and morning alertness in summer. In addition, there were significant differences in deep sleep duration and morning alertness between different groups of lighting exposure accumulation in summer. There was no significant correlation between the lighting exposure accumulation or max value of illuminance and the physiological and psychological indexes in winter.

Evaluating lemborexant for the treatment of insomnia

ABSTRACT Introduction Insomnia is a complex sleep disorder that compromises quality of life and affects approximately 10% of the general population. Insomnia, defined as trouble initiating or maintaining sleep associated with impaired daytime function or distress, is treated using a comprehensive approach comprised of cognitive behavioral therapy and pharmacotherapy. Lemborexant, a dual orexin receptor antagonist, is a new pharmacotherapeutic option recently approved for the treatment of insomnia. Areas covered Here, the authors describe lemborexant, assess its efficacy and safety profile in clinical trials, and evaluate its role in the current insomnia treatment landscape. Expert opinion Lemborexant may offer an improved treatment option compared with other pharmacotherapies for insomnia because it is effective both over the long term and over a wide range of outcome measures. Importantly, lemborexant improves latency to sleep onset and sleep maintenance and is able to help people who experience early morning awakenings. Safety data reveal that lemborexant has minimal residual effects on morning alertness or next day function, and that patients are able to respond to an external auditory stimulus in the middle of the night. In conclusion, lemborexant represents a new, effective, and well-tolerated medication for patients with insomnia.

Melatonin (MEL) and its use in neurological diseases and insomnia: Recommendations of the French Medical and Research Sleep Society (SFRMS)

The French Medicine and Research Sleep Society had organized a consensus conference about sleep/wake circadian rhythms and their disorders. During this conference a subgroup of 11 sleep doctors/researchers looked specifically at the use of MEL in different pathologies. This article gives a summary of the main results of MEL therapy in some neurological diseases and insomnia approved by this consensus group. Exogenous MEL, which crosses the blood-brain barrier, has been used as a treatment in its two available forms: an immediate release form that principally shows a chronobiotic action and a long release form that mimics the physiological MEL secretion rhythm and is used to replace reduced physiological secretion. MEL secretion decreases frequently with age, mostly in elderly insomniacs and dementia patients. Results of level A studies show that MEL therapy, used as an add-on treatment, has beneficial effects in mild cognitive impairment (MCI) and Alzheimer patients with sleep disorders in improving sleep quality and in regulating the sleep/wake rhythm. MEL has to be prescribed as early as possible and for a long period, at a dose of 2 to 5 or 10 mg. It may have a beneficial effect on cognitive function in MCI but shows no effect in moderate to severe Alzheimer's disease. It should be emphasized that there are no serious side effects with MEL treatment. In these diseases, light therapy used 12 hours before melatonin treatment has a positive synergic effect. In REM sleep behavior disorder, immediate release MEL should be prescribed first as its side effect profile is much better than clonazepam shortly before bedtime. MEL has a good efficacy on clinical symptoms and PSG REM sleep without atonia episodes and is well tolerated. In Parkinson disease with sleep disorders and without REM sleep behavior disorder, MEL seems to improve subjective sleep quality but no conclusions can be drawn. There is insufficient scientific proof for using MEL as a prophylactic treatment in primary headache, migraine and cluster headache. In epileptic patients, MEL can be safely used to regulate the sleep/wake rhythm and to improve insomnia but more randomized controlled studies are necessary. In primary or no-comorbid insomnia, only a 2 mg dose of slow release MEL, 1 to 2 hours before bedtime, over a period of 3 to 12 weeks, is recommended. It decreases sleep onset latency, improves quality of sleep, morning alertness and quality of life without serious side effects and without withdrawal symptoms.

