Melatonin for sleep disturbance in children with

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Original Research

Melatonin for sleep disturbance in children with neurodevelopmental disorders: prospective observational naturalistic study Expert Rev. Neurother. Early online, 1–7 (2015)

Hani F Ayyash*1–3, Phillip Preece4, Richard Morton5 and Samuele Cortese*6–8 1 Integrated Paediatrics, Child and Adolescent Mental Health Services, Cambridgeshire and Peterborough NHS Mental Health Foundation Trust, A Member of Cambridge University Health Partners, Winchester Place, Peterborough, PE3 6AP, UK 2 Academic Committee GSF, National Paediatric ADHD Networking, RCPCH, 3 Child and Psychiatric Surveillance System, RCPsych, London, UK 4 Chesterfield and North Derbyshire Royal Hospital NHS Trust, Chesterfield, Derbyshire, S445 BL, UK 5 Derbyshire Children’s Hospital, Derby, South Yorkshire, DE22 3NE, UK 6 Developmental Brain-Behaviour Laboratory, Psychology, University of Southampton, Highfield Campus, Southampton, SO17 1 BJ, UK 7 School of Medicine, University of Nottingham, Triumph Road, NG7 2TU, UK 8 New York University Child Study Center, One Park Ave, New York City, New York, 10016, USA *Authors for correspondence: Tel.: +44 238 059 4604 Fax: +44 238 059 500 [email protected] [email protected]

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Background: Although melatonin is increasingly used for sleep disturbances in children with neurodevelopmental disorders, evidence on effective dose and impact on specific types of sleep disturbance is limited. Method: We assessed 45 children (35 males, mean age: 6.3 ± 1.7 years) with neurodevelopmental disorders (n = 29: intellectual disability; n = 9: autism spectrum disorder; n = 7: attention-deficit/hyperactivity disorder) and sleep disturbances, treated with melatonin (mean duration: 326 days) with doses increased according to response. Results: Thirty-eight percent of children responded to low (2.5–3 mg), 31% to medium (5–6 mg) and 9% to high doses (9–10 mg) of melatonin, with a significant increase in total hours of sleep/night, decreased sleep onset delay and decreased number of awakenings/night (all: p = 0.001), as measured with sleep diaries. No serious adverse events were reported. Conclusions: Melatonin is generally effective and safe in children with neurodevelopmental conditions. Increasing above 6 mg/night adds further benefit only in a small percentage of children. KEYWORDS: attention-deficit/hyperactivity disorder . autism spectrum disorder . children . intellectual disability .

melatonin . sleep

Children with neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD) [1–5], autism spectrum disorder (ASD) [6,7] and intellectual disability (ID) [8], may present with sleep disturbances that further impact on their cognitive and emotional development [9], aggravating the functional impairment associated with these conditions. Thus, effective management of comorbid sleep disturbances is pivotal to improve the outcome and quality of life in children with neurodevelopmental disorders and their families. While non-pharmacological strategies, including behavioral interventions, are recommended as first treatment option for sleep disturbances in children with neurodevelopmental disorders [2,10], medications are considered when non-

10.1586/14737175.2015.1041511

pharmacological interventions are not effective or not feasible. Among the agents used for sleep disturbances associated with neurodevelopmental conditions, there is an increasing interest for melatonin, an indoleamine normally secreted by the pineal gland. Recently, a working group of experts in the field of neurodevelopment and sleep reviewed evidence on melatonin in pediatric neurological disorders and provided clinical recommendations for its use in the daily practice with children with neurological disorders [11]. In relation to ADHD, the working group retrieved a total of five trials of melatonin [12–16], including three randomized controlled trials [13,14,16], all showing positive effects of melatonin on sleep disturbances, with, overall, a safe tolerability profile. With

