Melatonin for Sleep in Children with Autism: A Controlled Trial
Examining Dose, Tolerability, and Outcomes
Beth Malow•Karen W. Adkins•Susan G. McGrew•
Lily Wang•Suzanne E. Goldman•Diane Fawkes•
? Springer Science+Business Media, LLC 2011
treating sleep onset insomnia in children with autism
spectrum disorders (ASD). Twenty-four children, free of
psychotropic medications, completed an open-label dose-
escalation study to assess dose–response, tolerability,
safety, feasibility of collecting actigraphy data, and ability
of outcome measures to detect change during a 14-week
intervention. Supplemental melatonin improved sleep
latency, as measured by actigraphy, in most children at 1 or
3 mg dosages. It was effective in week 1 of treatment,
maintained effects over several months, was well tolerated
and safe, and showed improvement in sleep, behavior, and
parenting stress. Our findings contribute to the growing
Supplemental melatonin has shown promise in
literature on supplemental melatonin for insomnia in ASD
and inform planning for a large randomized trial in this
Clinical trial ? Children’s sleep habits questionnaire ?
Child behavior checklist ? Autism diagnostic
Melatonin ? Insomnia ? Actigraphy ?
Sleep difficulties, particularly insomnia, occur in 50–80%
of children with autism spectrum disorders (Couturier et al.
2005; Krakowiak et al. 2008; Souders et al. 2009; Goldman
et al. 2011b) and are often accompanied by child and
family distress (reviewed in Richdale and Schreck 2009;
and Hollway and Aman 2011). Disordered sleep may
exacerbate core and related symptoms of autism including
social interactions, repetitive behaviors, affective prob-
lems, and inattention/hyperactivity (Schreck et al. 2004;
Gabriels et al. 2005; Malow et al. 2006; Goldman et al.
2009, 2011a). Therefore, interventions that target sleep
may not only improve child health and child and family
distress, but may also ameliorate core and related symp-
toms of autism.
Supplemental melatonin has a favorable side-effect
profile and is inexpensive. Along with other complemen-
tary and alternative therapies, it has gained widespread
acceptance by parents of children with ASD as an alter-
native to FDA-approved medications (Harrington et al.
2006). Three recent reviews have been published on the use
of melatonin for insomnia in children with ASD (Doyen
et al. 2011; Rossignol and Frye 2011; Gue ´nole ´ et al. 2011).
These reviews summarized the limitations of the existing
literature, which includes small sample sizes (majority of
studies containing 20 subjects or fewer), a mix of ASD
Dr. Burnette has moved to University of New Mexico subsequent to
the time of study.
B. Malow (&) ? S. E. Goldman ? D. Fawkes
Sleep Disorders Division, Department of Neurology and
Kennedy Center, Vanderbilt University School of Medicine,
1161 21st Avenue South, Room Room A-0116,
Nashville, TN 37232, USA
K. W. Adkins
Sleep Disorders Division, Department of Neurology, Vanderbilt
University School of Medicine, Nashville, TN 37232, USA
S. G. McGrew ? C. Burnette
Department of Pediatrics, Monroe Carell Children’s
Hospital at Vanderbilt, Nashville, TN 37232, USA
Department of Biostatistics, Vanderbilt University School
of Medicine, Nashville, TN 37232, USA
J Autism Dev Disord
with other neurodevelopmental disorders, limited con-
trolled trials, and limited studies using objective outcome
measures or examining dose–response or tolerability in a
systematic fashion. The reviews concluded that while
supplemental melatonin appears safe, well tolerated, and
promising in terms of efficacy, its use in ASD is not yet
To address the limitations of prior trials, we carried out a
pilot open-label study of supplemental melatonin. The
primary objective of the study was to evaluate the possible
therapeutic effectiveness of melatonin. If effective, we
wanted to also (1) Determine which doses were effective,
(2) Assess how quickly effective doses improve sleep, (3)
Collect safety and tolerability data in a systematic fashion,
(4) Define the feasibility of actigraphy data as an outcome
measure, and (5) Assess the ability of questionnaire data to
detect change with a 14-week intervention in this popula-
tion. Our findings presented here will allow for planning of
larger randomized multicenter trials of supplemental mel-
atonin for insomnia in ASD.
