Paul Gringras

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.

Childhood sleep duration and associated demographic characteristics in an English cohort

STUDY OBJECTIVES To provide reference data on sleep duration throughout childhood and explore the demographic characteristics associated with sleep. DESIGN Population-based prospective longitudinal birth-cohort study. SETTING South-West England, children born in 1991-1992 and followed since birth. PARTICIPANTS Eleven thousand five hundred children with repeat measures of sleep from birth based on parent-reported questionnaires. Data on daytime and nighttime sleep duration and timings and night awakenings at 8 timepoints from age 6 months to 11 years. RESULTS Total sleep duration steadily fell from 13 hours and 12 minutes during infancy to 9 hours and 49 minutes at 11 years of age. Compared with earlier studies, the younger children in this cohort slept for a shorter period. The variation in sleep duration was very wide: from 10 to 17 hours in early infancy, narrowing to 8.5 to 11 hours at 11 years. Half of the children at preschool age woke at least once during the night, but frequent waking (> 3 times) peaked in infancy (10% of all infants) and steadily declined in the preschool-aged years. Despite going to bed at the same time, girls slept consistently longer than boys (by 5-10 minutes). Children from low-income families went to bed later and woke up later, but there was little difference in total sleep duration. Children of younger mothers (< 21 years) slept longer, whereas children of older mothers (> 35 years) slept persistently less. Children in larger families tended to go to bed later, as did the minority group of non-White children in the cohort. CONCLUSIONS Given the wide natural variation of sleep in the childhood population, any recommendations on optimal sleep duration at any age must take into account considerable individual variability.

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.

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.

Sleep patterns in children with ADHD: a population-based cohort study from birth to 11 years

Associations between sleep duration and disturbance in infancy and early childhood and attention deficit hyperactivity disorder diagnoses were investigated. Data from the Avon Longitudinal Study of Parents and Children, a population‐based prospective longitudinal birth‐cohort study of children born in 1991–1992 in South‐West England, were employed. Eight thousand, one hundred and ninety‐five children were assessed using the Development and Well‐Being Assessment. One hundred and seventy‐three cases (2.1%) met criteria for attention deficit hyperactivity disorder. Parental report at eight time points showed children with attention deficit hyperactivity disorder slept less than peers. Absolute differences were small and mainly restricted to night‐time sleep, with no strong evidence of differences from controls, except at 69 months [5 years 9 months; 12 min (95% CI: 5–19), P = 0.001], at 81 months [6 years 9 months; 15 min (95% CI: 8–22), P < 0.001] and at 115 months [9 years 7 months; 11 min (95% CI: 4–18), P = 0.001]. The attention deficit hyperactivity disorder group had more night‐waking at every age, significant from about 5 years. When tracking childrens sleep along a normative centiles chart, a shift in sleep duration from one centile to a lower centile was a useful predictor of attention deficit hyperactivity disorder. Age‐specific decreases of >1SD in sleep duration across adjacent time points was a significant predictor of attention deficit hyperactivity disorder at 3–5 years (P = 0.047). In children with attention deficit hyperactivity disorder, shorter sleep duration and sleep disturbances appear early and predate the usual age of clinical diagnosis. The rate of change of sleep duration relative to an individual, rather than absolute sleep duration at any stage, may prove beneficial in identifying increased risk of attention deficit hyperactivity disorder.

Clinical experience suggests that modafinil is an effective and safe treatment for paediatric narcolepsy