0261 A Randomized Trial on The Effects of Standard and Flexible Duty-Hour Rules on Intern Sleep and Alertness

Abstract Introduction Duty hour regulations affect resident sleep, education, and patient care in complex ways. We performed a national cluster-randomized trial (iCOMPARE) in 63 internal medicine residency programs comparing the effects of the 2011 duty-hour standards to a more flexible set of duty hour rules characterized by maintaining an 80-hour workweek but without limits on shift length or mandatory time off between shifts, relative to patient mortality, intern educational outcomes, and intern sleep and alertness. Methods In the sleep and alertness sub-study, sleep duration and morning sleepiness and alertness were assessed with actigraphy, the Karolinska Sleepiness Scale, and a 3-minute Psychomotor Vigilance Test (PVT-B) for 14 days in 193 interns from 6 standard programs and 205 interns from 6 flexible programs. Results During the 14-day study periods, interns in standard and flexible programs averaged 7.03h sleep/24h (95% confidence interval [CI] 6.78h, 7.27h) and 6.85h sleep/24h (95% CI 6.61h, 7.10h), respectively. Sleep duration (difference between arms of -0.17h/24h; 1-sided lower 95% confidence limit -0.45h; NIM -0.5h; P=0.02 for noninferiority) and KSS sleepiness (difference 0.12 points; 1-sided upper 95% confidence limit 0.31 points; NIM 1 point; P&amp;lt;0.001) were noninferior in flexible versus standard programs. We could not establish noninferiority for PVT-B alertness (difference -0.3 lapses; 1-sided upper 95% confidence limit 1.6 lapses; NIM 1 lapse; P=0.10). Based on analyses by shift type, sleep duration was 1.77h shorter on days when interns in flexible programs finished an overnight shift relative to a regular day shift (p&amp;lt;.001), with significant decreases in subjective and objective alertness, and frequent reports of excessive sleepiness, especially between 12am and 6am. Conclusion There were no signs of relevant chronic sleep loss across shifts in interns in flexible programs relative to their standard program counterparts. Interns were able to compensate for the sleep lost during extended overnight shifts by increasing sleep duration on nights prior to day shifts, night shifts, and days off. Increased sleepiness and reduced alertness of interns following extended overnight shifts need to be mitigated and suggest a role for fatigue-risk management programs. Support Supported by NHLBI grants U01HL125388 and U01HL126088 and grants from the ACGME.

Investigation of the effects of awakening daylight on the morning alertness, mood, and sleep quality of male college students

A dormitory is one of the most important places for college students at a university. The daylight of a dormitory has an important impact on students' work efficiency, mood, and sleep quality. To explore the influence of daylight exposure on morning alertness, mood, and sleep quality before waking up, a study was conducted based on the hourly dynamic meteorological parameters of Beijing to simulate the daylight exposure at eye level of students on different beds on the sixth floor of the No. 11 apartments at Tsinghua University. The data for sleep quality, morning alertness, and mood were collected by a subjective questionnaire in November and December in 2017 for 88 male students in 28 dormitories and in May and June for 90 male students in 36 dormitories. The results showed that the positive correlation between the eye light exposure before waking up and the quality of sleep and morning alertness was significant. This study can provide a reference for the daylight design of dormitory spaces and the scientific arranging of beds and orientations; it can also provide a reference for a rotation system.

Mélatonine : aspects physiologiques et pharmacologiques en relation avec le sommeil, intérêt d’une forme galénique à libération prolongée (Circadin®) dans l’insomnie

