Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial.

OBJECTIVE: To assess the effectiveness and safety of melatonin in treating severe sleep problems in children with neurodevelopmental disorders. DESIGN: 12 week double masked randomised placebo controlled phase III trial. SETTING: 19 hospitals across England and Wales. PARTICIPANTS: 146 children aged 3 years to 15 years 8 months were randomised. They had a range of neurological and developmental disorders and a severe sleep problem that had not responded to a standardised sleep behaviour advice booklet provided to parents four to six weeks before randomisation. A sleep problem was defined as the child not falling asleep within one hour of lights out or having less than six hours' continuous sleep. INTERVENTIONS: Immediate release melatonin or matching placebo capsules administered 45 minutes before the child's bedtime for a period of 12 weeks. All children started with a 0.5 mg capsule, which was increased through 2 mg, 6 mg, and 12 mg depending on their response to treatment. MAIN OUTCOME MEASURES: Total sleep time at night after 12 weeks adjusted for baseline recorded in sleep diaries completed by the parent. Secondary outcomes included sleep onset latency, assessments of child behaviour, family functioning, and adverse events. Sleep was measured with diaries and actigraphy. RESULTS: Melatonin increased total sleep time by 22.4 minutes (95% confidence interval 0.5 to 44.3 minutes) measured by sleep diaries (n=110) and 13.3 (-15.5 to 42.2) measured by actigraphy (n=59). Melatonin reduced sleep onset latency measured by sleep diaries (-37.5 minutes, -55.3 to -19.7 minutes) and actigraphy (-45.3 minutes, -68.8 to -21.9 minutes) and was most effective for children with the longest sleep latency (P=0.009). Melatonin was associated with earlier waking times than placebo (29.9 minutes, 13.6 to 46.3 minutes). Child behaviour and family functioning outcomes showed some improvement and favoured use of melatonin. Adverse events were mild and similar between the two groups. CONCLUSIONS: Children gained little additional sleep on melatonin; though they fell asleep significantly faster, waking times became earlier. Child behaviour and family functioning outcomes did not significantly improve. Melatonin was tolerable over this three month period. Comparisons with slow release melatonin preparations or melatonin analogues are required. TRIAL REGISTRATION: ISRCT No 05534585.

The use of MElatonin in children with neurodevelopmental disorders and impaired sleep: a randomised, double-blind, placebo-controlled, parallel study (MENDS).

BACKGROUND: Difficulties in initiating and maintaining sleep are common in children with neurodevelopmental disorders. Melatonin is unlicensed in children yet widely prescribed for sleep problems. OBJECTIVE: To determine whether or not immediate-release melatonin is beneficial compared with placebo in improving total duration of night-time sleep in children with neurodevelopmental problems. DESIGN: Randomised, double-blind, placebo-controlled, parallel study. SETTING: Hospitals throughout England and Wales recruited patients referred by community paediatricians and other clinical colleagues. PARTICIPANTS: Children with neurodevelopmental problems aged from 3 years to 15 years 8 months who did not fall asleep within 1 hour of lights out or who had < 6 hours of continuous sleep. Before randomisation, patients meeting eligibility criteria entered a 4- to 6-week behaviour therapy period in which a behaviour therapy advice booklet was provided. Sleep was measured using sleep diaries and actigraphy. After this period the sleep diaries were reviewed to determine if the sleep problem fulfilled the eligibility criteria. Eligible participants were randomised and followed for 12 weeks. INTERVENTIONS: Melatonin or placebo capsules in doses of 0.5 mg, 2 mg, 6 mg and 12 mg for a period of 12 weeks. The starting dose was 0.5 mg and the dose could be escalated through 2 mg and 6 mg to 12 mg during the first 4 weeks, at the end of which the child was maintained on that dose. MAIN OUTCOME MEASURES: The primary outcome was total night-time sleep time (TST) calculated using sleep diaries at 12 weeks compared with baseline. Secondary outcome measures included TST calculated using actigraphy data, sleep-onset latency (SOL) (time taken to fall asleep), sleep efficiency, Composite Sleep Disturbance Index score, global measure of child's sleep quality, Aberrant Behaviour Checklist, Family Impact Module of the Pediatric Quality of Life Inventory (PedsQL™), the Epworth Sleepiness Scale, number and severity of seizures and adverse events. Salivary melatonin concentrations and association of genetic variants with abnormal melatonin production were also investigated. RESULTS: A total of 275 children were screened to enter the trial; 263 (96%) children were registered and completed the 4- to 6-week behaviour therapy period and 146 (56%) children were randomised, of whom 110 (75%) contributed data for the primary outcome. The difference in TST time between the melatonin and placebo groups adjusted for baseline was 22.43 minutes [95% confidence interval (CI) 0.52 to 44.34 minutes; p = 0.04] measured using sleep diaries. A reduction in SOL, adjusted for baseline, was seen for melatonin compared with placebo when measured by sleep diaries (-37.49 minutes, 95% CI -55.27 to -19.71 minutes; p < 0.0001) and actigraphy (-45.34 minutes, 95% CI -68.75 to -21.93 minutes; p = 0.0003). There were no significant differences between the two groups in terms of the reporting of adverse events. The results of other secondary outcomes favoured melatonin but were not statistically significant. CONCLUSIONS: On average, the children treated with melatonin slept 23 minutes longer than those in the placebo group; however, the upper limit of the confidence interval was less than 1 hour, the minimum clinically worthwhile difference specified at the outset of the trial. Melatonin is effective in reducing SOL in children with neurodevelopmental delay by a mean of 45 minutes; a value of 30 minutes was specified a priori to be clinically important. Future studies should be conducted over longer periods and directly compare different formulations of melatonin with conventional hypnotic and sedative medications. It would also be important to study groups of children with specific neurological disorders. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05534585. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 40. See the HTA programme website for further project information.