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Original Research

Ayyash, Preece, Morton & Cortese

regards to ASD, a meta-analysis of 18 trials [17] found significant improvements in sleep duration and sleep onset latency, but not in night time awakenings. Finally, in relation to ID, the working group retrieved a meta-analysis of nine randomized controlled trials [18] showing that melatonin treatment significantly decreased sleep latency and number of wakes per night, and increased total sleep time. While the rigorous design of conventional (indicated also as explanatory) randomized trials allows for a reduction of many biases, such studies may be hampered by selection bias, since, as recently pointed out by Purgato et al. [19], they often include a selected sub-population of subjects usually seen in the clinical practice and use rigid medication schedules and ways of treatment delivery, thus making their conclusions not fully applicable to the daily clinical practice. In this respect, naturalistic, observational studies may provide additional valuable evidence for the daily practice. In particular, in relation to melatonin, there are three aspects that deserve further evidence and that may be addressed in naturalistic studies. The first one relates to the maximum effective dose of melatonin. Although the expert consensus of the working group members recommended a maximum dose of 5 mg/day, reflecting the highest dose used in the majority of the trials (5–6 mg/day), higher doses have been used in other individual trials (e.g., up to 12 mg/day in youths with ID in the study by Coppola et al. [20] and up to 10 mg/day in children with ASD in the report by Wright et al. [21]). Therefore, it is not clear if and to which extent doses higher than 5– 6 mg/day may be effective and safe. Tolerability of melatonin is particularly relevant in light of recent concerns about its safety [22]. Second, the majority of available trials are usually limited to a few weeks/months; although some follow-up studies have been published (e.g., [15]), additional data on longer term effects of melatonin in children with neurodevelopmental disorder are needed. Finally, while melatonin is used mainly to decrease sleep onset delay, its effects on other sleep problems, such as night time awakenings and reduction of total sleep time, deserve further investigation. Here, we draw on data from an 11-month naturalistic, observational, prospective study to assess the effects of melatonin on sleep onset delay, total sleep time and night awakenings in children with ADHD, ASD or ID using a broad range of doses, increased based on clinical response. Given the exploratory nature of the study, no a priori hypotheses were formulated.

Study settings

Participants were recruited, using the same protocol, either at the Child Development Centre, Department of Paediatrics, Chesterfield and North Derbyshire Royal Hospital, UK or at the Ronnie Mackeith Centre, Derbyshire Children’s Hospital, Derby, UK. Participants

Children with a diagnosis of ADHD, ASD or ID were included if they presented with severe sleep problems, defined by the presence of one of more of the following (rated by parents via structured sleep diaries) at least 3 times/week: ‘Does not sleep within 1 h of putting him/her in bed’; ‘Wakes up once or more during the night’; ‘Wakes up before 6 am’; and ‘Gets less than 6 h of continuous sleep’. Only children who failed to respond to behavioral management strategies for sleep disturbances, as implemented in the daily clinical practice, were included, since behavioral strategies are the recommended firstline option for the majority of pediatric sleep disturbances. We excluded children with a diagnosis of obstructive sleep apnea or nocturnal seizures since sleep disturbances associated with these conditions require a specific treatment. To maximize the applicability of our findings to the daily clinical practice, no other inclusion/exclusion criteria were used. In particular, all children with ADHD were treated with psychostimulants and were allowed to continue this treatment for obvious ethical reasons (i.e., it would be unethical to stop an effective medication); similarly, children with epilepsy continued the treatment with anticonvulsant drugs. Assessment

The study was approved by the Drug and Therapeutic Committee of the Chesterfield and North Derbyshire Royal Hospital, UK. Informed written consent from all participants’ parents and assent from each participant were obtained before their inclusion into the study.

Neurodevelopmental disorders (ADHD, ASD and ID) were diagnosed based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (the diagnostic system used at the time of the study) by a multidisciplinary team including consultant pediatricians, neurodevelopmental pediatricians, clinical psychologists, speech and language therapists, physiotherapists, occupational therapists, nursery nurses, orthoptists and audiologists, child neurologists and clinical geneticists. Clinical assessment included: physical and neurological examination, neuropsychiatric interview, rating scales completed by parents and teachers to collect additional information regarding child’s behavior in different contexts, vision and hearing tests to assess comorbid impairment or differential diagnoses and hematological, biochemical as well as chromosomal analysis to define possible etiology underlying the neurodevelopmental disorder (details of this assessment are not reported here since they go beyond the scope of this article but are available upon request). Sleep was assessed by parents via a structured sleep diary (available upon request) for at least 2 weeks before and after the start of melatonin treatment.

Study design

Melatonin formulation & dose

Prospective, observational, naturalistic study before and after treatment with melatonin.

Melatonin immediate-release was initially administered at a starting dose of 2.5 mg, half an hour before the desired

Methods

doi: 10.1586/14737175.2015.1041511

Expert Rev. Neurother.

