In this open-label dose-escalation study of supplemental melatonin, we found that (1) The majority of children responded to a 1 mg or 3 mg dose given 30 minutes before bedtime with an improvement in sleep latency; (2) This improvement was seen within the first week of dosing at the effective dose; (3) The medication was tolerated well with minimal adverse effects and no changes in laboratory values; (4) Actigraphy data was collectable over 17 weeks; and (5) Actigraphy, as well as parent-completed surveys focusing on sleep and behavior, showed change with the intervention.
Our findings are unique in that our study design allowed us to identify the doses at which children responded to melatonin (defined as sleep latency of 30 minutes or less on five or more nights in the week) and to define the time course of responsiveness (e.g., how many weeks were needed to observe a response). These results are not only helpful in the clinical care of children with ASD but also in planning for future randomized clinical trials. Safety and tolerability were also addressed in a comprehensive fashion, with reference to a side effects scale and laboratory testing. In agreement with a retrospective review of 107 children with ASD (Andersen et al. 2007), side effects were minimal.
We also documented that actigraphy can be used successfully in a 17-week trial in ASD. To our knowledge, no prior studies of melatonin in ASD have used actigraphy in a trial lasting several months. Actigraphy provided an important outcome measure that was objective and complemented that of parent report. Its use of 17 weeks allowed us to identify a satisfactory dose and document that effects were maintained over several months. The use of an alternative placement allowed us to optimize data collection and include children who did not tolerate standard wrist actigraphy.
In agreement with prior studies, we documented an improvement in sleep latency with melatonin treatment. Because our study criteria were designed to enroll children with sleep-onset delay, we cannot definitively comment on the effects of melatonin on sleep duration or night wakings. A meta-analysis of randomized double-blind placebo-controlled studies in ASD that reported quantitative data (5 studies, 57 participants total), comparing melatonin treatment with baseline (pre-melatonin treatment) and with placebo, showed improved sleep latency and improved sleep duration but not night wakings (Rossignol and Frye 2011
). Our findings were consistent with prior reports in that CSHQ sleep duration improved significantly with melatonin treatment, but night wakings did not. Neither sleep duration or night wakings, as measured by actigraphy, showed significant improvement with melatonin treatment. Large randomized controlled trials using objective measures of sleep will be needed to definitely establish the impact of melatonin on sleep duration and night wakings. The design of such trials may take several forms, depending on the questions of interest. Given our findings showing that a satisfactory response in sleep latency occurred within one week of dosing, a randomized trial of melatonin (parallel or crossover design) with a treatment phase as short as one week is reasonable to document improvements in sleep-onset insomnia. Alternatively, if more longer term outcome measures besides sleep latency were of interest, such as parenting stress, a longer treatment phase (e.g., one month or longer) may be appropriate.
The behavioral outcome measures that showed change with melatonin (e.g., attention-deficit hyperactivity, withdrawn, affective problems, stereotyped behaviors, compulsive behaviors) resemble that of prior work. The literature emphasizes that the behavioral construct of hyperactivity is affected by sleep disturbance—this had been documented in ASD populations (Goldman et al 2009
; Mayes and Calhoun 2009
) as well as typically developing children treated for obstructive sleep apnea (Chervin et al 2006
). Other behavioral parameters which have been associated with poor sleep in children with ASD include repetitive behavior, including compulsive behavior, and oppositional and aggressive behavior, anxiety, depression, and mood variability (Malow et al 2006
; Goldman et al, 2009
; Mayes and Calhoun 2009
). In an intervention study of parent education, hyperactivity and restricted behaviors showed improvements with treatment (Reed 2009
Parenting stress, as measured by the Difficult Child Subscale, improved with treatment. We did not find improvement in the PSI parent-related domains (Parental Distress or Parent-Child Dysfunctional Interaction) suggesting that parental stress in autism is multifactorial and may not be addressed with a single intervention.
Although melatonin is safe and well tolerated, we believe that it should be administered under the treatment of a physician. This is because of the importance of assessing children with ASD and insomnia for medical, neurological, and psychiatric comorbidities, which may cause or contribute to insomnia. This point is illustrated by the one non-responder in our study, a child subsequently diagnosed with bipolar disorder.
Strengths of our design include: (1) Participants limited to those meeting clinical and research criteria for ASD; (2) Relatively large sample size compared to prior studies; (3) Standardized parent sleep education protocol administered prior to the treatment with melatonin; (4) Use of objective primary outcome measures (actigraphy); (5) Screening for medical comorbidities which can contribute to insomnia; (6) Assessment of effect of improved sleep on behavioral outcomes (e.g., ameliorating core and associated features of autism and family functioning); and (7). Of patients whose cognitive skills were evaluated, all had an IQ of 70 or higher on the verbal or non-verbal scales, or both. Thus, our population had ASD with normal intelligence, eliminating any concerns about the impact of intellectual disability. The lack of significant findings on some of the behavioral subscales may reflect our small sample size. Another limitation is that we did not include a placebo group; large randomized multicenter trials will need to include a placebo group to establish efficacy. While our children were free of psychotropic medications, which can be viewed as a relative strength, our results are less generalizable to the autism population with sleep-onset delay, in which some children are taking medications (e.g., antidepressants and stimulants) which interfere with sleep or with hepatic enzymes (CYP1A2) that metabolize melatonin. Finally, we cannot comment on the dosing, safety, and tolerability of melatonin in children older than age 10 or who have entered puberty.
In summary, our findings provide unique information on dosing, tolerance/safety, and outcome measures for the use of melatonin in pre-pubertal children with ASD. They add to the growing literature documenting that melatonin shows promise for treating sleep-onset insomnia in ASD, and address key issues needed to design a large controlled trial of melatonin in this population.