Ensuring successful admission to hospital for young people with learning difficulties, autism and challenging behaviour: a continuous quality improvement and change management programme.

BACKGROUND: Children and young people with autism spectrum conditions frequently have adverse experiences in accessing health care. METHODS: An audit of experiences of families known to our tertiary service and hospital staff was conducted. A checklist asking about particular aspects of behaviour and communication was developed and incorporated into pre-admission planning. RESULTS: Awareness of the child/young person's communication needs and behaviours, plus good preplanning by all staff involved and a team member allocated to ensure that the care plan is carried through, has resulted in a vastly improved 'patient experience' from the perspective of family and staff. CONCLUSION: Children and young people with autism spectrum disorder, often with co-existing learning difficulties, vary greatly in their reactions to hospital admission. Preplanning that involves the family with a dedicated informed staff member can dramatically reduce distress and improve the patient and staff experience.

British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders.

Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.

Rest-activity disturbances in children with septo-optic dysplasia characterized by actigraphy and 24-hour plasma melatonin profiles.

INTRODUCTION: A trial of melatonin treatment in children with septo-optic dysplasia (SOD) and sleep disruption is accepted clinical practice in many centers. However, no objective measurements of sleep/activity patterns with 24-h melatonin profiles have been published for these individuals, and the pathophysiological basis underlying sleep disorders in SOD remains largely unknown. METHODS: We studied six children with rest-activity disturbances and SOD. All wore an Actiwatch-Mini (a noninvasive method of detecting and recording movement intensity) for 2 wk and were admitted to hospital for a 24-h period during which hourly measurements of serum melatonin were taken. Sleep data were analyzed in conjunction with a detailed sleep diary. Ethical approval was obtained for these studies. RESULTS: Two children produced virtually no melatonin throughout the 24-h period of measurement and had fragmented sleep patterns with no evidence of a non-24-h sleep-wake disorder or delayed sleep-phase disorder. One child had a normal melatonin profile despite actigraphy showing an arrhythmic sleep pattern. The remaining three children had fragmented sleep, with two having normal melatonin profiles and one having a modest increase in daytime melatonin concentrations, making the timing of dim-light melatonin onset difficult to discern. CONCLUSIONS: There is considerable variation in timing and amount of melatonin secretion in these children. Surprisingly, none of the children had either actigraphic or melatonin profile evidence of a non-24-h sleep-wake disorder or delayed sleep-phase disorder. Understanding the heterogeneous nature of underlying sleep disorders in this group of children is important and has implications for their management.

Administration of melatonin mixed with soft food and liquids for children with neurodevelopmental difficulties.

It is sometimes necessary for the contents of medication capsules to be mixed with certain foods and drinks because children are not always able to swallow the capsules. The compatibility and short-term stability (6h) of melatonin capsules mixed in a variety of liquids and foodstuffs (water, orange juice, semi-skimmed milk, strawberry yogurt, and strawberry jam) were analyzed for degradation. Extraction of melatonin from these common administration vehicles and an analytical assay for the drug and its potential degradation products were developed and validated. The results showed good recovery of melatonin from low- and high-strength capsules for all administration vehicles (between 89% minimum and 111% maximum). The drug was found to be stable in the common liquids and foods tested for up to 6 hours at room temperature (no degradation peak); hence it is unlikely to compromise the results of the Use of Melatonin in Children with Neurodevelopmental Disorders and Impaired Sleep trial.

When to use drugs to help sleep.