This study was approved by our Institutional Review
Board. The principal investigator holds an approved FDA
Investigational New Drug Application (#76105) to use
supplemental melatonin (Natrol?) for insomnia in ASD.
From subspecialty clinics, as well as from the commu-
nity (e.g., local autism society, public schools), using flyers
given to potential participants, accompanied by letters and
emails to referring practitioners, we recruited children ages
3–10 years with a clinical diagnosis of an autism spectrum
disorder (autism, pervasive developmental disorder, not
otherwise specified, or Asperger’s disorder) whose parents
reported sleep onset delay of 30 min of longer on three or
more nights per week. A study coordinator was responsible
for screening all potential participants to ensure that the
above criteria were met, and consulted with the physician
investigators as needed. Parents of these children provided
informed consent and were enrolled in the protocol to
begin study procedures. Children were free of psychotropic
medications; allergy medications and medications for
constipation were allowed. Parents agreed to avoid changes
in current medications or the start of new medications
during the time of study participation. Children with fragile
X syndrome, Down syndrome, neurofibromatosis, or
tuberous sclerosis complex and children who had a non-
febrile unprovoked epileptic seizure within the last 2 years
After enrollment, all children received:
1. Verification of the clinical diagnosis of ASD using a
clinical interview that incorporated DSM–IV-TR cri-
teria (American Psychiatric Association 2000) and the
Autism Diagnostic Observation Schedule (ADOS;
Lord et al. 2000). A clinical psychologist with
expertise in ASD diagnosis and who is research
reliable on the ADOS administered these instruments
to confirm participants’ diagnoses.
the authors, a pediatrician with expertise in ASD.
Because of the effect of puberty on sleep and the
unknown effects of melatonin on puberty, only children
who were prepubertal continued in the study (excluded
Tanner II or higher stage of physical development on
medical examination or those with hormonal values for
ACTH, cortisol, estrogen, testosterone, FSH, LH, and
prolactin that were not consistent with prepubertal
status). Children were also evaluated for comorbidities
that affect sleep, including gastroesophageal reflux
disease and psychiatricdisorders. Ifthese comorbidities
were clinically determined to affect sleep, they were
addressed prior to beginning melatonin. Children were
platelets) and metabolic panel, including liver and renal
function, were outside of the normal range.
A comprehensive sleep history of all children was
performed by the principal investigator. Children
suspected of having sleep apnea were evaluated with
polysomnography prior to enrollment and excluded if
sleep apnea was diagnosed.
As illustrated in Fig. 1, a one-week baseline and two-week
acclimation phase preceded the administration of supple-
mental melatonin. During the one-week baseline phase,
parents received one hour of structured sleep education by
the principal investigator, including establishment of a
regular bedtime and wake time. Parents also received
education in actigraphy procedures (see below). Children
wore actigraphy watches to confirm that sleep latency (time
to fall asleep) was at least 30 min on three or more nights in
the week. During the two-week acclimation phase, parents
gave their children an inert liquid 30 min before bedtime
that was flavored similar to supplemental melatonin
(compounded by Pharmacare, Mt. Juliet, TN?), in order to
acclimate the child to taking a liquid medication before
bedtime. Children were then given liquid supplemental
melatonin (Natrol?, Chatsworth CA) 30 min before bed-
time according to an optional escalating dose protocol
based on three-week periods (Fig. 1). The rationale for this
design was to determine the lowest possible dose that was
J Autism Dev Disord
effective and well tolerated. The child was initially given
1 mg (4 ml) melatonin for 3 weeks. If a satisfactory
response occurred, defined as falling asleep within 30 min
in five or more nights/week (for at least one of the weeks)
as documented by actigraphy, melatonin was continued at
its current dose until the end of the 14 week dosing period.
If a satisfactory response did not occur at the 1 mg dose,
melatonin was increased to 3 mg for 3 weeks. If a satis-
factory response did not occur at the 3 mg dose, melatonin
was increased to 6 mg for 3 weeks. If a satisfactory
response did not occur at the 6 mg dose, melatonin was
increased to 9 mg for 3 weeks. In the last 2 weeks of the
dosing period, the child remained on the dose at which the
satisfactory response occurred.
