Off-label low dose amitriptyline for insomnia disorder: Patient-reported outcomes.

PURPOSE: Low dose amitriptyline is prescribed off-label to improve sleep maintenance in patients with insomnia disorder. Data on treatment outcomes are limited. We aimed to assess patient-reported treatment effect and side effects of low dose amitriptyline for insomnia in routine care data. METHODS: Cross-sectional study: Seven hundred fifty-two consecutive patients with insomnia disorder having sleep maintenance problems were treated in an outpatient sleep clinic with low dose amitriptyline (10-20 mg based on self-titration). Treatment was intended to improve sleep maintenance. Before the planned follow-up consultation (approximately 6 weeks after start treatment) patients completed an online treatment evaluation questionnaire. Treatment (dose, adherence), sleep, fatigue, satisfaction and side effects were assessed by multiple-choice questions with room for free-text elaboration. RESULTS: 53.7% of the patients reported to use amitriptyline up to 10 mg/day, 42.9% used a self-increased dose of mostly 20 mg/day, while 3.5% had discontinued treatment. 73.9% of the total study population reported improvement of sleep maintenance, 31.3% improved sleep onset, 35.2% improved daytime fatigue, and 45.8% reported to be (very) satisfied with treatment results. 66.1% reported at least one side effect. The reported side effects were generally the already known side effects of amitriptyline. CONCLUSION: These patient-reported outcomes support the clinical observations that low dose amitriptyline improves sleep maintenance on the short term and that it is generally well tolerated. This further justifies randomized controlled trials in patients with insomnia disorder and sleep maintenance problems to assess the effectiveness and safety of low dose amitriptyline on the short and long term.

Chronic sleep reduction in adolescents-clinical cut-off scores for the Chronic Sleep Reduction Questionnaire (CSRQ).

The Chronic Sleep Reduction Questionnaire is a validated questionnaire that measures symptoms of prolonged insufficient and/or poor sleep and therefore accounts for individuals' sleep need and sleep debt. This study extends its psychometric properties by providing cut-off scores, using a matched sample of 298 healthy adolescents (15.38 ± 1.63 years, 37.9% male, mean Chronic Sleep Reduction Questionnaire score: 32.98 ± 6.51) and 298 adolescents with insomnia/delayed sleep-wake phase disorder (15.48 ± 1.62 years; 37.9% male, mean Chronic Sleep Reduction Questionnaire score: 42.59 ± 7.06). We found an area under the curve of 0.84 (95% confidence interval: 0.81-0.87). Cut-off scores for optimal sensitivity, optimal specificity and based on Youden's criterion are provided. These cut-off scores are highly relevant for use of the Chronic Sleep Reduction Questionnaire in future studies and clinical practice.

Prevalence of Restless Legs Syndrome in Adult ADHD and Its Subtypes.

In this observational cross-sectional study, 49 subjects were assessed for sleep disorders and for ADHD symptoms. Thirty-six received an ADHD diagnosis (29: combined type (ADHD-C); 7: inattentive type). An RLS and RLS symptoms prevalence of 34.5% was found, with a higher prevalence rate in the ADHD-C subgroup, although not significantly (p = 0.066). RLS symptoms were correlated with particularly hyperactivity-impulsivity (ρ = 0.742; p: 0.000). ADHD patients with positive RLS scores reported higher scores on the ADHD-Rating scale compared with patients with negative RLS scores (Z: -2.968, p = 0.003), mainly due to higher hyperactivity-impulsivity scores (Z: -3.145; p = 0.002). Our findings show that clinicians need to be aware of RLS among adult ADHD patients, particularly those with severe hyperactivity-impulsivity symptoms.

Sleep and the Social Profiles of Individuals With Rett Syndrome.