Paediatric sleep medicine is a relatively new but important and rapidly growing field. It is increasingly recognised that many "adult" sleep disorders begin in childhood where the consequences of missed diagnoses can be devastating. Adequate training of all health care professionals and careful eliciting of symptoms remains the first step in ensuring accurate and timely diagnoses. Although behavioural approaches play a huge role in paediatric sleep medicine, at times severe sleep disorders also require pharmacological treatments. However, the evidence base for these is weak, and currently treatments of conditions including insomnia, narcolepsy and restless legs syndrome in childhood still rely on hopeful extrapolation from adult data. A growth in randomised controlled trials over the last 5 years is encouraging; trial methodologies are also improving. International working groups and multicentre trials will increasingly be needed to evaluate the new technologies and pharmacological treatments that are emerging.

Absence of urinary opioid peptides in children with autism.

OBJECTIVE: It has been claimed for a number of years that the urine of children with autism contains exogenously derived opioid peptides. This finding is said to reflect a disturbance in the integrity of the gut epithelium, act as a diagnostic marker for autism and predict treatment response to a diet excluding gluten and casein. The aim of the present study was to determine whether exogenous or endogenous peptides were present in the urine of children with autism or of control children. DESIGN: Case-control study SETTING: Cases were recruited from two tertiary referral centres specialising in autistic spectrum disorders, while controls were recruited from mainstream primary and secondary schools in the same geographical area. PARTICIPANTS: 65 boys with autism, mean age 7.4 years (range 5-11) and 158 control boys, mean age 7.8 years (range 4.2-11). INVESTIGATIONS: Urine samples were examined by high pressure liquid chromatography (HPLC) and matrix assisted laser desorbtion ionisation-time of flight mass spectrometry (MALDI-TOF MS) for the presence of a number of putative opioid peptides. OUTCOMES: There were no significant differences between the HPLC urinary profiles of the children affected by autism and the typically developing controls. In those cases where HPLC showed peaks in the locations at which opioid peptides might be expected to be found, MALDI-TOF established that these peaks did not, in fact, represent opioid peptides. CONCLUSIONS: Given the lack of evidence for any opioid peptiduria in children with autism, opioid peptides can neither serve as a biomedical marker for autism nor be employed to predict or monitor response to a casein- and gluten-free diet.

Impact of comorbid autism spectrum disorders on stimulant response in children with attention deficit hyperactivity disorder: a retrospective and prospective effectiveness study.

BACKGROUND: In the recent past, psychiatrists and paediatricians have avoided prescribing stimulant medication, such as methylphenidate and dexamphetamine to patients with autism spectrum disorders (ASD) because of both doubts about efficacy and concern that these medications make stereotypies worse. Recently, a number of small trials have suggested that methyphenidate does have a role in the management of hyperactivity in children with autistic spectrum disorders. METHODS: Children with ASD and attention deficit hyperactivity disorder (ADHD), and children with ADHD without ASD received standard treatment with methyphenidate from one specialist centre. A combination of standardized and novel outcome tools was used to allow both an exploratory retrospective study of 174 children and then a prospective study of a further 52 children to be carried out. RESULTS: After treatment with stimulants, the subjects in both groups showed statistically significant improvements in target symptoms of 'hyperactivity', 'impulsivity', 'inattention', 'oppositionality', 'aggression' and 'intermittent explosive rage'. The Clinical Global Impression-Improvement and efficacy index measures also improved in each group. In both the retrospective and the prospective studies, there was no statistically significant difference in the degree of improvements between each group. Importantly, neither tics nor repetitive behaviours worsened in either group. Children in the 'ADHD-only' group who were prescribed stimulants experienced significant 'nausea', 'giddiness', 'headaches' and 'sleep difficulties', whereas sleep difficulties were the only side effect that emerged in children in the ASD with ADHD group. CONCLUSIONS: Both studies presented here support previous findings from smaller studies that show children with autism and ADHD can respond as well to stimulants as children with ADHD alone. Although randomized controlled trials remain the gold standard for efficacy studies, systems like this that allow clinicians to continue rigorous and consistent monitoring for many years have a valuable role to play. Furthermore, such monitoring systems which now exist electronically can easily accumulate large data sets and reveal details about long-term effectiveness and long-term side effects of medication that are unlikely to be discovered in short-term trials.

Development of an Internet-based real-time system for monitoring pharmacological interventions in children with neurodevelopmental and neuropsychiatric disorders.

