J. Sleep Res.

(2012) Regular Research Paper

Controlled-release melatonin, singly and combined with cognitive

behavioural therapy, for persistent insomnia in children with
autism spectrum disorders: a randomized placebo-controlled trial
FLAVIA CORTESI, FLAVIA GIANNOTTI, TERESA SEBASTIANI,
SARA PANUNZI and DONATELLA VALENTE
Department of Pediatrics and Developmental Neuropsychiatry, Center of Pediatric Sleep Disorders,
University of Rome La Sapienza, Italy SUMMARY
Although melatonin and cognitive–behavioural therapy have shown efficacy in
treating sleep disorders in children with autism spectrum disorders, little is
Keywords
known about their relative or combined efficacy. One hundred and sixty
actigraphy, autism spectrum disorders, cognitive–
behavioural therapy, insomnia, melatonin children with autism spectrum disorders, aged 4–10 years, suffering from sleep
onset insomnia and impaired sleep maintenance, were assigned randomly to
Correspondence either (1) combination of controlled-release melatonin and cognitive–
Flavia Cortesi MD, Center of Pediatric Sleep behavioural therapy; (2) controlled-release melatonin; (3) four sessions of
Disorders, Department of Pediatrics and
cognitive–behavioural therapy; or (4) placebo drug treatment condition for 12
Developmental Neuropsychiatry, University of
Rome La Sapienza, via dei Sabelli 108, 00185 Rome, weeks in a 1 : 1 : 1 : 1 ratio. Children were studied at baseline and after 12
Italy. Tel.: +390644712293; fax: +39064957857; e- weeks of treatment. Treatment response was assessed with 1-week
mail: flavia.cortesi@uniroma1.it actigraphic monitoring, sleep diary and sleep questionnaire. Main outcome
measures, derived actigraphically, were sleep latency, total sleep time, wake
Accepted in revised form 5 April 2012; received 9
January 2012
after sleep onset and number of awakenings. The active treatment groups all
resulted in improvements across all outcome measures, with moderate-to-
DOI: 10.1111/j.1365-2869.2012.01021.x large effect sizes from baseline to a 12-week assessment. Melatonin treatment
was mainly effective in reducing insomnia symptoms, while cognitive–
behavioural therapy had a light positive impact mainly on sleep latency,
suggesting that some behavioural aspects might play a role in determining
initial insomnia. The combination treatment group showed a trend to
outperform other active treatment groups, with fewer dropouts and a greater
proportion of treatment responders achieving clinically significant changes
(63.38% normative sleep efficiency criterion of >85% and 84.62%, sleep onset
latency <30 min). This study demonstrates that adding behavioural
intervention to melatonin treatment seems to result in a better treatment
response, at least in the short term.

may predispose children with ASD to intrinsic stressors that

threaten sleep.

INTRODUCTION

Autism spectrum disorders (ASD) are lifelong neurodevelopmental
disorders, characterized by markedly abnormal or impaired social
interaction and communication, restricted interests and
stereotypical behaviours. Core deficits of ASD and their underlying
neurophysiology and neurochemistry According to available
studies, sleep disorders, consisting mainly of problems of
sleeplessness, have been reported clinically in an estimated 40–
80% of children (Honomichl et al., 2002; Krakowiak et al., 2008;
Souders et al., 2009). Although sleep disorders often remain
untreated in ASD, the severity and frequency of these disorders