BACKGROUND: This study investigates the distinctive social behaviors observed in individuals with Rett syndrome (RTT), characterized by the loss of spoken language, impaired eye gaze communication, gait abnormalities, and sleep issues. The research aims to identify social profiles in RTT and explore their correlation with sleep, sleep-disordered breathing (SDB), and daytime sleepiness. METHODS: Standard overnight sleep macrostructure and respiratory parameters were assessed. Extracting 25 social-related items and one for daytime sleepiness from the Rett Syndrome Behavioral Questionnaire, factor analysis was applied to establish latent social profiles. These profiles were then correlated with sleep parameters. The nonparametric Mann-Whitney U test compared social profiles based on the presence of SDB (defined by an apnea-hypopnea index greater than one per hour) and daytime sleepiness. RESULTS: The study involved 12 female subjects with confirmed RTT diagnoses and MECP2 mutations, aged 8.54 ± 5.30 years. The Rett Syndrome Behavioral Questionnaire revealed a total average score of 25.83 ± 12.34, indicating varying degrees of social impairments. Comprising 25 social-related items, factor analysis yielded four social profiles: "interactive motricity," "mood change," "anxiety/agitation," and "gazing." Longer sleep onset latency correlated with increased socio-behavioral impairments, particularly in interactive motricity reduction. Conversely, higher rapid eye movement sleep was associated with fewer interactive socio-motor behaviors. No significant differences in social profiles were found concerning the presence of SDB or daytime sleepiness. CONCLUSIONS: The findings suggest four distinct social profiles in RTT individuals, hinting at shared disrupted circuits between sensorimotor functioning and sleep-related neuronal pathways. Despite the absence of differences in SDB or daytime sleepiness, the study highlights the relationship between sleep parameters, such as sleep onset latency and rapid eye movement sleep, and socio-behavioral outcomes in RTT with MECP2 mutations.

An investigation of the sleep macrostructure of girls with Rett syndrome.

OBJECTIVE/BACKGROUND: Methyl-CpG-binding protein 2 (MeCP2) is of utmost importance in neuronal function. We aim to characterize phenotypic traits in the sleep of individuals with Rett Syndrome (RTT, OMIM # 312750), a rare disorder predominantly caused by mutations of the MECP2 gene. PATIENTS/METHODS: An overnight polysomnographic recording was performed. Outcomes investigated were parameters of nocturnal sleep macrostructure, and sample stratification per genetic and clinical characteristics, and six key features of clinical severity was applied. RESULTS: The sleep of our 21 RTT female subjects with a mutant MECP2 gene, aged 8.8 ± 5.4 years, showed no significant differences within strata. However, compared to a normative dataset, we found longer duration of wake time after sleep onset and total sleep time (TST) but shorter sleep onset latency, in RTT. Regarding the proportion of sleep stages per TST, higher stage N3 (%) with lower stage N2 (%) and REM (%) were generally seen. Such abnormalities became more uniformly expressed at the severe level of clinical features, particularly for hand functioning and walking. CONCLUSIONS: RTT girls with MECP2 mutations in our study demonstrated an increased deep sleep and reduced rapid eye movement sleep proportion, which is mostly allied with their hand dysfunction severity. Poor sleep-on/off switching in RTT since embryogenesis is possibly linked to (psycho)motor impairment in the cases with MECP2 mutations.

Domestication of the Dromedary Revisited and Its Consequences for Legislation as to Keeping Livestock or Pet Animals.

Being in an advanced stage of domestication is a newly proposed requirement to decide which animals can be safely kept by humans. Dutch legislators were the first to apply it and other European countries may be tempted to adopt a similar approach. Unexpectedly, the Dutch assessors considered the dromedary (Camelus dromedarius) as being insufficiently domesticated and this species will therefore no longer be able to be kept as a production animal from 2024 onwards. In a recent publication on this topic, we showed that the domestication of the dromedary is actually very advanced. In this paper, we apply the same criteria that were used by the Dutch assessors to determine the degree of domestication, taking into account the most recent scientific developments in this area, even though it should be noted that these criteria have neither been peer-reviewed, nor published in an international scientific journal. For the sake of comparison, and in order to validate the procedure, we also applied these criteria to the house cat. The results confirm that the dromedary is highly domesticated, but also that the house cat (Felis silvestris catus) is at most semi-domesticated. Obviously, we agree with the decision of the Dutch legislators to place the house cat on the positive list, but our analysis demonstrates that this was decided on false grounds. Our analysis makes it clear that the requirement of being in an advanced stage of domestication is not suitable. Instead of maintaining this requirement, we recommend implementing evidence-based, peer-reviewed methods to decide which animals can be kept by humans, and to include species specific-guidelines in the legislation on how this can be achieved safely.