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Melatonin for sleep disturbance in children with neurodevelopmental disorders

bedtime, regardless of age or weight. If there was no significant improvement in sleep patterns after 4 weeks (i.e., persistence of the inclusion criteria for sleep disturbance, as assessed by the clinician), dose was increased up to 5 mg and after a further 4 weeks to a maximum of 10 mg if no response to 5 mg was observed. Participants were reviewed regularly, every 4 weeks, and interviewed, along with their parents/carers, about compliance to treatment and any possible adverse events occurring during the treatment with melatonin. Follow-up assessment was performed after about 11 months (326 days) from the start of the treatment. Statistical analysis

Study outcomes were: total sleep time (hours/night), time to sleep onset and night awakenings (number/night), as reported in the sleep diaries. Two measurements per child were taken, one before and one after the intervention. A paired t-test was carried out separately on each of the three differences (i.e., after minus before treatment) in outcomes. Ninety-five percent CIs were also calculated. In addition, a one-way analysis of variance (ANOVA) was performed to assess possible differences on study outcomes in the three participant categories (ADHD, ASD and LD); in the event of significant p-values (i.e., p < 0.05), ANOVA was followed by multiple pairwise comparisons between any two of the three groups, with Bonferroni adjustment to allow for multiple significance tests. Finally, mean differences in outcomes between the three dosage groups (low, medium and high) were assessed with ANOVA followed by pairwise comparison with Bonferroni adjustment. All analyses were performed using SPSS for Windows version, 10th edition (SPSS, Chicago, IL, USA). Statistical significance was defined as p < 0.05 (two-tailed). Results

Original Research

Table 1. Age distribution and gender proportion of participants. Age range (years)

Children (n, %)

Males (n, %)

Females (n, %)

10

6 (13)

5 (11)

1 (2)

Total

45 (100)

35 (78)

10 (22)

morning awakenings). As reported in TABLE 3, 20 participants received the lowest dose of melatonin (2.5–3 mg). Of these, 17 were considered responders by the clinician, while three stopped the treatment: two because of an increase in irritability and hyperactivity and one because of an improvement in sleep problems, although this participant was successfully restarted on melatonin after 1 week due to deterioration in sleep patterns. Sixteen children were treated with a medium dose of melatonin (5–6 mg) since they failed to respond to the lowest dose. Of these, 14 were considered responders, while two stopped the treatment due to an increase in irritability and night time awakenings, respectively. The remaining nine participants (20%) were treated with high doses of melatonin as they failed to respond to lower doses. Four of them (9%) were considered responders, while five children (11%) withdrew since three did not have any beneficial effects; one participant presented with decreased appetite; one child, who was diagnosed with comorbid epilepsy before entering the study, presented with increased fitting, but came back to his previous condition after melatonin was stopped. Therefore, in total, 78% of participants responded to treatment, while 22% withdrew due to side effects or ineffectiveness. In terms of type of sleep problems for which melatonin was effective, we found a significant improvement in all three sleep problems assessed via sleep diaries (sleep onset delay, frequent awakenings and early morning awakenings) (TABLE 4). The mean difference in the total sleep time was 1.93 ± 1.41 h. The reduction in time to sleep onset was 1.25 ± 1.13 h. TABLE 5 reports the difference in the mean ± standard deviation (SD) of the total sleep time, time to sleep onset and number of awakenings as response to treatment by diagnosis. A one-way

Initially, a total of 47 children (mean age: 6.3 ± 1.7 years) were recruited. However, two children (aged 5.7 and 15.9 years, respectively) were excluded since parents failed to complete sleep diaries. The baseline characteristics of the 45 participants are reported in TABLES 1 & 2. Thirty-five of them (78%) were males. Twentynine participants presented with ID (moderate to severe), nine with ASD and seven with ADHD. In terms of sleep problems, the majority of participants (n = 37, 82%) presented with sleep onset delay or frequent Table 2. Clinical diagnoses of participants. awakenings (n = 36, 80%). Early morning Primary diagnosis Associated conditions awakenings were observed in 14 (31%) of participants. While only 10 children pren (%) Visual Epilepsy Cerebral sented with a single sleep problem, a double impairment (n, %) (n, %) palsy (n, %) sleep problem (a combination of sleep onset Intellectual disability 29 (64) 9 (20) 8 (18) 8 (18) delay plus frequent awakenings, sleep onset Autism spectrum 9 (20) 2 (4) 1 (2) – delay plus early morning awakenings or fredisorder quent awakenings plus early morning awakenings) was present in 28 children (62%). Attention-deficit/ 7 (16) 1 (2) 1 (2) – Finally, seven participants (16%) presented hyperactivity disorder with all three sleep conditions (sleep onset Total 45 (100) 12 (26) 10 (22) 8 (18) delay, frequent awakenings and early informahealthcare.com

