Single case reports |
Horrigan and Barnhill, 1997 [81] | J. Am. Academy Child and Adolesc. Psychiatry | 17 year old boy with Asperger’s Syndrome (AS) | _____ | Not Given | 3 mg | 20–30 min before bedtime (BB) | Sleep | Sleep improvement. No side effects | Daytime behavior improvement | _____ |
Hayashi, 2000 [82] | Psychiatry Clin. Neurosc. | 14-year-old boy with autistic disorder, severe intellectual disability and phase delay with polyphasic sleep | _____ | 4 months | Immediate Release (IR) 6 mg | 11:00 PM | Sleep | Melatonin increased sleep duration. No side effects | None | _____ |
Jan et al., 2004 [83] | Dev. Med.Child Neurol. | 12 year-old boy with AS and complex sleep disturbance (phase delay and parasomnias) | _____ | 6 months | Controlled Release (CR) 5 mg | 30 min BB | Sleep | Normalization of the sleep-wake rhythm and disappearance of parasomnias. No side effects | None | _____ |
Retrospective studies |
Gupta and Hutchins, 2005 [84] | Arch. Dis. Child | 9 cases of children with Autistic Disorder (AD) aged from 2–11 years. Chronic sleep problems | Not Given | 1 week to 1 year | IR 2.5–5 mg | 45 min BB | Parental evaluation of sleep | 56% showed improvement in total sleep duration | None | No standardized collection of sleep variables |
Andersen et al., 2008 [85] | J. Child. Neurol. | 107 children and adolescents aged from 2–18 years with ASD (DSM-IV): 71% AD, 5% AS, 19% PDDNOS (Pervasive Developmental Disorder Not Otherwise Specified) | Not Given | Mean Duration: 1.8 years | IR in 91% of the cases. Dose escalation protocol from 1 to 6 mg based upon age | 30–60 min BB | Parental evaluation of sleep | Parents reported full (25%) or partial (60%) improvement. Beneficial effects of melatonin seem to stop after 3 to 12 months despite the use of higher doses. Side effects observed in 3 children: sleepiness, fogginess, increased enuresis | None | No standardized collection of sleep variables. The loss of response to melatonin treatment is discussed in the text |
Galli-Carminatti et al., 2009 [86] | Swiss. Med. Wkly | 6 adult patients with AD (CIM-10) and intellectual disability, aged from 19–52 years | Not Given | 6 months | IR. Dose escalation protocol from 3 to 9 mg if clinically required | 45 min BB | Sleep (CGI-S and CGI-I) | Improvement in sleep onset latency, night and early morning awakenings. No side effects | None | No standardized collection of sleep variables. 2 to 4 associated psychotropic drugs per patient |
Open label trials |
Jan et al., 1994 [87] | Dev. Med. Child Neurol. | 15 children with multiple neurological disabilities and severe sleep disorders | Not Given | Not Given | 2–10 mg | bedtime | Not Given | Partial improvement in sleep disorders. No side effects | Behavior and social improvement | Heterogeneous sleep disorders and neurological disabilities |
Ishizaki et al., 1999 [88] | No To Hattatsu | 50 children and young adults with autism (n = 27) or mentally retardation (n = 20) or severe motor/intellectual disability (n = 3) aged from 3–28 years with sleep disorders | Not Given | Not Given | Not Given | Not Gven | Sleep disorders and emotional/behavior disturbances | 34 patients experienced improvement in response to melatonin. Side effects reported in 17 patients | Improvements in excitability when sleep also improved. No change in contrariness, stereotyped behavior and in school/workshop refusal | Various types of insomnia and diagnoses |
Paavonen et al., 2003 [89] | J. Child. Adolesc. Psychopharmacol. | 15 children with AS (DSM-IV) aged from 6–17 years with severe sleep problems for at least 3 months | Not Given | 14 days | IR 3 mg | 30 min BB | Sleep (72h-period actigraphy, sleep diaries), daytime behavior (Karolina Sleepiness Scale: KSS), Child Behavior Check List (CBCL) | Melatonin treatment was associated with significant decrease in sleep onset latency and nocturnal activity. Discontinuation of melatonin led to a significant decrease in sleep duration and more nocturnal activity. Side effects in 20% of the cases: tiredness, headaches, severe sleepiness, dizziness, diarrhoea | Significant improvement of daytime behavior (CBCL) | No principal outcome specified. KSS is not validated in children nor in ASD |
