Wiebe Braam

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.

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.

Melatonin treatment in individuals with intellectual disability and chronic insomnia: a randomized placebo-controlled study

BACKGROUND While several small-number or open-label studies suggest that melatonin improves sleep in individuals with intellectual disabilities (ID) with chronic sleep disturbance, a larger randomized control trial is necessary to validate these promising results. METHODS The effectiveness of melatonin for the treatment of chronic sleep disturbance was assessed in a randomized double-blind placebo-controlled trial with 51 individuals with ID. All of these individuals presented with chronic ideopatic sleep disturbance for more than 1 year. The study consisted of a 1-week baseline, followed by 4 weeks of treatment. Parents or other caregivers recorded lights off time, sleep onset time, night waking, wake up time and epileptic seizures. Endogenous melatonin cycle was measured in saliva before and after treatment. RESULTS Compared with placebo, melatonin significantly advanced mean sleep onset time by 34 min, decreased mean sleep latency by 29 min, increased mean total sleep time by 48 min, reduced the mean number of times the person awoke during the night by 0.4, decreased the mean duration of these night waking periods by 17 min and advanced endogenous melatonin onset at night by an average of 2.01 h. Lights off time, sleep offset time and the number of nights per week with night waking did not change. Only few minor or temporary adverse reactions and no changes in seizure frequency were reported. CONCLUSIONS Melatonin treatment improves some aspects of chronic sleep disturbance in individuals with ID.

Psychometric properties of a sleep questionnaire for use in individuals with intellectual disabilities

We examined the psychometric properties of one part of the Sleep Questionnaire developed by Simonds and Parraga (SQ-SP; 1982), a questionnaire that is frequently used to explore sleep problems and behaviors related to sleep in individuals with intellectual disability (ID). The SQ-SP was completed for 345 individuals with ID (sleep clinic n = 146; control group n = 103; published studies n = 68; psychiatric clinic n = 28). Internal consistency was good (Cronbachs α = .80) and test-retest reliability for the total SQ-SP score was also good (Spearmans rank correlation = .83, p<.01). Convergent validity was adequate (r = .79, p<.001) and concurrent validity was satisfactory (r = .52, p<.001). Exploratory factor analysis suggested a 5-factor structure (Snoring, Daytime sleepiness, Complaints related to sleep, Sleep apnea and Anxiety related to sleep). Internal consistency of the five factors ranged from modest (Cronbachs α = .57) to good (Cronbachs α = .82). Confirmatory factor analysis corroborated the 5-factor structure. The Composite Sleep Index, the total SQ-SP score and the factor scores on Daytime Sleepiness and Complaints related to sleep were able to differentiate the control group from the sleep clinic group. The SQ-SP appears to be a reliable and valid tool in assessing sleep and different types of sleep disturbance in individuals with ID.

Melatonin decreases daytime challenging behaviour in persons with intellectual disability and chronic insomnia

BACKGROUND Persons with intellectual disability (ID) and sleep problems exhibit more daytime challenging behaviours than persons with ID without sleep problems. Several anecdotal reports suggest that melatonin is not only effective in the treatment of insomnia, but also decreases daytime challenging behaviour. However, the effect of melatonin treatment on daytime challenging behaviour in persons with ID has not been investigated in a randomised controlled trial. METHOD We investigated the effects of melatonin on challenging behaviour using data from two randomised controlled trials on the efficacy of melatonin on sleep problems in 49 persons (25 men, 24 women; mean age 18.2 years, SD = 17.1) with ID and chronic insomnia. Participants received either melatonin 5 mg (<6 years 2.5 mg) or placebo during 4 weeks. Daytime challenging behaviour was measured by the Storend Gedragsschaal voor Zwakzinnigen - Maladaptive Behaviour Scale for the Mentally Retarded (SGZ; Kraijer & Kema, 1994) at baseline week and the end of the fourth treatment week. Salivary dim light melatonin onset (DLMO) was measured at baseline and the last day of the fourth treatment week. Sleep logs were used to gather information on sleep parameters. RESULTS Melatonin treatment significantly reduced SGZ scores, sleep latency, and number and duration of night wakes, and treatment increased total sleep time and advanced DLMO. However, after 4 weeks of treatment, change in SGZ scores did not significantly correlate with change in sleep parameters, nor with change in DLMO. Relatively strong correlations were found between change in SGZ scores, change in DLMO and number of night wakes. CONCLUSIONS Melatonin treatment in persons with ID and chronic insomnia decreases daytime challenging behaviour, probably by improving sleep maintenance or by improving circadian melatonin rhythmicity.