doi: 10.1586/14737175.2015.1041511

Original Research

Ayyash, Preece, Morton & Cortese

the number of awakenings per night. This should be taken with caution given that the number of children in the LD group outDose (mg/day) Children Responders Non-responders weighed that in the other two groups (ADHD and ASD). (n, %) treated (n, %) In terms of dose, low or medium, rather than high, doses were (n, %) effective for the majority of the participants. Our findings suggest Low dose (2.5–3) 20 (44) 17 (38) 3 (7) that, if a child with a neurodevelopmental disorder does not respond to low or moderate doses of melatonin, increasing the Medium 16 (36) 14 (31) 2 (4) dose (5–6) dose is unlikely to increase the chances of response. However, the clinician should bear in mind that a small proportion of children High dose (9–10) 9 (20) 4 (9) 5 (11) might respond to the highest doses. Overall, the results of our natTotal 45 (100) 35 (78) 10 (22) uralistic study support the recommendations by the aforementioned consensus group, based mostly on randomized controlled ANOVA did not find any statistically significant difference studies and group members’ clinical experience, to use a dose among the three groups in terms of changes in total sleep time between 3 and 5 mg/night of melatonin. This is of relevance (p = 0.312) or time to sleep onset (p = 0.757), while the dif- since, in daily practice, clinicians may use doses well beyond ference in the number of awakenings per night was significant 5 mg/night. For example, a survey [24] conducted in Australia (p = 0.045): compared to children with ADHD, those with ID reported that maximum doses of melatonin were 10 mg in chilor ASD displayed a significantly greater reduction in the num- dren and 18 mg in adolescents. ber of awakenings per night. Finally, there was no statistical It has been noted that in individuals with a decreased activity evidence of a significant difference among the dosage groups in of the CYP1A2 enzyme, high levels of melatonin may accumuterms of changes in total sleep time (p = 0.123), time to sleep late during treatment, with a consequent loss of circadian melaonset (p = 0.638) or number of awakenings (p = 0.216). tonin rhythm, and, thus, effectiveness [25,26]. This would contribute to explain why, in some individuals who do not Discussion respond to low or moderate doses, a further increase is not We assessed the effectiveness and tolerability of melatonin in chil- effective. Decreased CYP1A2 activity has been reported in dren with neurodevelopmental disorders (ID, ASD and ADHD) 12–14% of individuals in the general population [11]. Interestby means of an 11-month naturalistic prospective study providing ingly, 11% of the children enrolled in our study did respond to a data on the effects of a range of doses (low, medium and high) on further increase of dose; therefore, it is possible that they, or at three different sleep disturbances: sleep onset delay, frequent least a subgroup of them, had a deficit of the CYP1A2 enzyme. awakenings and early morning awakenings. In addition, and in line with previous research [27], our Overall, melatonin was effective in the majority of participants results showed that response is not related to dose. Overall, it (78%). This is consistent with early findings by Jan and seems safe to conclude that currently there is no specific clinical O’Donnell [23] in a different type of population; these authors or neurobiological predictor of the most effective dose and use reported that melatonin improved sleep–wake cycle disorders in of high doses (i.e., > 5–6 mg/night) is unlikely to be effective about 80% of the children with disabilities (such as blindness, except for a small subsample of patients. deaf-blindness, mental retardation, autism and CNS disease) Participants took melatonin half an hour before the desired included in their study. Our results are also in line with a more bedtime. There is a lot of discussion around the most effective recent meta-analysis of five randomized double-blind placebo- time for melatonin assumption. Indeed, melatonin is a peculiar controlled studies in children with ASD, showing a significant drug since the timing of its administration plays a critical role improvement in sleep latency and total sleep duration in 80% of in its effectiveness. As pointed out by the recent expert consenthe participants [17]. Overall, there were no significant differences sus [11], due to its chronobiotic effects, phase advances occur in effectiveness according to the neurodevelopmental disorder, when melatonin is administered from ±8 h before the dim although our data suggest that compared to children with light melatonin onset (DLMO) to ±2 h after it, with ADHD, those with ID or ASD may have a greater reduction in maximum effect at 3–5 h before DLMO. When administered 2–3 h after DLMO, no effects or even reverse effect (phase delay) can occur. As Table 4. Changes in sleep study outcomes from baseline to follow-up such, measuring DLMO (periodic sam(total sample). pling of saliva) is informative to predict melatonin effectiveness. However, it may Outcome Baseline Follow-up Difference p-value be challenging to routinely measure Mean ± SD Mean ± SD Mean ± SD DLMO in the daily busy clinical practice Total sleep time (hours/night) 7.68 ± 1.44 9.61 ± 1.49 1.93 ± 1.41 < 0.001 and this was beyond the scope of the present study. We also note that adminisTime to sleep onset 2.63 ± 1.42 1.38 ± 0.72 1.25 ± 1.13 < 0.001 tering melatonin half an hour before the Awakenings (n/night) 0.92 ± 0.77 0.54 ± 0.63 0.38 ± 0.47 < 0.001 desired time is consistent with several

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Table 3. Dose of melatonin and response rates.

doi: 10.1586/14737175.2015.1041511

Expert Rev. Neurother.