Monitoring for Adverse Effects
Parents were asked to review the Hague Side Effects Scale
(Carpay et al. 1996) each week throughout the 14-week
dosing period. They were called at the end of each week by
the study coordinator, and during the call, responses on the
scale was reviewed with them.
All children wore the AW-64 Actiwatch?device (Phillips
Respironics, Bend, OR) during the 17-week protocol
(1 week of baseline, 2 weeks of acclimation, and 14 weeks
of melatonin dosing; Fig. 1). Each device contains an
accelerometer, which detects motion and translates it into
an electrical signal, stored in memory within the devices as
actigraphy counts. The devices were configured using a
one-minute epoch with medium threshold and the validated
software (Phillips Respironics 2010) algorithm was used to
estimate sleep parameters, based on thresholds for wake
and sleep, as described in prior work (Kushida et al. 2001;
Lichstein et al. 2006; Mezick et al. 2009).
During the training session, the parent and child were
introduced to the actigraphy device for placement on the
non-dominant wrist. Parents were given a quiz to test their
knowledge of the actigraphy device. The parent completed
a daily sleep diary throughout the 17-week protocol to
assist in interpretation of actigraphy data and was also
asked to use the event marker present on the device to mark
lights out (the time that the child first attempted to fall
asleep). Children who had difficulty tolerating the device
on the wrist were allowed to use an alternate validated
method which consisted of placing the device on a non-
dominant shoulder location (Souders et al. 2009; Adkins
et al. in press).
Parent-Completed Survey Forms
Parents completed a battery of surveys to determine the
ability of questionnaires to detect change with intervention.
The battery was completed at the beginning of the study
and a second time at the conclusion of the study inter-
vention procedures. These survey forms included the
Children’s Sleep Habits Questionnaire (CSHQ), the Child
Behavior Checklist (CBCL), The Repetitive Behavior
Scale-Revised (RBS-R), and the Parenting Stress Index
Short Form (PSI-SF).
The CSHQ (Owens et al. 2000) was included as a par-
ent-reported measure of sleep to complement the objective
measurement obtained by actigraphy. We hypothesized
that the CSHQ insomnia-related domains would be more
likely to improve with melatonin than the non-insomnia
domains (e.g., sleep related breathing, parasomnias). The
CSHQ was initially validated in ages 4–10 years (Owens
et al. 2000) and subsequently validated in younger ages
(Goodlin-Jones et al. 2008). A higher score indicates more
difficulty with sleep.
The CBCL (Achenbach and Rescorla 2001a, b) was
included as a parent-reported measure of daytime behavior.
Because separate CBCL forms spanned the age range of
our participants (one for ages 1?–5 years and one for ages
6–18 years), we included scales common to both forms
which we believed might improve after improvement in
sleep with supplemental melatonin, based on the available
literature (Hollway and Aman 2011). These included the
syndrome scales of anxious/depressed, withdrawn, atten-
tion problems, and aggressive behavior, and the Diagnostic
and Statistical Manual (DSM) scales of affective problems,
attention-deficit hyperactivity, and oppositional defiant
disorder. The CBCL contains modules for ages 2–5 years
(Achenbach and Rescorla 2001a) and 6–18 years (Achenbach
and Rescorla 2001b). A higher score indicates more diffi-
culty with behavior.
Fig. 1 Optional escalation study design. After the baseline and
acclimation (inert liquid) phases, supplemental melatonin was
increased if the child did not exhibit a satisfactory response, defined
as a sleep latency of 30 min or less on five or more nights in any given
week within the 3 weeks dosing period. In the last 2 weeks of the
dosing period, the child remained on the dose at which the
satisfactory response occurred
J Autism Dev Disord
The RBS-R (Bodfish et al. 2000) was included as a
parent-reported measure of repetitive behavior and restric-
ted interests that include the following behavioral sub-
scales: stereotyped, self-injurious, compulsive, ritualistic,
sameness, and restricted. The RBS-R has been validated in
children (Lam and Aman 2007; Mirenda et al. 2010). A
higher score indicates more difficulty with behavior.