Giannotti et al., 2006 [90] | J Autism Dev. Disord. | 29 children with AD (DSM-IV) aged from 2–9 years with current sleep problems | Controlled-release melatonin | 6 months | Dose escalation protocol from 3 mg (1 mg of IR+2mg of CR) to 6 mg when clinically required, based upon age (max 4 mg under 4 years old and max 6mg over 6 years old) | 08:00 PM | Sleep (diaries and Children Sleep Habits Questionnaire CSHQ), daytime behavior, Children Autistic Rating Scale (CARS) | Melatonin treatment was associated with improvement in sleep onset latency, night awakenings and sleep duration which vanished after melatonin discontinuation. No side effects | Parents reported less irritability, less anxiety and better mood. Significant improvement of depression, anxiety and withdrawal symptoms during melatonin treatment in children with AS. No effect was reported on the CARS | No principal outcome specified. Missing data: analyses on 25 patients |
De Leersnyder et al., 2011 [91] | Pediatr. Neurolog. | 88 children with heterogeneous neurodevelopmental disorders (Smith Magenis syndrome, mental retardation, encephalopathy, Angelman syndrome, Rett syndrome, Bourneville syndrome, blindness and autism) aged 5–20 years. 7 patients with autism, mean age 12 years old | 6 years of open label follow up | 3 months | CR 2–4 mg (<40 kg) or 6 mg (>40 kg) based upon weight | 60 min BB | Parental evaluation of sleep and mood (self-constructed questionnaire) | According to parental reports, both sleep latency and sleep duration improved within 3 months such as night awakenings, sleep quality and daytime napping. 11 children experienced adverse events (daytime nap, difficulties in swallowing tablets) that the parents attributed to melatonin treatment | 12% of the parents reported improvements of mood in their children | Heterogeneous neurodevelopmental disorders. Results can’t apply to a population with autism spectrum disorders. No standardized collection of sleep and mood parameters. Mean dose for patients with autism: 5.7 mg |
Malow et al., 2011 [92] | J. Autism Dev. Disord. | 24 children with ASD (DSM-IV, ADOS): AD, AS and PDDNOS aged from 3–9 years. Sleep onset delay of 30 min or longer confirmed on actigraphy. Exclusion of neurodevelopmental disabilities such as fragile X, Down and Rett syndromes | Before treatment families received structured sleep education and children underwent a treatment acclimatation phase in order to be sure the melatonin will be taken | 14 weeks | CR. Dose escalation protocol from 2–9 mg when clinically required | 30 min BB | Sleep (actigraphy, Children Sleep Habits Questionnaire CSHQ, diaries), daytime behavior (Child Behavior Check List CBCL, Repetitive Behavior Scale-Revisited), parental stress (Parenting Stress Index Short Form), side effects (Hague Side Effects Scale) | Significant improvement in sleep latency within the first week of treatment but not for other sleep parameters such as night awakenings and sleep quality | Significant improvement in children behavior (withdrawal, affective problems, attention-deficit hyperactivity, stereotyped and compulsive behaviors). Significant improvement in parental stress | No placebo |
Placebo-controlled trial |
McArthur and Budden, 1998 [93] | Dev. Med. Child Neurol. | 9 children and adolescents with Rett syndrome aged from 4 to 17 years. Mean age :10 years old | Randomised double-blind crossover trial | 2 periods of 4 weeks with a wash out period of 1 week | 2.5–7.5 mg based on weight | 60 min BB | Sleep (actigraphy, diaries) | Significant improvement in total sleep time. No side effects. | None | _____ |
Garstang and Wallis, 2006 [94] | Child Care Health Dev. | 11 children and adolescents with ASD aged from 5–15 years with chronic sleep disorders resistant to behavioral treatment | Randomised double-blind crossover trial | 2 periods of 4 weeks with a wash out period of 1 week | IR 5 mg | 60 min BB | Sleep (diary) | Melatonin and placebo were associated with significantly decreased sleep latency and nocturnal awakenings, increased total sleep time. No side effects | Several parents and class teachers commented that their children were easier to manage and less rigid in their behavior while taking melatonin | ASD criteria were not consensual. Only 7 children completed the trial. Investigators found that some of the placebo capsules were empty. Missing data |
