Marcel G. Smits

Idiopathic chronic sleep onset insomnia in attention-deficit/hyperactivity disorder: a circadian rhythm sleep disorder

To investigate whether ADHD‐related sleep‐onset insomnia (SOI) is a circadian rhythm disorder, we compared actigraphic sleep estimates, the circadian rest‐activity rhythm, and dim light melatonin onset (DLMO) in ADHD children having chronic idiopathic SOI with that in ADHD children without sleep problems. Participants were 87 psychotropic-medication-naïve children, aged 6 to 12 yrs, with rigorously diagnosed ADHD and SOI (ADHD‐SOI) and 33 children with ADHD without SOI (ADHD‐noSOI) referred from community mental health institutions and pediatric departments of non‐academic hospitals in The Netherlands. Measurements were 1 wk, 24 h actigraphy recordings and salivary DLMO. The mean (±SD) sleep onset time was 21:38±0:54 h in ADHD‐SOI, which was significantly (p<0.001) later than that of 20:49±0:49 h in ADHD‐noSOI. DLMO was significantly later in ADHD‐SOI (20:32±0:55 h), compared with ADHD‐noSOI (19:47±0:49 h; p<0.001). Wake‐up time in ADHD‐SOI was later than in ADHD‐noSOI (p=0.002). There were no significant between‐group differences in sleep maintenance, as estimated by number of wake bouts and activity level in the least active 5 h period, or inter‐ and intradaily rhythm variability. We conclude that children with ADHD and chronic idiopathic sleep‐onset insomnia show a delayed sleep phase and delayed DLMO, compared with ADHD children without SOI.

Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial.

To establish the efficacy of melatonin treatment in childhood sleep onset insomnia, 40 elementary school children, 6 to 12 years of age, who suffered more than 1 year from chronic sleep onset insomnia, were studied in a double-blind, placebo-controlled study. The children were randomly assigned to receive either 5-mg melatonin or placebo. The study consisted of a 1-week baseline, consecutively followed by a 4-week treatment period. After that period, treatment was continued if the parents wished so. The studys impact was assessed by measurements of lights-off time, sleep onset, and wake-up time, recorded in a diary (n = 33). Sleep onset was also recorded with an actigraph (n = 25). Endogenous dim light melatonin onset was measured in saliva (n = 27). Sustained attention was evaluated with the Bourdon-Vos reaction time test (n = 36). In the melatonin group, mean (95% CI) lights-off time advanced 34 (6-63) minutes, diary sleep onset 63 (32-94) minutes, actigraphic sleep onset 75 (36-114) minutes, and melatonin onset 57 (24 to 89) minutes; total sleep time increased 41 (19-62) minutes. In the placebo group, these parameters did not shift significantly. The change during the 4-week treatment period differed between the treatment groups significantly as to lights-off time, diary and actigraphic sleep onset, sleep duration, and melatonin onset. There were no significant differences between the treatment groups in the change of sleep latency, wake-up time, and sustained attention reaction times. Mild headache occurred in 2 children during the first 2 days of the melatonin treatment. Eighteen months after the start of the trial, in 13 of the 38 children who could be followed up, melatonin treatment was stopped because their sleep problem was solved and in 1 child because sleep was not improved. Twelve children used melatonin 5 mg, the other 1.0 to 2.5 mg. One child developed mild generalized epilepsy 4 months after the start of the trial. The results show that melatonin, 5 mg at 6 PM, was relatively safe to take in the short term and significantly more effective than placebo in advancing sleep onset and dim light melatonin onset and increasing sleep duration in elementary school children with chronic sleep onset insomnia. Sustained attention was not affected. (J Child Neurol 2001;16:86-92).

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

Abstract:u2002 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 3.7u2003yr. 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.

Current role of melatonin in pediatric neurology: Clinical recommendations

BACKGROUND/PURPOSEnMelatonin, an indoleamine secreted by the pineal gland, plays a key role in regulating circadian rhythm. It has chronobiotic, antioxidant, anti-inflammatory and free radical scavenging properties.nnnMETHODSnA conference in Rome in 2014 aimed to establish consensus on the roles of melatonin in children and on treatment guidelines.nnnRESULTS AND CONCLUSIONnThe best evidence for efficacy is in sleep onset insomnia and delayed sleep phase syndrome. It is most effective when administered 3-5xa0h before physiological dim light melatonin onset. There is no evidence that extended-release melatonin confers advantage over immediate release. Many children with developmental disorders, such as autism spectrum disorder, attention-deficit/hyperactivity disorder and intellectual disability have sleep disturbance and can benefit from melatonin treatment. Melatonin decreases sleep onset latency and increases total sleep time but does not decrease night awakenings. Decreased CYP 1A2 activity, genetically determined or from concomitant medication, can slow metabolism, with loss of variation in melatonin level and loss of effect. Decreasing the dose can remedy this. Animal work and limited human data suggest that melatonin does not exacerbate seizures and might decrease them. Melatonin has been used successfully in treating headache. Animal work has confirmed a neuroprotective effect of melatonin, suggesting a role in minimising neuronal damage from birth asphyxia; results from human studies are awaited. Melatonin can also be of value in the performance of sleep EEGs and as sedation for brainstem auditory evoked potential assessments. No serious adverse effects of melatonin in humans have been identified.