1
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2 F. Cortesi et al.
associated with high levels of maternal stress, negative attitudes
to the child and increased rates of child behaviour problems and
autistic symptoms suggest the need for effective intervention
(Williams et al., 2004).
There is increasing evidence that sleep disorders in children with
ASD are associated with disrupted melatonin (MLT) secretion
(Kulman et al., 2000; Melke et al., 2008; Tordjman et al., 2005).
Thus, several studies suggested the use of melatonin for sleep
problems of children with neurodevelopmental disabilities (Braam
et al., 2008; Garstang and Wallis, 2006; Giannotti et al., 2006;
Wasdell et al., 2008; Wright et al., 2011).
However, sleep problems might occur as a result of complex
interactions between biological, psychological, social ⁄
environment and family factors, including child-rearing practices
that are not conducive to good sleep (Richdale and Schreck, 2009).
It has been reported that ASD children often display a preference
for unusual bedtime routines which may be maladaptive in terms
of promoting good sleep (Henderson et al., 2011). The increasing
recognition of the mediating role of behavioural factors in
insomnia has led to the development of non-pharmacological
interventions for clinical management in this population.
A recent literature review of behavioural interventions for sleep
problems in ASD children concluded that they have been
considered efficacious in treating sleep onset and maintenance
problems (Vriend et al., 2011). However, only small studies or case
reports have been performed, with inclusion of children having a
variety of diagnoses, not limited to ASD, and without collection of
objective sleep data.
There are efficacious approaches to behavioural interventions in
children with neurodevelopmental disabilities (Moon et al., 2011;
Weiskop et al., 2005), and as suggested by Vriend et al. (2011):
promoting positive sleep hygiene when combined with standard
extinction is likely to improve problems initiating and maintaining
sleep in children with ASD.
To our knowledge, no studies have compared directly the
efficacy of melatonin and cognitive–behavioural therapy (CBT),
singly or combined, for sleep disorders in children with ASD.
Study objectives were, first, to determine the relative efficacy of
the three active treatments with placebo, and secondly to
compare the combination therapy with either melatonin or CBT
alone. We hypothesized that all three active treatments would be
superior to the placebo, and that combination therapy would be
superior to either melatonin or CBT alone.
METHOD
Participants
Patients were referred from 2007 to 2010 to the Department of
Pediatrics and Developmental Neuropsychiatry, University of
Rome La Sapienza.
Inclusion criteria were: (i) age 4–10 years; (ii) DSM-IV-TR
diagnosis of Autistic Disorder confirmed by the Autistic Diagnostic
Interview–revised (ADI-R) (Lord et al., 1994) and the Autism
Diagnostic Observation Schedule–generic ADOSG (Lord et al.,
2000); (iii) mixed sleep onset and maintenance insomnia, defined
as a sleep onset latency (SOL) and wake after sleep onset (WASO)
>30 min that occurred on 3 or more nights a week. We chose these
criteria because most statements about pathological SOL and sleep
maintenance in children define a cutoff of 20–30 min. As sleep
patterns change with age, we recruited subjects in a narrow age
range, avoiding the pitfall of many studies that included a wide
range of age. These criteria had to be fulfilled 3 months prior to
screening and again during the 14-day run-in period of parental
daily recording of sleep data; and (iv) absence of other serious
neurological, psychiatric or medical conditions. In order to rule out
associated pathologies and structural alterations of the central
nervous system, high-resolution banding karyotype, brain
magnetic resonance imaging and neurometabolic screening, multi-
modal evoked responses and prolonged awake and sleep
electroencephalography (EEG) recordings were performed. No
subjects were obese and parents did not report breathing
disturbances during sleep or periodic limb movement disorders at
the time of the study. All subjects were drug-free for at least 6
months prior to the beginning of the study and throughout the
study. In order to exclude the associated behaviours and
psychiatric comorbidities seen frequently in ASD children, parents
completed the Child Behavior Checklist (CBCL; Achenbach and
Rescorla, 2000) during the initial screening. Children reporting a T-
score ±70 on any of the syndrome scales and three composite
scales were not included in this study. Children currently in
psychotherapy or receiving other behavioural interventions, as
well as families currently in family therapy, were not enrolled.
Measures
Sleep behaviour was assessed using the Childrens Sleep Habits
Questionnaire (CSHQ) (Owens et al., 2000) a 33-item parent
questionnaire. It includes items relating to a number of key sleep
domains grouped conceptually into subscales reflecting: (i)
bedtime resistance; (ii) sleep onset delay; (iii) sleep duration; (iv)
sleep anxiety; (v) night-wakings; (vi) parasomnias; (vii) sleep-
disordered breathing; and (viii) daytime sleepiness. A higher score
is indicative of more disturbed sleep. In the present study, the
CSHQ showed adequate internal consistency (Cronbachs alpha
0.80).
Each child was monitored with an actigraph in the zero crossing
mode from the Ambulatory Monitoring Inc. (Ardsley, NY, USA).