The Flourishing Camel Milk Market and Concerns about Animal Welfare and Legislation.

The worldwide dromedary milk production has increased sharply since the beginning of this century due to prolonged shelf life, improved food-safety and perceived health benefits. Scientific confirmation of health claims will expand the market of dromedary milk further. As a result, more and more dromedaries will be bred for one purpose only: the highest possible milk production. However, intensive dromedary farming systems have consequences for animal welfare and may lead to genetic changes. Tighter regulations will be implemented to restrict commercialization of raw milk. Protocols controlling welfare of dromedaries and gene databases of milk-dromedaries will prevent negative consequences of intensive farming. In countries where dromedaries have only recently been introduced as production animal, legislators have limited expertise on this species. This is exemplified by an assessment on behalf of the Dutch government, recommending prohibiting keeping this species from 2024 onwards because the dromedary was deemed to be insufficiently domesticated. Implementation of this recommendation in Dutch law would have devastating effects on existing dromedary farms and could also pave the way for adopting similar measures in other European countries. In this paper it is shown that the Dutch assessment lacks scientific rigor. Awareness of breeders and legislators for the increasing knowledge about dromedaries and their products would strengthen the position of dromedaries as one of the most adapted and sustainable animals.

Sleep Respiratory Disturbances in Girls with Rett Syndrome.

Individuals with Rett Syndrome (RTT), a rare neurodevelopmental disorder, present disordered breathing during wakefulness. Whilst findings on breathing during sleep are contradictory, the relation between sleep breathing and their clinical features, genetic characteristics, age, and sleep phase is rarely investigated, which is the objective of this study. Overnight polysomnography (PSG) was performed. Sleep macrostructure parameters were compared between the RTT subjects with and without sleep-disordered breathing (SDB). The association between the apnea-hypopnea index (AHI) with age at PSG was tested. Particularly for RTT subjects with SDB, the respiratory indexes in REM and NREM sleep were compared. Stratified analyses per clinical characteristics, genetic characteristics, and clinical features' severity were performed. Non-parametric statistics were applied. A sample of 11 female RTT subjects, aged 8.69 ± 5.29 years with ten confirmed with MECP2 mutations, were studied. The average AHI was 3.94 ± 1.19/h TST, of which eight (72.73%) had obstructive sleep apnea, i.e., six in 1/h TST ≤ AHI ≤ 5/h TST, and two in AHI > 5/h TST. The mean SpO2% was 81.00 ± 35.15%. The AHI was not significantly correlated with their age at PSG (rs = -0.15, p = 0.67). Sleep macrostructure in SDB-absent and SDB-present groups was not different. Respiratory indexes in those with obstructive sleep apnea showed no difference between REM and NREM sleep nor any of the strata. In our clinical sample, more than half of the RTT subjects with MECP2 mutations had obstructive sleep apnea in both NREM and REM sleep which was unrelated to their clinical features. Our results also indicated hypoxemia throughout nocturnal sleep in RTT. To conclude, our results suggest that disordered breathing during sleep is prevalently present in RTT as an independent clinical feature.

The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis.