The PSI-SF (Abidin 1995) was included as a parent-
reported measure of parenting stress that yields a total
stress score from three scales: Parental Distress, Parent–
Child Dysfunctional Interaction, and Difficult Child. It has
been validated in children younger than 12 years. A higher
score indicates higher levels of parent stresss.
Parents were also asked to complete information about
their education and occupation to provide estimates of
socioeconomic status based on the Hollingshead Four
Factor Index of Social Status (Hollingshead 1975).
The Peabody Picture Vocabulary Test- III (PPVT-III; Dunn
1997) and The Kaufman Brief Intelligence Test- Second
Edition (K-BIT-2; Kaufman and Kaufman 2004) were used
to characterize the receptive language skills and verbal and
non-verbal cognitive functioning of our sample. Since the
KBIT-2 was designed for children 4 years of age and older,
it was not used for participants below this age group
Data were analyzed using SAS statistical software (version
9.1, SAS Institute Inc., Cary, NC) and SPSS statistical
software (version 19, SPSS Inc., Chicago, IL). Given that
this is a pilot study, in Tables 2 and 3, we present means,
standard deviations, and uncorrected p-values for all
parameters analyzed. However, to assist with selecting the
most robust measures for a larger controlled trial, we
interpreted our data conservatively by controlling family
wise error rate for the multiple measures. More specifi-
cally, as suggested in Westfall et al. (1999), we defined a
family of tests to be all the tests that formed a natural and
coherent unit (e.g., all items in a subscale of a question-
naire, or all the sleep parameters), and a more stringent
Table 1 Participant
SES = Socioeconomic status
based on Hollingshead four
factor index of social status,
PPVT = Peabody Picture
KBIT = Kaufman Brief
14 Male17.9 55 11597 731
28 Male 3450 119113 1243
34 Male19.144 8154 713
145 Male 17.445n/an/an/a3
J Autism Dev Disord
threshold for p-values (i.e. 0.05/number of tests in the
family) was used to determine statistical significance.
For each participant, average sleep parameters were com-
puted at each phase: baseline, acclimation dosing phase,
satisfactory dosing phase, and end of study dosing phase.
Within group comparison of the sleep parameters at dif-
ferent phases were then analyzed with the Wilcoxon
signed-rank test. This nonparametric test was used because
the outcomes measured do not necessarily follow the nor-
mal distribution. Our major outcome variable was sleep
latency. We also examined, as secondary outcome vari-
ables, total sleep time and sleep efficiency (total sleep time/
time in bed), and wake time after sleep onset. In Table 2,
since there were a total of 8 tests conducted for the set of
sleep parameters, we considered p-values of less than 0.05/
8 (or 0.006) to be significant.
Parent-Completed Survey Forms
For each participant, we compared the pre- and post-
treatment variables for each scale using the Wilcoxon
signed rank test. For the CSHQ (nine comparisons),
p-values of less than 0.0056 were considered significant.
Similarly, for the CBCL (seven comparisons), significance
level was set at 0.0071, for the RBS (six comparisons),
significance level was set at 0.0083, and for the PSI (three
comparisons), significance was set at 0.017.
Forty-six participants were enrolled in the study, and 24
completed all study procedures. Of the 22 children who were
melatonin for the following reasons–Eight children did not
have confirmatory diagnoses of ASD, six parents withdrew
because the protocol was too time-consuming, two were lost
falling asleep within 30 min on most nights (based on actig-
raphy), one child started medications, one child was Tanner
stage 2, and one child had elevated liver enzymes. Two chil-
separate research protocol, an EEG-polysomnogram done
prior to the initiation of melatonin showed evidence for an
epileptic seizure and interictal epileptiform activity. Melato-
nin was discontinued and the child was withdrawn from the
study. Our medical safety monitor and Institutional Review
Board reviewed this adverse event and determined it was not
related to melatonin treatment. A second child, who was
subsequently diagnosed with bipolar disorder, was unable to
method was not developed at the time of her testing) and did
study protocol up to 3 mg, and based on parent diary, the
child’s sleep did not improve with melatonin treatment. The
higher melatonin doses were not given based on the child’s
status was reevaluated. She was diagnosed with bipolar dis-
order, begun on respiridone, and both behavioral symptoms
did not complete post-intervention surveys;however,clinical
follow-up at one year indicated maintenance of the improve-
ment in sleep and psychiatric symptoms.