Melatonin is a hormone secreted by the pineal gland. It displays a very marked nycthohemeral rhythm, which is entrained to the light dark cycle. The secretion spreads over 8–10 hours, with a maximum around 3–4 a.m. Melatonin plays the role of an endogenous synchronizer which regulates circadian rhythms, especially the sleep/wake and temperature rhythms. Acute melatonin administration reduces sleep latency, increases theta/alpha power and spindle activity (soporific activity). Fast-release melatonin preparations showed inconstant effects in insomnia. Melatonin displays a short blood half-life, a fast turn over and undergoes a high first-pass hepatic metabolism. More than 80% is excreted exclusively in the urine as 6-sulfatoxymelatonin. The individual's capacity to produce the endogenous hormone, the decline in circadian clock output and the increase in complaints of poor sleep quality at older age led to develop a prolonged-release melatonin preparation to mimic the endogenous secretion in patients. This reviews provides data on physiological and pharmacological melatonin effects related to sleep and summarizes trials published about Circadin® efficacy and tolerance in insomnia. Preliminary therapeutic data on other indications are given. The main clinically relevant benefits are improvements in sleep quality and latency, next-day morning alertness and quality of life. The response develops over several days. An oral 2-mg dose once daily, for 3 months, is generally well tolerated with no rebound, withdrawal or ‘hangover’ effects and no safety concerns on concomitant therapy with antihypertensive, antidiabetic, lipid-lowering or anti-inflammatory drugs. Untoward effects of hypnotics on cognition, memory, postural stability and sleep structure are not seen with Circadin®. Given as a first-line prescription, with 13 weeks’ posology and the lack of rebound effects, Circadin® has the potential to improve quality of life in insomnia patients aged 55 years and older and avoid long-term use of hypnotics.

A randomised controlled trial of bright light therapy and morning activity for adolescents and young adults with Delayed Sleep-Wake Phase Disorder

A randomised controlled trial evaluated bright light therapy and morning activity for the treatment of Delayed Sleep-Wake Phase Disorder (DSWPD) in young people. 60 adolescents and young adults (range = 13–24 years, mean = 15.9 ± 2.2 y, 63% f) diagnosed with DSWPD were randomised to receive three weeks of post-awakening Green Bright Light Therapy (∼507 nm) and Sedentary Activity (sitting, watching TV), Green Bright Light Therapy and Morning Activity (standing, playing motion-sensing videogame), Red Light Therapy (∼643 nm) and Sedentary Activity or Red Light Therapy and Morning Activity. Sleep (ie sleep onset time, wake up time, sleep onset latency, total sleep time) and daytime functioning (ie morning alertness, daytime sleepiness, fatigue, functional impairment) were measured pre-treatment, post-treatment and at one and three month follow-up. Contrary to predictions, there were no significant differences in outcomes between treatment groups; and interaction effects between treatment group and time for all outcome variables were not statistically significant. However, adolescents and young adults in morning activity conditions did not meaningfully increase their objective activity (ie movement frequency). Overall, adolescents reported significantly improved sleep timing (d = 0.30–0.46), sleep onset latency (d = 0.32) and daytime functioning (d = 0.45–0.87) post-treatment. Improvements in sleep timing (d = 0.53–0.61), sleep onset latency (d = 0.57), total sleep time (d = 0.51), and daytime functioning (d = 0.52–1.02) were maintained, or improved upon, at the three month follow-up. However, relapse of symptomology was common and 38% of adolescents and young adults requested further treatment in addition to the three weeks of light therapy. Although there is convincing evidence for the short-term efficacy of chronobiological treatments for DSWPD, long-term treatment outcomes can be improved. To address this gap in our current knowledge, avenues for future research are discussed. Clinical TrialAustralian & New Zealand Clinical Trials Registry, https://www.anzctr.org.au, ACTRN12614000308695.

Greater spindle density in insomnia is associated with subjective morning alertness and more sustained attention

Greater spindle density in insomnia is associated with subjective morning alertness and more sustained attention

Association of CLOCK, ARNTL, PER2, and GNB3 polymorphisms with diurnal preference in a Korean population