Few children have a 'pure' diagnosis of neuropsychiatric disorders such as attention deficit hyperactivity disorder or autism. Most have complex, overlapping symptoms, and it is often these associated and common comorbidities that cause as much, if not more impairments, than the core symptoms. Prescribing decisions are therefore complex and made on the basis of eliciting a range of agreed 'target symptoms'. At present, however, there are no agreed systems that allow monitoring of all areas of potential change, and few services are able to monitor symptoms, side effects, impact on family life and individual children's quality of life systematically. At best many clinics use a plethora of paper-based standardized questionnaires, based on individual diagnoses. This article describes the development of a novel biomedical informatics system that has been designed to allow parents, professionals and children to use a web-based, real-time symptom monitoring system to enable more effective treatments, better pathways of shared care, and more equitable and efficient service delivery for this group of vulnerable children.

Mechanisms for differences in monozygous twins.

Monozygous (MZ) twins are often described as being physically and genetically identical. Clinical determination of zygosity relies on the assumption that any physical differences between a pair of twins imply they are dizygous. Most twin research relies on the assumption that dizygous twins share approximately 50% of the same genes, whereas monozygous twins share 100%. There is, however, increasing evidence to challenge both these assumptions. In this review, we describe a number of intrauterine effects and genetic mechanisms that may result in phenotypic, genotypic, and epigenetic differences between monozygous twins. Newer molecular techniques are resulting in such differences being increasingly commonly recognised. The potential for differences in monozygotic twin pairs is an important consideration for both clinicians and researchers involved in twin work.

The interaction of prematurity with genetic and environmental influences on cognitive development in twins.

OBJECTIVE: To investigate how the degree of prematurity interacts with genetic and environmental influences in their effect on verbal and nonverbal cognitive development. STUDY DESIGN: The target sample consisted of more than 2000 pairs of twins born in England and Wales in 1994. At 24 months, measures of verbal and non-verbal cognitive development were obtained from the twins' parents. The sample was divided into 3 groups according to degree of prematurity: very preterm or high-risk (<32 weeks), moderately preterm or medium-risk (32-33 weeks), and mildly preterm/term or low-risk (>34 weeks). Quantitative genetic analyses were used to assess the contributions of genetic and environmental influences on vocabulary and cognitive development. RESULTS: The results indicated gene-environment interactions. For the high-risk group, genetic effects on both verbal and non-verbal cognitive ability were completely overshadowed by shared environmental factors, whereas for both medium- and low-risk groups, additive genetic effects explained 18% to 33% of the variance. CONCLUSIONS: Our findings indicate that genetic factors are not responsible for cognitive outcomes of very preterm infants and suggest that early environmental influences appear to affect verbal and non-verbal cognitive development at 2 years of age.

Developing rational protocols for paediatric psychopharmacological prescribing.

The number of child psychiatrists, paediatricians and general practitioners prescribing psychotropic medication for children in the UK is increasing. Medication is being used not just to treat children of normal intelligence with hyperkinetic disorder or depression, but also to modify behavioural problems in children with developmental disorders and severe learning difficulties. Literature reviews highlight the lack of robust randomized controlled drug trials on which to base clinical practice and the authors have found no appropriate existing protocols to help develop a systematized approach. Against such a background the authors have developed a comprehensive set of protocols covering prescribing details for individual drugs, and also addressing issues such as informed consent, long-term monitoring and school liaison. All children referred to the authors' clinics go through a standardized decision-making process. This article describes both the protocols themselves and the philosophies that guided their development. The authors describe how such a system benefits the children, their families, general practitioners and schools, whilst also facilitating audit and research.

Choice of medical investigations for developmental delay: a questionnaire survey.

The aim of this study was to describe the range and cost of investigations ordered by paediatricians for children with mild to moderate developmental delay. A total of 79 consultants on the Thames Regions Consultant Community Paediatricians database were sent a faxed questionnaire and 86% of the paediatricians responded. The number of tests ordered by each paediatrician ranged from none to 15; 26 different medical investigations were selected. The four most common tests were chromosomes for karyotyping, fragile X testing, thyroid function testing and metabolic studies which each appeared in over half of the responses. The median cost of the investigations chosen was 386 Pounds with a range from 0-1181 Pounds. This study revealed marked variations in clinical practice when paediatricians investigate a developmentally delayed child. This was found to reflect both personal bias and a lack of consensus in the medical literature. There is a need for accurate community based prevalence data on causes of developmental delay, and critical appraisal of the available diagnostic tests.

Retesting for fragile X syndrome in cytogenetically normal males.

This case series describes four males who presented with learning and behavioural difficulties. In each case, the diagnosis of fragile X syndrome was delayed because of an initial false-negative cytogenetic result. Although most children are currently investigated for fragile X syndrome using highly sensitive and specific molecular techniques, there still remain a large number of older children who have been tested using only cytogenetic analysis. The clinical presentation of these four children and the reason for the occurrence of the false-negative results are considered. In addition, there is a discussion and illustration of how a screening checklist can be used to help clinicians to decide which children should be retested.