Sleep Problems in Individuals With Angelman Syndrome

Prevalence of severe sleep problems and its association with other variables were investigated with 109 individuals who have Angelman syndrome. Severe settling problems, frequent night waking, and early waking were found in 2%, 37%, and 10% of the individuals, respectively. Sleep problems were persistent in this sample. No statistically significant associations were found between presence of a severe sleep problem and other variables (e.g., epilepsy, age, living environment, cause of genetic disorder, parents and caregivers coping strategies). Most parents reported adverse effects of their childs sleep problems on their own well-being. Implications for analysis and treatment of sleep problems in individuals with Angelman syndrome are discussed.

Sleep hygiene and actigraphically evaluated sleep characteristics in children with ADHD and chronic sleep onset insomnia

In the present study we investigated sleep hygiene and actigraphically evaluated sleep in 74 medication‐naïve children, aged 6–12u2003years, with rigorously diagnosed attention‐deficit/hyperactivity disorder (ADHD) and chronic sleep onset insomnia (ADHD‐SOI) and 23 ADHD controls without insomnia (ADHD‐noSOI). Between‐group differences were analysed for lights out (sleep log), actigraphically evaluated sleep onset, sleep latency, total sleep duration, actual sleep time and sleep hygiene as measured with the Childrens Sleep Hygiene Scale. We found a significant difference (Pu2003<u20030.001) in mean (±SD) sleep onset between the ADHD‐SOI group (21:49u2003±u20030:56u2003h) and ADHD‐noSOI groups (20:41u2003±u20030:45u2003h). Sleep latency was significantly (Pu2003<u20030.001) longer in ADHD‐SOI (00:53u2003±u20030:25u2003h) compared to ADHD‐noSOI (00:26u2003±u20030:25u2003h). The difference in total sleep duration between ADHD‐SOI (9:42u2003±u20030:44u2003h) and ADHD‐noSOI (10:09u2003±u20030:43u2003h) was not significantly different (Pu2003=u20030.18). The group difference in actual sleep time was also not significant (8:43u2003±u20030:52u2003h in ADHD‐SOI versus 9:13u2003±u20031:16u2003h; Pu2003=u20030.40). There was no significant difference (Pu2003=u20030.17) in mean (±SD) total sleep hygiene score between the ADHD‐SOI (56.4u2003±u200310.5) and ADHD‐noSOI groups (53.0u2003±u200310.6). We conclude that there were differences in sleep onset and sleep latency in ADHD children with chronic SOI and those without insomnia; however, sleep hygiene practices were similar and did not relate to sleep characteristics.

Melatonin-responsive headache in delayed sleep phase syndrome : preliminary observations

The occurrence of headache and its change after treatment with melatonin 5 mg were studied in 30 patients with delayed sleep phase syndrome. The medication was taken 5 hours before the endogenous nocturnal plasma melatonin concentration had reached 10 pg/mL.

Sleep-related Disorders in ADHD: A Review

The relationship of attention-deficit/hyperactivity disorder (ADHD) with sleep-related disorders has received remarkable interest. The comorbidity warrants close attention since sleep-related disorders impinge on the same functional domains as those impaired in ADHD, such as sustained attention, inhibition, and working memory. Hence, it has been alleged that sleep-related disorders might possibly lead to an aggravation or mimicry of the symptoms of ADHD. A second reason for the interest is that stimulants, the treatment of f irst choice for ADHD, are notorious for their deleterious effect on sleep. A vast number of studies on the issue of sleep in ADHD has recently been published, including several reviews1-3 and book chapters.4,5 However, a clear overview of the recent findings with a focus on the clinical implications is yet missing. The present review discusses studies published after the date of the introduction of DSMIV.6 The sleep disorders that have been linked to ADHD are discussed separately. First, elementary methodological aspects of sleep assessment are summarized.

Effects of melatonin on the quality of life in patients with delayed sleep phase syndrome

OBJECTIVEnThe purpose of this study was to compare health-related quality of life of delayed sleep phase syndrome (DSPS) patients with a random Dutch sample and four samples of patients with other chronic conditions. We also investigated the effectiveness of treatment with 5 mg of melatonin on the quality of life of DSPS patients.nnnMETHODSnForty-three DSPS patients completed a quality-of-life questionnaire (Medical Outcome Study Short Form-36 [MOS SF-36] health survey) just before and 2-9 months after participation in a clinical trial involving the administration of melatonin. Scores were compared with responses to the same survey by a random Dutch sample and by patients with sleep apnea, clinical depression, migraine, and osteoarthritis.nnnRESULTSnMOS SF-36 scales scores were significantly lower in DSPS patients relative to age- and gender-adjusted norms for the Dutch sample. Some health dimensions were more affected, and others less affected, by DSPS compared with the other chronic conditions. Melatonin treatment improved all scales except the scale role due to emotional problems.nnnCONCLUSIONnDSPS has a unique significant quality-of-life burden that seems to be improved by treatment with melatonin.