Sleep in Individuals with Cri du Chat Syndrome: A Comparative Study.

BACKGROUND Sleep problems are common in individuals with intellectual disability. Little is known about sleep in children and adults with Cri du Chat syndrome (CDC). METHOD Sleep was investigated in 30 individuals with CDC using a sleep questionnaire. Sleep problems and sleep behaviours in individuals with CDC were compared with individuals with non-specific intellectual disabilities (NS) (n = 30) and Downs syndrome (DS) (n = 30). RESULTS Nine individuals with CDC (i.e. 30%) had a sleep problem, compared with seven individuals with NS (i.e. 23%) and three individuals with DS (i.e. 10%). Though there were few differences between diagnostic groups, night waking problems were most common in CDC. Individuals with CDC frequently showed behaviours related to disordered breathing and poor-quality sleep. Several behaviours related to sleep had a higher occurrence in CDC than in DS (P < 0.05) but not in NS. CONCLUSIONS It is concluded that individuals with CDC do not have an increased probability of sleep problems as compared with other individuals who share similar demographic characteristics. Hypotheses about causes of night waking problems in CDC are generated and suggestions for future research of sleep in individuals with CDC are given.

Sleep in Angelman syndrome: A review of evidence

Sleep problems are reported to be extremely prevalent in individuals with developmental disabilities. The consensus guidelines for Angelman syndrome (AS) consider abnormal sleep-wake cycles and diminished need for sleep as associated features. We report an integrative research review and a meta-analysis of studies with sleep as the primary aim of investigation in an AS sample. 14 studies met eligibility criteria with half of them being surveys. Thirteen of the 17 conceptually formed sleep disorder item-groups showed to be significant for individuals with AS. There is evidence that arousal during sleep, somnolence and possibly short sleep duration are the primary sleep problems in individuals with AS. According to the results of this review and meta-analyses, there is clear evidence for sleep problems in individuals with AS. Individual effect sizes remain overall small, but nevertheless findings suggest disorders of arousal and sleepiness to be distinctive. In light of these findings, other sleep complaints in individuals with AS should be carefully examined. Consistent standards for research on sleep in individuals with AS are critical for new lines of investigation.

Sleep Complaints and the 24-h Melatonin Level in Individuals with Smith-Magenis Syndrome: Assessment for Effective Intervention.

Individuals with Smith–Magenis syndrome (SMS) are reported to have a disrupted circadian rhythm. Our aim was to examine problematic sleeping in those attending our sleep clinic for the first time.

Immediate and prolonged-release melatonin in children with neurodevelopmental disabilities. Author reply to Prof. Zisapel

We thank Prof. Zisapel for her remarks, which gave us the possibility to clarify our recommendations. Prof. Zisapel agrees with our note that melatonin (MLT) is particularly recommended for sleep in children with neurodevelopmental disorders (NDDs), including autism. In these childrenmelatonin levels are often low, resulting in problems with sleep initiation, maintaining sleep and/or early waking. In this case, treatment with melatonin effectively decreases sleep onset latency and increases total sleep time. Prof. Zisapel stated that “the authors do not differentiate between use aimed at shifting the biological clock phase ... and use aimed at treating sleep disorders”, and that we “misinterpret prolonged sleep latency (sleep onset insomnia) with delayed sleep phase syndrome (DSPS)” in terms of melatonin treatment. We believe that this is a misinterpretation of our recommendations. Indeed, we clearly specified in table 2 that MLT can be used to advance the phase when administered 2e3 h before dim-light melatonin onset (DLMO), while it acts as sleep inducer when administered 30 min before bedtime. We have not recommended consideration of MLT administration 3e4 h before desired sleep onset in all children with NDDs and sleep onset insomnia; this mode of administration is only indicated if there is a DSPS (for example, in some cases of children and adolescents with ADHD). Importantly, we also note that sleep maintenance problems may occur in patients with DSPS and delayed endogenous melatonin onset. We are perfectly aware of the phase-shifting effect of melatonin and this has been clearly highlighted in our paper (page 125), but there is no solid empirical base to support the notion that this effect is different between immediate and prolonged-release formulations. Moreover, solid empirical evidence suggesting that the prolonged-releasemelatonin is superior to immediate-release melatonin is lacking and, to our knowledge, no studies comparing the different effects of immediate vs. prolongedrelease melatonin have been published in children with NDDs.