Melatonin for sleep disturbance in children with neurodevelopmental disorders

Original Research

Table 5. Changes in sleep study outcomes from baseline to follow-up in the three study groups. Outcome

Intellectual disability

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Mean ± SD (difference follow-up baseline), p-value

Autism spectrum disorder

Attention-deficit/hyperactivity disorder

Mean ± SD (difference follow-up baseline), p-value

Mean ± SD (difference follow-up baseline), p-value

Total sleep time (hours/night)

1.78 ± 1.40, < 0.001

1.81 ± 1.57, < 0.001

2.68 ± 1.22, < 0.001

Time to sleep onset

1.33 ± 1.11, < 0.001

1.00 ± 1.23, < 0.02

1.24 ± 1.20, < 0.02

Awakenings (n/night)

0.51 ± 0.50, < 0.001

0.10 ± 0.17, < 0.1

0.23 ± 0.22, < 0.02

previous studies (e.g., [28–30]) and its rationale is based on melatonin’s soporific, rather than chronobiotic, properties. We used melatonin immediate-release. Therefore, our study is not informative on the effectiveness of extended-release formulations that are used in several countries. However, according to the aforementioned expert consensus [11], there is no evidence that extended-release melatonin has advantages over immediate-release acting melatonin. Besides effectiveness, an important aspect of our study relates to tolerability. There has been an increasing concern around possible serious side effects of melatonin in children based on data from animal models (rodents, sheep and primates) suggesting putative effects on the reproductive cardiovascular, immune and metabolic systems [22]. However, so far, data in children with neurodevelopmental disorders from short-term (e.g., [13,14,16,21]) and available long-term follow-up studies (e.g., [15,31]) failed to point to serious adverse events associated with the use of melatonin, although clearly further evidence is needed. The most remarkable side effect in our study was worsening of seizure activity following treatment with high doses of melatonin (10 mg) in one participant with ASD who was also taking dexamphetamine and sodium valproate, although seizure control returned back to normal after stopping melatonin. We cannot rule out the possibility that melatonin interacted in some way with the other drugs. We note that the effects of melatonin on seizure frequency are uncertain and indeed some reports pointed to positive effects, rather than negative effects, on seizure controls [32]. However, subsequent reviews [33,34] concluded that it is not possible, based on available empirical evidence, to draw any definitive conclusion about the role of melatonin in reducing seizures frequency.

Our findings should be considered in the light of study limitations. First, sleep disturbances were assessed by means of a subjective method (sleep diary) rather than rigorous objective assessment with polysomnography (PSG). However, contrary to PSG, especially when performed at the hospital/clinic, sleep diaries provide a naturalistic assessment of sleep and capture sleep parameters over a prolonged period of time, which is often not feasible using PSG. Additionally, PSG is expensive and difficult to perform in children with neurodevelopmental disorders, due to poor cooperation. Second, our study was not controlled double-blinded. Third, our study was not designed to assess drug interactions. Fourth, the sample size was small which may be problematic since, given that the sleep problems in children with neurodevelopmental disorders may have different etiologies, they may have different responses on melatonin treatment. Therefore, a larger sample size would allow better characterization of participants’ response to treatment. Acknowledgements

The authors are very grateful to Prof. Rudolf and Dr. Wyatt for advice on the study design and to Prof. Walter for his guidance on the statistical analyses. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues .

Melatonin is safe and effective in the majority of children with neurodevelopmental disorders.

.

Melatonin improves total hours of sleep/night, sleep onset delay and number of awakenings/night.

.

If a child with a neurodevelopmental disorder does not respond to low or moderate dose of melatonin, increasing to higher does is unlikely to add further benefit.

.

However, although higher doses might indeed be beneficial for a small percentage of children.

.

A key area of research for the future is the investigation of the added value of combining behavioral therapies to melatonin to improve sleep patterns in children with neurodevelopmental disorders.

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Original Research

Ayyash, Preece, Morton & Cortese

neurology: Clinical recommendations. Eur J Paediatr Neurol 2015;19:122-33

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