STUDY OBJECTIVES: To perform a meta-analysis of the efficacy and safety of exogenous melatonin in advancing sleep-wake rhythm in patients with delayed sleep phase disorder. DESIGN: Meta analysis of papers indexed for PubMed, Embase, and the abstracts of sleep and chronobiologic societies (1990-2009). PATIENTS: Individuals with delayed sleep phase disorder. INTERVENTIONS: Administration of melatonin. MEASUREMENTS AND RESULTS: A meta-analysis of data of randomized controlled trials involving individuals with delayed sleep phase disorder that were published in English, compared melatonin with placebo, and reported 1 or more of the following: endogenous melatonin onset, clock hour of sleep onset, wake-up time, sleep-onset latency, and total sleep time. The 5 trials including 91 adults and 4 trials including 226 children showed that melatonin treatment advanced mean endogenous melatonin onset by 1.18 hours (95% confidence interval [CI]: 0.89-1.48 h) and clock hour of sleep onset by 0.67 hours (95% CI: 0.45-0.89 h). Melatonin decreased sleep-onset latency by 23.27 minutes (95% CI: 4.83 -41.72 min). The wake-up time and total sleep time did not change significantly. CONCLUSIONS: Melatonin is effective in advancing sleep-wake rhythm and endogenous melatonin rhythm in delayed sleep phase disorder.

Automated genomic DNA extraction from saliva using the QIAxtractor.

BACKGROUND: Venipuncture is an invasive procedure to obtain whole blood in order to obtain high quality and sufficient amounts of genomic DNA. Obtaining DNA from non-invasive sources is preferred by patients, medical doctors and researchers. Saliva collected with cotton swabs (Salivette) is increasingly being used to study chemical compounds, and it can also be a source of DNA. However, extracting DNA from Salivettes is very laborious and time consuming. Therefore, we developed a protocol for automated genomic DNA extraction from saliva collected in Salivette using the QIAxtractor. METHODS: Saliva (0.1-2.0 mL) was collected by chewing on a Salivette for 1-2 min. A total of 70 samples, collected from healthy volunteers, were extracted with the QIAxtractor robot and a Qiagen DX reagent pack. Quantity and quality was assessed using UV spectrometry and real-time polymerase chain reaction (PCR) (substitution at position -729 in the CYP1A2 gene). RESULTS: The average DNA concentration from the saliva samples was 6.0 microg/mL (95% CI 5.4-6.6 microg/mL). In 100% of the saliva samples, PCR products were detected with an average cycle threshold of 23.1 (95% CI 22.6-23.6). CONCLUSIONS: DNA can be extracted in sufficient amounts from Salivette with a fully automated system with a short turnaround time. Real-time PCR can be performed with these samples.

Loss of response to melatonin treatment is associated with slow melatonin metabolism.

BACKGROUND: In some of our patients with intellectual disability (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment, while the good response returned only after considerable dose reduction. The cause for this loss of response to melatonin is yet unknown. We hypothesise that this loss of response is associated with slow melatonin metabolism. METHOD: In this study, we determined melatonin clearance in two female (aged 61 and 6 years) and one male (aged 3 years) patients who had chronic insomnia, late melatonin onset and mild ID, and whose sleep quality worsened a few weeks after initial good response to melatonin treatment, suggesting melatonin tolerance. After a 3-week washout period, patients received melatonin 1.0, 0.5 or 0.1 mg, respectively. Salivary melatonin level was measured just before melatonin administration, and 2 and 4 h thereafter. After this melatonin clearance test, melatonin treatment was resumed with a considerably lower dose. RESULTS: In all patients melatonin concentrations remained >50 pg/mL at 2 and 4 h after melatonin administration. After resuming melatonin treatment sleep problems disappeared. The same procedure was followed in three patients who did not show loss of response to melatonin after 6 months of treatment. In all patients in the control group melatonin concentrations decreased between 2 and 4 h after melatonin administration with a mean of 83%. CONCLUSION: We hypothesise that loss of response to melatonin treatment can be caused by slow metabolisation of exogenous melatonin. As melatonin is metabolised in the liver almost exclusively by cytochrome P450 enzyme CYP1A2, this slow melatonin metabolism is probably due to decreased activity/inducibility of CYP1A2. In patients with loss of response to melatonin, a melatonin clearance test should be considered and a considerably dose reduction is advised.

Chrono-Nutrition and Diet Quality in Adolescents with Delayed Sleep-Wake Phase Disorder.