Narcolepsy with cataplexy is a chronic, life-long, disabling condition that occurs during childhood in approximately onethird of subjects. It usually begins during the first or second decade of life, and symptoms may develop rapidly over a few weeks or months, with excessive daytime sleepiness (EDS) and cataplexy being the most dramatic and observable symptoms. Pharmacological treatments in children with narcolepsy are mostly based on empirical data and clinical experience; randomized clinical trials are lacking and treatment guidelines have not yet been established in narcoleptic children (Ivanenko et al., 2003; Nevsimalova, 2009). Based on the experience of all the undersigned, wakepromoting medications have significantly improved the symptoms and well-being of young patients with narcolepsy. However, all available treatments are delivered off-label in the paediatric population (Aran et al., 2010; Peraita-Adrados et al., 2011). Modafinil is a non-amphetamine type stimulant that acts as a wakefulness-promoting drug, and is approved for managing EDS due to narcolepsy in adults. Following the findings of a safety review, the European Medicines Agency has recently recommended that the use of medicines containing modafinil should be restricted to sleepiness associated with narcolepsy only, with all other indications to be removed from product information. In addition, the Committee for Medicinal Products for Human Use recommended that the product information carry a recommendation stating that modafinil should not be prescribed to children, as the risk of developing serious skin and hypersensitivity adverse reactions appears to be higher in this age group. As an international group of paediatric sleep specialists with over two decades of experience using modafinil, we were surprised by this decision. Our concerns were that this decision might be based on the absence of safety data from well-conducted trials in children. This recommendation has the potential to adversely affect our ability to use of one of the few efficient and safe drugs available for the treatment of narcolepsy in children and adolescents. Based on our clinical experience, we collected all cases providing here a description of efficacy and side-effects. Summarizing the data from all authors, 205 children and adolescents (99 M; 106 F) with narcolepsy were treated with modafinil; the age range was 4–18 years, and the prescribed dose of modafinil varied from 50 to 600 mg (Table 1). Patients have been treated for more than 10 years in the majority of the Centres, with the longest period of treatment of 19 years in France. According to literature, increasing modafinil doses above 400 mg has not usually conferred any additional benefit, and most co-authors used a maximum daily dose of 400 mg. In the French paediatric cohort, the average daily dose of modafinil was 388 ± 140 mg. In some rare cases, and for adolescents over 16 years old, modafinil had progressively been titrated to twice-daily 300 mg doses. In these cases, increasing the dose was beneficial, safe and well tolerated. We found modafinil to be effective in more than 85% of patients, and in the remaining cases lack of efficacy, habituation or mild adverse effects led to drug discontinuation. The most frequent side-effects were represented by headache in 13.7% of cases, nervousness and irritability in 6.5%, and loss of appetite in only 2.2%. No severe hypersensitivity reactions were reported by any author, and particularly no serious skin reactions were recorded. Although these data are based on clinical experience and cannot replace randomized studies, the number of patientyears we have accrued suggests modafinil can be used safely in children and adolescents. Prior to this recommendation the major limitation for utilization of modafinil within different countries was related to the availability and price of the compound. For instance, in France, modafinil was used for decades as the first-line treatment for adults with narcolepsy before sodium oxybate was licensed. In Italy it is the only first-line treatment for narcolepsy in children, as methylphenidate is licensed only for attention deficit hyperactivity disorder. In Spain it is a highcost treatment, as the public health system refunds only 60% of the price of modafinil. The Spanish Narcolepsy Association has lobbied both to the Health National Service and the Health Commission in Parliament without success. A specific Working Group for Narcolepsy in Children has been recently constituted as part of the European Network of Rare Pediatric Neurological Diseases (http://www.neuro ped.eu). Its far-reaching aims are to identify current research, treatment and patient care challenges, to develop a registry for observational and prospective studies, and to disseminate recommendations on diagnosis and treatment on narcolepsy in children. Although not specific for children, the European Narcolepsy Network (http:// www.narcolepsy-network.eu) is another non-profit organization with the purpose of gaining a better insight into narcolepsy and related hypersomnias by pooling the resources of a variety of Sleep Centres, and creating an international database of patients with narcolepsy and hypersomnias. Together these initiatives will provide additional valuable information about the safety of modafinil. Across our European Centres, both the young people we treat and their careers attest to the potential for modafinil to restore a high quality of alertness and attention throughout J. Sleep Res. (2012) 21, 481–483 Modafinil and paediatric narcolepsy

Sleep patterns in children with autistic spectrum disorders: a prospective cohort study