All children who completed the study tolerated actig-
raphy for the entire 17-week monitoring period, with
five requiring an alternative placement. There were no
Table 2 Sleep parameters
Sleep latency (minutes)38.2 42.921.622.5
Sleep efficiency (percent)74.675.0 76.579.3 0.0260.16
Wake time after sleep onset
Total sleep time (minutes)442.7450.1459.0457.30.0110.18
* Comparing satisfactory dosing phase to acclimation dosing. Significance was adjusted for multiple comparisons (0.05/number of comparisons
within a family of tests) with values meeting significance bolded
** Comparing end of study dosing phase to satisfactory dosing phase
J Autism Dev Disord
significant differences in sleep parameters between the
baseline and acclimation phase. Table 2 shows the sleep
parameters by study phase, and Fig. 1 illustrates the change
in sleep latency with melatonin treatment, which decreased
significantly with treatment (p\0.0001). The improve-
ment in sleep latency was maintained until the end of the
study. Analysis of sleep latency within the 1 and 3 mg
dosing periods showed that the satisfactory response was
achieved within the first week of treatment (i.e., the second
and third week sleep parameters were not significantly
different from the first week). Sleep duration, wake time
after sleep onset, and sleep efficiency were not significantly
different with melatonin treatment.
All 24 children who completed study procedures obtained a
satisfactory response (as defined above) to melatonin at
doses between 1 mg and 6 mg. Seven children obtained a
satisfactory response at 1 mg, 14 at 3 mg, and only 3
required 6 mg. The child’s age or weight was not associ-
ated with melatonin dose response. The mean age/weight
(standard deviation) of children responding to 1 mg was
5.9 (1.9) years/26.4 (11.1) kg; and to 3 or 6 mg was 5.9
(2.3) years/25.4 (11.2) kg.
Questionnaires (Table 3)
On the Children’s Sleep Habits Questionnaire (CSHQ), a
parent-based measure of sleep difficulties, the sleep onset
delay, sleep duration, and sleep total subscales improved
significantly after treatment with melatonin. Of note, sev-
eral subscales (e.g., parasomnia, sleep disordered breath-
ing) that would not be expected to improve with melatonin
treatment did not improve, suggesting that parents were not
Table 3 Parental report
On these scales, higher values
indicate more difficulties
* Comparing baseline phase to
end of study phase. Significance
was adjusted for multiple
comparisons (0.05/number of
comparisons within a family of
tests) with values meeting
Study phase, mean (SD)
Baseline End of study
Children’s sleep habits questionnaire
Bedtime resistance10.7 (4.2)8.3 (2.3)0.008
Sleep onset delay2.6 (0.6) 1.3 (0.6)
Sleep duration6.4 (1.8)3.7 (1.3)
Sleep anxiety 6.8 (1.9)6.3 (1.7)0.270
Night wakings5.3 (1.9)4.3 (1.4) 0.023
Parasomnias9.7 (2.0)9.2 (2.1) 0.780
Sleep disordered breathing 3.8 (1.2)3.5 (0.6)0.170
Daytime sleepiness 14.1 (2.4)12.6 (2.7) 0.129
Sleep total 55.2 (6.9)45.1 (4.7)
Child behavior checklist
Anxious/depressed59.1 (9.3)57.6 (7.8)0.129
Withdrawn 71.5 (9.3)66.0 (7.8)
Attention problems 65.6 (8.3)63.0 (9.3)0.069
Aggressive behavior 62.3 (11.5)60.0 (9.4)0.073
Affective problems69.2 (7.1) 60.8 (6.5)
DSM attention/deficit hyperactivity63.6 (8.2)60.4 (8.2)
DSM oppositional behavior62 (9.6)59 (8.3) 0.026
Repetitive behavior scale
Stereotyped6.6 (3.5)5.2 (3.1)
Self-injurious2.6 (2.9)2.1 (203)0.325
Compulsive7.1 (5.2)4.5 (3.7)
Ritualistic7.5 (4.5)5.5 (3.7)0.013
Sameness10.0 (6)7.6 (6.4)0.017
Restricted5.3 (3.4)4 (2.6)0.130
Parenting stress index
Parental distress32.4 (11.1) 30.3 (8.2)0.204
Parent–child dysfunctional interaction29.1 (9.0)25.9 (8.4)0.098
Difficult child41.3 (7.2)36.1 (7.0)
J Autism Dev Disord
answering indiscriminately that sleep difficulties has
improved (Fig. 2).