Background: Delayed sleep-wake phase disorder (DSPD), characterized by delayed sleep-onset and problems with awakening in the morning, is mostly prevalent in adolescents. Several studies have suggested chrono-nutrition could present a possible modifiable risk factor for DSPD. Objective: To describe differences in chrono-nutrition and diet quality in adolescents with DSPD compared to age-related controls. Methods: Chrono-nutrition and diet quality of 46 adolescents with DSPD, aged 13-20 years, and 43 controls were assessed via questionnaires. Diet quality included the Dutch Healthy Diet index (DHD-index) and Eating Choices Index (ECI). Results were analysed using logistic regression and Spearman's partial correlation. Results: Compared with controls, DSPD patients consumed their first food of the day significantly later on weekdays (+32 ± 12 min, p = 0.010) and weekends (+25 ± 8 min, p = 0.005). They consumed their dinner more regularly (80.4% vs. 48.8%, p = 0.002) and consumed morning-snacks less frequently (3.0 ± 2.1 days vs. 4.2 ± 1.7 days, p = 0.006). No differences in clock times of breakfast, lunch, or dinner were found. Moreover, no significant differences in overall diet quality were observed. Conclusion: This descriptive study showed chrono-nutritional differences between adolescents with and without DPSD. Further studies are needed to explore features of chrono-nutrition as a possible treatment of DPSD.

Efficacy and safety of supplemental melatonin for delayed sleep-wake phase disorder in children: an overview.

Delayed sleep-wake phase disorder (DSPD) is the most frequently occurring intrinsic circadian rhythm sleep-wake disorder, with the highest prevalence in adolescence. Melatonin is the first-choice drug treatment. However, to date melatonin (in a controlled-release formulation) is only authorised for the treatment of insomnia in children with autism or Smiths-Magenis syndrome. Concerns have been raised with respect to the safety and efficacy of melatonin for more general use in children, as melatonin has not undergone the formal safety testing required for a new drug, especially long-term safety in children. Melatonin is known to have profound effects on the reproductive systems of rodents, sheep and primates, as well as effects on the cardiovascular, immune and metabolic systems. The objective of the present article was therefore to establish the efficacy and safety of exogenous melatonin for use in children with DSPD, based on in vitro, animal model and clinical studies by reviewing the relevant literature in the Medline database using PubMed. Acute toxicity studies in rats and mice showed toxic effects only at extremely high melatonin doses (>400 mg/kg), some tens of thousands of times more than the recommended dose of 3-6 mg in a person weighing 70 kg. Longer-term administration of melatonin improved the general health and survival of ageing rats or mice. A full range of in vitro/in vivo genotoxicity tests consistently found no evidence that melatonin is genotoxic. Similarly long term administration of melatonin in rats or mice did not have carcinogenic effects, or negative effects on cardiovascular, endocrine and reproductive systems. With regard to clinical studies, in 19 randomised controlled trials comprising 841 children and adolescents with DSPD, melatonin treatment (usually of 4 weeks duration) consistently improved sleep latency by 22-60 min, without any serious adverse effects. Similarly, 17 randomised controlled trials, comprising 1374 children and adolescents, supplementing melatonin for indications other than DSPD, reported no relevant adverse effects. In addition, 4 long-term safety studies (1.0-10.8 yr) supplementing exogenous melatonin found no substantial deviation of the development of children with respect to sleep quality, puberty development and mental health scores. Finally, post-marketing data for an immediate-release melatonin formulation (Bio-melatonin), used in the UK since 2008 as an unlicensed medicine for sleep disturbance in children, recorded no adverse events to date on sales of approximately 600,000 packs, equivalent to some 35 million individual 3 mg tablet doses (MHRA yellow card adverse event recording scheme). In conclusion, evidence has been provided that melatonin is an efficacious and safe chronobiotic drug for the treatment of DSPD in children, provided that it is administered at the correct time (3-5 h before endogenous melatonin starts to rise in dim light (DLMO)), and in the correct (minimal effective) dose. As the status of circadian rhythmicity may change during long-time treatment, it is recommended to stop melatonin treatment at least once a year (preferably during the summer holidays).