Objective To investigate longitudinal sleep patterns in children with autistic spectrum disorders (ASDs). Study design Prospective longitudinal study using Avon Longitudinal Study of Parents and Children, an English cohort born in 1991–1992. Parental reports of sleep duration were collected by questionnaires at 8 time points from 6 months to 11 years. Children with an ASD diagnosis at age 11 years (n=73) were identified from health and education records. Results From aged 30 months to 11 years old, children with ASD slept for 17–43 min less each day than contemporary controls. No significant difference in total sleep duration was found in infancy, but from 30 months of age children with ASD slept less than their peers, a difference that remained significant after adjusting for sex, ethnicity, high parity and epilepsy. The reduction in total sleep was wholly due to changes in night rather than daytime sleep duration. Night-time sleep duration was shortened by later bedtimes and earlier waking times. Frequent waking (3 or more times a night) was also evident among the children with ASD from 30 months of age. Age-specific decreases of >1SD within individuals in sleep duration across adjacent time points was a predictor of ASD between 18 months and 30 months of age (p=0.04) and from 30 months to 42 months (p=0.02). Conclusions Sleep duration in children with ASD is reduced from 30 months of age and persists until adolescence.

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 childs 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.

The Effect of Intrauterine Growth on Verbal IQ Scores in Childhood: A Study of Monozygotic Twins

OBJECTIVE: Given the adverse neurobiological effects of suboptimal nutrition on the developing brain, it is of social and medical importance to determine if the global prevalence of poor intrauterine growth causes lasting cognitive deficits. We examined whether suboptimal intrauterine growth relates to impaired cognitive outcome by comparing birth weight and cognition in monozygotic twins and considered whether children within-pair differences in birth weight were related to within-pair differences in IQ scores. METHODS: A total of 71 monozygotic twin pairs (aged 7 years 11 months to 17 years 3 months) participated. The Wechsler Intelligence Scale for Children, Third Edition, was administered, and verbal IQ (VIQ) and performance IQ (PIQ) scores were calculated. Regression was used to relate within-pair differences in birth weight to within-pair differences in IQ scores. RESULTS: VIQ but not PIQ score was affected by prenatal growth restriction. The results suggest that the mean advantage for heavier twins relative to their lighter co-twins can be as much as half an SD in VIQ points. In pairs with minimal discordance, heavier twins had lower VIQ scores than their lighter co-twins. CONCLUSIONS: Our study results suggest that lower birth weight in monozygotic twins can also have a negative long-term impact on cognition both in infants who are small at birth and also those with birth weights across the spectrum. Studying monozygotic twins enabled us to examine the effect of reduced intrauterine growth on cognition independently of confounding factors, including parental IQ and education and infant gender, age, genetic characteristics, and gestation.

Weighted blankets and sleep in autistic children: a randomized controlled trial

OBJECTIVE: To assess the effectiveness of a weighted-blanket intervention in treating severe sleep problems in children with autism spectrum disorder (ASD). METHODS: This phase III trial was a randomized, placebo-controlled crossover design. Participants were aged between 5 years and 16 years 10 months, with a confirmed ASD diagnosis and severe sleep problems, refractory to community-based interventions. The interventions were either a commercially available weighted blanket or otherwise identical usual weight blanket (control), introduced at bedtime; each was used for a 2-week period before crossover to the other blanket. Primary outcome was total sleep time (TST) recorded by actigraphy over each 2-week period. Secondary outcomes included actigraphically recorded sleep-onset latency, sleep efficiency, assessments of child behavior, family functioning, and adverse events. Sleep was also measured by using parent-report diaries. RESULTS: Seventy-three children were randomized and analysis conducted on 67 children who completed the study. Using objective measures, the weighted blanket, compared with the control blanket, did not increase TST as measured by actigraphy and adjusted for baseline TST. There were no group differences in any other objective or subjective measure of sleep, including behavioral outcomes. On subjective preference measures, parents and children favored the weighted blanket. CONCLUSIONS: The use of a weighted blanket did not help children with ASD sleep for a longer period of time, fall asleep significantly faster, or wake less often. However, the weighted blanket was favored by children and parents, and blankets were well tolerated over this period.