ABSTRACTPolymorphisms in human circadian genes are potential genetic markers that affect diurnal preference in several populations. In this study, we evaluated whether four polymorphisms in circadian genes CLOCK, ARNTL, PER2, and GNB3 were associated with diurnal preference in a Korean population. In all, 499 healthy subjects were genotyped for four functional polymorphisms in CLOCK, ARNTL, PER2, and GNB3. Composite scale of morningness (CSM) was applied to measure phenotype patterns of human diurnal preference. In addition, three subscale scores, i.e. “morningness,” “activity planning,” and “morning alertness,” were extracted from the CSM. No significant associations were observed between CSM scores and CLOCK (rs1801260) genotype or T allele carrier status, CSM scores and ARNTL (rs2278749) C allele carrier status, and CSM scores and GNB3 (rs5443) genotype or C allele carrier status. However, total CSM scores and scores of its subscales were significantly associated with PER2 (rs934945) genotype (p = 0.010, p = 0.018, and p = 0.005 for total, morningness, and activity planning, respectively) and G allele carrier status (p = 0.003, p = 0.005, and p = 0.002 for total, morningness, and activity planning, respectively). The best model result obtained by performing multifactor dimensionality reduction analysis (2 = 11.2798, p = 0.0008) indicated that interaction among C/T single nucleotide polymorphism (SNP) in ARNTL, C/T SNP in GNB3, and G/A SNP in PER2 synergistically affected the risk associated with diurnal preference toward eveningness. These results suggest that circadian gene PER2 is associated with diurnal preference in healthy Korean population. Although polymorphisms in ARNTL and GNB3 were not significantly associated with diurnal preference, their interactions with the polymorphism in PER2 may synergistically increase the risk of diurnal preference toward eveningness.

Melatonina na insônia primária: Quais as evidências?

Objetivos: rever as evidências existentes sobre o uso da melatonina no alívio da sintomatologia da Insônia Primária e na melhoria da qualidade de vida em doentes com ≥55 anos de idade. Métodos: pesquisa bibliográfica na base de dados Pubmed e sites de Medicina Baseada de meta-análises (MA), revisões sistemáticas (RS), ensaios clínicos aleatorizados e controlados (ECAC) e normas de orientação clínicas (NOC) utilizando os termos MeSH Melatonin e Sleep Initiation and Maintenance Disorders, publicados entre março de 2007 e janeiro de 2013 nas línguas inglesa, portuguesa e espanhola. Para atribuição de níveis de evidência e forças de recomendação, foi utilizada a escala Strenght of Recommendation Taxonomy (SORT) da American Family Physician. Resultados: foram encontrados 72 artigos; destes, foram incluídos seis: cinco ECAC e uma NOC. Os ECAC referem que a melatonina melhora de forma estatisticamente significativa a qualidade de sono, o estado de alerta matinal e a qualidade de vida comparativamente com o placebo. Também se verificou uma diminuição significativa da latência de sono. Nestes ECAC não se verificaram efeitos de privação após a descontinuação do tratamento. A NOC recomenda que o uso de melatonina em pacientes maiores de 55 anos de idade é preferencial ao uso de um hipnótico no tratamento da insônia. Conclusão: existe evidência suficiente para aconselhar a utilização da melatonina no alívio sintomático da Insônia Primária (SOR A), e na melhoria da qualidade de vida (SOR B). Contudo, são necessários mais estudos, com metodologias rigorosas e seguimento a longo prazo, para a obtenção de resultados mais consistentes.

Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a 2-week randomized outpatient trial

BackgroundEsmirtazapine (Org 50081), a high-affinity antagonist at 5-HT2A and H1 receptors, was assessed for its hypnotic efficacy. MethodsIn this double-blind, randomized study, non-elderly patients with primary insomnia (but otherwise healthy) were treated with esmirtazapine (1.5, 3.0, or 4.5 mg) or placebo for two weeks. The primary end point was patient-reported total sleep time (TST); other patient–reported end points included sleep latency (SL), wake time after sleep onset (WASO), number of awakenings, sleep quality, and satisfaction with sleep duration. Measures to assess the potential adverse effects of treatment included morning alertness, daytime function/napping, and rebound insomnia during a single-blind placebo run-out week after treatment ended. Adverse events (AEs) were also assessed. ResultsOverall, 526 patients were randomized and 463 (88%) completed treatment. All esmirtazapine doses significantly improved TST, SL, sleep quality, and satisfaction with sleep duration versus placebo. Relative to placebo, TST was increased by 30–40 min and SL decreased by ~12 min for all doses. The highest dose (4.5 mg) also significantly reduced WASO and number of awakenings. Across doses, AEs occurred in 25.5–32.8% of patients, compared with 20.7% with placebo. The most common AE was somnolence (~10% for esmirtazapine and 2% for placebo). The incidence of AEs leading to discontinuation was low (≤7%), and there were no serious drug–related AEs. Finally, there was no evidence of a rebound insomnia after discontinuation of esmirtazapine. ConclusionsTwo weeks of treatment with esmirtazapine consistently and significantly improved patient-reported sleep parameters, and it was well tolerated in patients with primary insomnia.