Efficacy and safety of melatonin for sleep onset insomnia in children and adolescents: a meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the efficacy and safety of melatonin in the treatment of sleep onset insomnia in children and adolescents. METHODS: Electronic databases and bibliographies of relevant reports were searched for randomized, placebo-controlled, clinical trials that used melatonin in children and adolescents with sleep onset insomnia. The quality of the included studies was assessed by the Cochrane Collaboration's risk-of-bias method. The mean differences (MD) and the odds ratios (OR) with 95% confidence interval (CI) were estimated by a random-effects model. Primary outcomes were sleep onset time (SOT), drop-out for all causes and drop-out for adverse events. Secondary outcomes included dim light melatonin onset (DLMO), sleep onset latency (SOL), total sleep time (TST), light-off time, and wake-up time. RESULTS: Seven trials with 387 participants were finally included after a systematic search. The overall quality of the included studies was low to moderate. SOT in patients receiving melatonin advanced more than patients receiving placebo (MD = -0.62 h, 95% CI -0.80, -0.45), as well as DLMO (MD = -0.82 h, 95% CI -1.23, -0.41). No differences were found in the outcome of drop-out for all causes (OR = 1.51, 95% CI 0.57, 4.05) or drop-out for adverse events (OR = 3.35, 95% CI 0.13, 86.03). Severe adverse events, migraine, and mild generalized epilepsy were reported in two cases. SOL decreased and TST increased, MD = -0.36 h (95% CI -0.49, -0.24) and MD = 0.38 h (95% CI 0.09, 0.66), respectively. Light-off time and wake-up time did not differ significantly. CONCLUSIONS: Melatonin was an effective and tolerable drug in the short-term treatment of sleep onset insomnia in children and adolescents. More studies, especially in adolescents, are needed to investigate the efficacy and safety of melatonin.

Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia.

We conducted this study to assess long-term melatonin treatment course, effectiveness and safety in children with attention-deficit/hyperactivity disorder (ADHD) and chronic sleep onset insomnia (CSOI). This was conducted by means of a structured questionnaire for the parents. The subjects of this study consisted of participants who previously participated in a randomised clinical trial on melatonin efficacy. The response rate was 93% (94/101). The mean time to follow up was 3.7 yr. No serious adverse events or treatment related co-morbidities were reported. Sixty-five percent of the children still used melatonin daily and 12% occasionally. Temporal discontinuation of treatment resulted in a delay of sleep onset in 92% of the children. Nine percent of the children could discontinue melatonin completely because of improvement of sleep onset insomnia. Long-term melatonin treatment was judged to be effective against sleep onset problems in 88% of the cases. Improvement of behaviour and mood was reported in 71% and 61% respectively. We conclude that melatonin remains an effective therapy on the long term for the treatment of CSOI in children with ADHD and has no safety concerns regarding serious adverse events or treatment related co-morbidity. Discontinuation of melatonin treatment usually leads to a relapse of sleep onset insomnia and in resuming melatonin treatment, even after several years of treatment.

Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis.

Recent meta-analyses on melatonin has raised doubts as to whether melatonin is effective in treating sleep problems in people without intellectual disabilities. This is in contrast to results of several trials on melatonin in treating sleep problems in individuals with intellectual disabilities. To investigate the efficacy of melatonin in treating sleep problems in individuals with intellectual disabilities, we performed a meta-analysis of placebo-controlled randomized trials of melatonin in individuals with intellectual disabilities and sleep problems. Data were selected from articles published on PubMed, Medline, and Embase between January 1990 and July 2008. We examined the influence of melatonin on sleep latency, total sleep time, and number of wakes per night. Quality of trials was assessed using the Downs and Black checklist. Nine studies (including a total of 183 individuals with intellectual disabilities) showed that melatonin treatment decreased sleep latency by a mean of 34 minutes (p<0.001), increased total sleep time by a mean of 50 minutes (p<0.001), and significantly decreased the number of wakes per night (p<0.05). Melatonin decreases sleep latency and number of wakes per night, and increases total sleep time in individuals with intellectual disabilities.

Melatonin for chronic insomnia in Angelman syndrome: a randomized placebo-controlled trial.