On the Child Behavior Checklist (CBCL), the with-
drawn, affective, and ADHD subscales improved signifi-
cantly after treatment with melatonin.
On the Repetitive Behavior Scale (RBS), the stereotyped
and compulsive subscales improved significantly after
treatment with melatonin.
On the Parenting Stress Index (PSI), the difficult child
subscale improved significantly after treatment with
No alterations in laboratory findings (CBC, metabolic
profile including liver and renal function, ACTH, cortisol,
estrogen, testosterone, FSH, LH, or prolactin) were noted
Adverse Effects and Tolerability
Only one child exhibited possible mild adverse effects
related to the melatonin preparation (loose stools). All
other children tolerated melatonin without difficulty.
In this open-label dose-escalation study of supplemental
melatonin, we found that (1) The majority of children
responded to a 1 or 3 mg dose given 30 min before bedtime
with an improvement in sleep latency; (2) This improve-
ment 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
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 min 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 fash-
ion, with reference to a side effects scale and laboratory
testing. In agreement with a retrospective review of 107
children with ASD (Andersen et al. 2008), side effects
We also documented that actigraphy can be used suc-
cessfully 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 com-
plemented 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 stan-
dard 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-con-
trolled studies in ASD that reported quantitative data (5
studies, 57 participants total), comparing melatonin treat-
ment 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 actigra-
phy, showed significant improvement with melatonin
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
controlled trials using
Fig. 2 Change in sleep latency with melatonin treatment. Median
sleep latency (y-axis) in minutes was measured by actigraphy at four
different time points: a baseline phase; b acclimation phase (weeks
1–2) when child received inert liquid; c stabilizing dose phase, the
first three-week period when child’s sleep latency was less than
30 min for 5 or more nights in at least one of the weeks; and d end of
study dose phase, the last 2 weeks of treatment. The lines in the box
plot correspond to maximum, 3rd quartile (75th percentile), median,
1st quartile (25th percentile) and minimum. The asterisk (*) indicates
that the median sleep latency in the acclimation phase was
significantly different than in the stabilizing dose or end of study
dose phase (p\0.0001)
J Autism Dev Disord
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. Alter-
natively, 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
The behavioral outcome measures that showed change
with melatonin (e.g., attention-deficit hyperactivity, with-
drawn, affective problems, stereotyped behaviors, com-
pulsive 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 behav-
ior, 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 et al. 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) sug-
gesting 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, elimi-
nating any concerns about the impact of intellectual dis-
ability. 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 gen-
eralizable to the autism population with sleep-onset delay,
in which some children are taking medications (e.g., anti-
depressants and stimulants) which interfere with sleep or
with hepatic enzymes (CYP1A2) that metabolize melato-
nin. 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.
HD59253), Autism Speaks, Vanderbilt General Clinical Research
Center (M01 RR-00095 from the National Center for Research
Resources, National Institutes of Health), and by the Vanderbilt
University Kennedy Center (NICHD HD15052). Natrol?, (Chats-
worth, CA) provided study drug but no other support. Dr. Shlomo
Shinnar provided valuable input into the study design and
Dr. Gregory Barnes served as the medical safety monitor. We
acknowledge Ms. Kyla Surdyka and Ms. Meg Touvelle for their
assistance with data entry, and are appreciative to the families who
participated in this project.
This work was supported by NICHD (RO1
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