Wasdell et al., 2008 [95] | J. Pineal Res. | 51 children and adolescents with neurodevelopmental disabilities (16 patients with ASD) from 2–18 years. Sleep delay phase syndrome and impaired sleep maintenance with resistant to sleep hygiene intervention | Randomised double-blind crossover trial. 3-weeks trial followed by a 3-month open-label study. Bahavioral sleep treatment before inclusion | 2 periods of 10 days with a wash out period of 3–5 days | Dose escalation protocol based on unspecified conditions: from 5 mg (1 mg FR + 4 mg CR) to 15 mg | 20–30 min BB | Sleep (actigraphy, diaries, CGI-S, CGI-I), familial stress (Family Stress Scale) | Significant improvement in total sleep duration and sleep latency as well as reduced stress levels in parents in the melatonin arm | Half of the patients with ASD had their dose increased during the open-label phase with no additional improvement in sleep latency or sleep duration, but caregivers reported less anxiety | Unspecified ASD criteria. 50 patients completed the trial and 47 completed the open-label phase. Selection bias due to previous melatonin treatment (25% of the cases). At the end of the trial, 29 patients received a dose of 10 or 15 mg. Higher doses were necessary in patients with bilateral cerebral lesions |
Wirojanan et al., 2009 [96] | J. Clin. Sleep Med. | 12 children and adolescents with unspecified sleep problems, aged from 2–15 years: 5 patients with AD (ADOS and ADI-R), 3 patients with fragile X syndrome with AD, 3 patients with AD and fragile X syndrome, and 1 patient with fragile X premutation | Randomized double-blind crossover trial | 2 periods of 2 weeks. No wash out period | IR 3 mg | 30 min BB | Sleep (actigraphy, diary) | Significant, but mild improvement in total sleep time (+21min) and decrease in sleep latency (−28min) | None | Missing data: only 12 patients completed the trial (order bias). No sub-group analysis in AD patients. No side effects |
Wright et al., 2011 [97] | J. Autism Dev. Disord. | 22 children and adolescents from 3–16 years with ASD (ICD-10, ADOS, ADI-R): AD (70%), AS (10%) and AA (20%). No fragile X or Rett syndrome. Current sleeplessness (confirmed on a 1 month-diary) and resistant to behavioral treatment. | Randomized double-blind crossover trial | 2 periods of 3 months separated by 1 month of washout | IR. Dose escalation protocol from 2 mg to 10 mg when clinically required | 30–40 min BB | Sleep (Sleep Difficulties Questionnaire, diary), daytime behavior (Developmental Behavior Checklist), Side Effect Questionnaire | Significant improvement in sleep latency (−47min) and total sleep duration (+52min) in the melatonin arm. No improvement in night awakenings. The side effect profile was not significantly different between the 2 groups | Improvement in children behavior in the melatonin arm that was significant for communication (p = 0.045) | Missing data. Analysis on 16 patients. No actigraphy. Mean melatonin dose: 7 mg |
Cortesi et al., 2012 [98] | J. Sleep Res. | 160 children with ASD (DSM-IV, ADI-R, ADOS) aged 4–10 years with sleep onset insomnia and impaired sleep maintenance | Randomized placebo- controlled. Randomization in 4 groups: 1) melatonin alone 2) melatonin+ Cognitive Behavioral Therapy (CBT) 3) CBT alone 4) placebo | 12 weeks | CR 3 mg | 09:00 PM | Sleep (actigraphy, Children Sleep Habits Questionnaire, diaries) | 144 patients completed the trial and 134 were analysed. Combination group showed greater significant improvements on sleep followed by the melatonin alone and the CBT alone compared to placebo group. No side effects | None | _____ |
Gringras et al., 2012 [99] | BMJ | 146 children from 3 to 15 years with neurodevelopmental disorders (60 patients with ASD) and severe sleep disorders that did not respond to standardised sleep advice | Double-blind randomised multicentre placebo- controlled phase III trial | 12 weeks | immediate release melatonin (dose escalation protocol from 0.5 mg to 12 mg) or matching placebo | 45 min before bedtime | total sleep time after 12 weeks (sleep diaries and actigraphy); sleep onset latency; child behavior (aberrant behavior checklist); family functioning; adverse events | Melatonin increased total sleep time by 22.4 min (diaries) and 13.3 (actigraphy); reduced sleep onset latency by 37.5 min (diaries) and 45.3 (actigraphy). Children in the melatonin group woke up earlier than the children in the placebo group. Melatonin was most effective in children with longest sleep latency. Adverse events were similar between the 2 groups | Child behavior and family functioning outcomes showed some (but not significant) improvement and favoured use of melatonin | The results are not specified by category of developmental disorder |