Lasting treatment effects in a postmarketing surveillance study of prolonged-release melatonin.

Surveillance studies are useful to evaluate how a new medicinal product performs in everyday treatment and how the patient who takes it feels and functions, thereby determining the benefit/risk ratio of the drug under real-life conditions. Prolonged-release melatonin (PRM; Circadin) was approved in Europe for the management of primary insomnia patients age 55 years or older suffering from poor quality of sleep. With traditional hypnotics (e.g. benzodiazepine-receptor agonists), there are concerns about rebound insomnia and/or withdrawal symptoms. We report data from a postmarketing surveillance study in Germany on the effects of 3 weeks of treatment with PRM on sleep in patients with insomnia during treatment and at early (1–2 days) and late (around 2 weeks) withdrawal. In total, 653 patients (597 evaluable) were recruited at 204 sites (mean age 62.7 years, 68% previously treated with hypnotics, 65% women). With PRM treatment, the mean sleep quality (on a scale of 1–5 on which 1 is very good and 5 is very bad) improved from 4.2 to 2.6 and morning alertness improved from 4.0 to 2.5. The improvements persisted over the post-treatment observation period. Rebound insomnia, defined as a one-point deterioration in sleep quality below baseline values, was found in 3.2% (early withdrawal) and 2.0% (late withdrawal). Most of the patients (77%) who used traditional hypnotics before PRM treatment had stopped using them and only 5.6% of naive patients started such drugs after PRM discontinuation. PRM was well tolerated during treatment and the most frequently reported adverse events were nausea (10 patients, 1.5%), dizziness, restlessness and headache (five patients each, <1%). There were no serious adverse events and no adverse events were reported after discontinuation. The persisting treatment effect and very low rebound rate suggest a beneficial role of sleep–wake cycle stabilization with PRM in the treatment of insomnia.

Middle-of-the-night administration of sleep medication: a critical review of the effects on next morning driving ability.

Sleep maintenance problems are common, hence treatments enabling patients to fall asleep more rapidly after middle-of-the-night (MOTN) awakenings, without impairing next morning alertness, are needed. This literature review compares the effects of MOTN administration of various hypnotics on morning driving ability, a potentially dangerous daily activity under conditions of impairment. A literature search was conducted identifying on-the-road driving studies examining the effects of MOTN administration of hypnotics on morning driving performance. In a standardized 100-km highway driving test in normal traffic, subjects were instructed to drive with a steady lateral position and constant speed of 95 km/h. The primary outcome measure of the driving test is the Standard Deviation of Lateral Position (SDLP, cm), i.e. weaving of the car. Four driving studies were identified. Driving performance after MOTN administration of traditional benzodiazepine hypnotics was not examined. Zolpidem (10 mg and 20 mg, oral immediate release tablets) significantly impaired driving in a dose-dependent manner, when tested 4 hours after MOTN administration. Also, gaboxadol (15 mg) and zopiclone (7.5 mg) significantly impaired next-morning driving after MOTN administration. In contrast, sublingual zolpidem (3.5 mg) and zaleplon (10 mg and 20 mg) did not significantly affect driving 4 hours after MOTN administration. Driving was not affected 4 hours after MOTN administration of sublingual zolpidem (3.5 mg) or zaleplon (10 mg and 20 mg). Significant driving impairment was found after MOTN administration of zolpidem (10 and 20 mg), gaboxadol (15 mg), and zopiclone (7.5 mg).