Previous studies suggested that melatonin improves sleep in insomniac patients with Angelman syndrome. To assess the efficacy of melatonin, a randomized placebo-controlled study was conducted in 8 children with Angelman syndrome with idiopathic chronic insomnia. After a 1-week baseline period, patients received, depending on age, either melatonin 5 or 2.5 mg, or placebo, followed by 4 weeks of open treatment. Parents recorded lights off time, sleep onset time, wake-up time, and epileptic seizures in a diary. Salivary melatonin levels were measured at baseline and the last evening of the fourth treatment week. Melatonin significantly advanced sleep onset by 28 minutes, decreased sleep latency by 32 minutes, increased total sleep time by 56 minutes, reduced the number of nights with wakes from 3.1 to 1.6 nights a week, and increased endogenous salivary melatonin levels. Parents were satisfied with these results. Indications that melatonin dose in Angelman syndrome patients should be low, are discussed.

Long-Term Melatonin Therapy for Adolescents and Young Adults with Chronic Sleep Onset Insomnia and Late Melatonin Onset: Evaluation of Sleep Quality, Chronotype, and Lifestyle Factors Compared to Age-Related Randomly Selected Population Cohorts.

The extent of continuance of melatonin therapy initiated in pre-pubertal children with chronic sleep onset insomnia (CSOI) was investigated in young adult life. Sleep timing, sleep quality, adverse events, reasons for cessation of therapy, and patient characteristics with regard to therapy regimen, chronotype and lifestyle factors possibly influencing sleeping behavior were assessed. With an online survey using questionnaires (Pittsburgh Sleep Quality Index, Insomnia Severity Index, Morningness-Eveningness Questionnaire, and Munich Chronotype Questionnaire), outcomes were measured and compared with age-related controls. These controls were extracted from published epidemiological research programs applying the same questionnaires. At the moment of the survey, melatonin was still continued by 27.3% of the patients, with a mean treatment duration of 10.8 years. The overall average treatment duration was 7.1 years. Sleep quality of both discontinued and persistent melatonin users did not deviate from controls. Sleep timing and chronotype scores indicated evening type preference in all responders. Adverse events were scarce but the perceived timing of pubertal development suggested a tendency towards delayed puberty in former and current users of melatonin. This study may underestimate the number of children that are able to stop using melatonin due to the response rate (47.8%) and appeal for continuing users. Sleep timing parameters were based on self-reported estimates. Control populations were predominantly students and were of varying nationalities. The statistical power of this study is low due to the limited sample size. Melatonin therapy sustained for 7.1 years does not result in substantial deviations of sleep quality as compared to controls and appears to be safe. The evening type preference suggests a causal relation with CSOI. This study shows that ten years after initiation of treatment with melatonin for CSOI, approximately 75% of the patients will have normal sleep quality without medication.

Low maternal melatonin level increases autism spectrum disorder risk in children.

BACKGROUND: It is assumed that autism spectrum disorder (ASD) is caused by a combination of de novo inherited variation and common variation as well as environmental factors. It often co-occurs with intellectual disability (ID). Almost eight hundred potential causative genetic variations have been found in ASD patients. However, not one of them is responsible for more than 1% of ASD cases. Low melatonin levels are a frequent finding in ASD patients. Melatonin levels are negatively correlated with severity of autistic impairments, it is important for normal neurodevelopment and is highly effective in protecting DNA from oxidative damage. Melatonin deficiency could be a major factor, and well a common heritable variation, that increases the susceptibility to environmental risk factors for ASD. ASD is already present at birth. As the fetus does not produce melatonin, low maternal melatonin levels may be involved. METHODS: We measured 6-sulfatoxymelatonin in urine of 60 mothers of a child with ASD and controls. RESULTS: 6-sulfatoxymelatonin levels were significantly lower in mothers with an ASD child than in controls (p = 0.012). CONCLUSIONS: Low parental melatonin levels could be one of the contributors to ASD and possibly ID etiology. Our findings need to be duplicated on a larger scale. If our hypothesis is correct, this could lead to policies to detect future parents who are at risk and to treatment strategies to ASD and intellectual disability risk.