Actigraphy, a non-invasive method used to study sleep–wake
patterns by assessing movement, provides continuous monitoring
of activity level that can be translated to valid estimates of sleep–
wake measures. Sleep–wake cycles were scored with the Action W
software program. Information is accumulated over a fixed 1-min
time interval, considered as an epoch. Sleep epochs were
determined based on the Sadeh algorithm. It was highly
recommended that parents recorded simultaneously a sleep diary
to edit the actigraphic data for potential artefacts and failures. If
parents noted on the sleep diary that their child was sick or had an
unusual night, the nights data were discarded and a minimum of 7
nights were necessary to obtain reliable data. Sleep measurements
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obtained through actigraphy were SOL (time from the parents note
of lights out to the actigraphically measured first sleep onset), total
duration of sleep (actual sleep time, excluding sleep latency and
wakening after sleep onset), number of night-wakings and WASO.
The number of night-wakings was scored manually and defined as
at least 5 min in duration per episode. Sleep efficiency [SE, the ratio
of total sleep time (TST) to total time in bed · 100] was also
calculated.
The sleep diary is a standardized weekly form that asks the
parents to note specific sleep-related events on a daily basis. At
bedtime, and during night-wakings of which parents were aware,
the parents were instructed to check on the child every 5 min to
track whether he or she was awake or asleep, otherwise they
noted their childs sleep in 30-min time blocks.
Trial design
After baseline assessment, participants were assigned randomly to
one of four conditions. Randomization was performed using a
computer-generated schedule independent of treatment
personnel. Subjects in the melatonin and placebo groups did not
know they were receiving active therapy, nor did their clinicians.
Participants underwent 7 consecutive nights of actigraphic
evaluations at baseline and at 12-week reassessment. Similarly,
CSHQ and sleep diary were completed at baseline and
readministered after 12 weeks of treatment. For safety reasons,
haematological parameters were monitored exclusively at
baseline and at 12-week assessment.
Sample size was determined on the basis of the ability to detect
a difference of at least 30 min [standard deviation (SD) 45] in
actigraphically recorded total sleep time between four treatment
groups from baseline to the 12-week assessment. A sample size of
32 subjects in each group (yielding a total number of 128) provided
90% power to detect an effect size of 0.6667 among the four
groups. These calculations were based on an alpha of 0.05.
Assuming a 25% dropout rate, we planned to recruit 160 children.
They were enrolled and assigned randomly to melatonin (40), CBT
(40), combined melatonin and CBT (40) or placebo (40).
The treatment protocol was described in detail and written
informed consent was obtained.
Intervention
Cognitive–behavioural therapy
Building upon previous research (Montgomery et al., 2004;
Weiskop et al., 2005), a treatment program was designed to
reduce insomnia in ASD. After the baseline evaluation, each family
receiving CBT attended four weekly individual treatment sessions,
each lasting approximately 50 min, and administered at the
outpatient university clinic. Treatment consisted of a sleep-
focused multi-factorial intervention that involved cognitive,
behavioural and educational components. The cognitive
component was focused to help recognize distorted sleep
cognition, and aimed at changing dysfunctional beliefs and
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Efficacy of melatonin singly or with CBT in ASD 3
attitudes about sleep. The behavioural and educational
components consisted of a set of oral instructions about
management of a childs sleep, identification of patient-specific
maladaptive sleep condition and implementation of methods for
replacing poor sleep habits with more appropriate behaviours
(Table 1).
CBT sessions were led by experienced clinical psychologists, and
all sessions were audiotaped and reviewed with principal
investigators to ensure adherence to protocol. Treatment
completion was defined using a minimum adequate trial cutoff
(baseline and at least two treatment sessions).
Melatonin
Participants assigned to the melatonin group were given orally a 3-
mg controlled-release (CR) dose of melatonin and administered at
approximately 21:00 h. Dose changes were not permitted. In Italy
melatonin is not a licensed drug, and it is sold as a food supplement
in a variety of preparations.
However, the product used in this study contains a highpurity
melatonin preparation (99.9%), formulated to provide
Table 1 Cognitive–behavioural therapy (CBT)
Session 1 Provided general information about nature, function
and regulation of sleep, sleep need and the
differentiation of normal and pathological sleep
changes. The importance of sleep, good sleep habits
and sleep as a learned behaviour were
explained to parents
Session 2 Parents were instructed to create a consistent sleep
schedule, to avoid long and late napping, to establish a
positive bedtime routine, including parent and child
engaging in enjoyable activities before the child went
to bed; to allow the child to fall asleep alone in his ⁄ her
bed (awake but drowsy); to allow the child to sleep in
his ⁄ her bed for the whole night. Parents were
instructed to limit their involvement in the sleep
initiation process gradually, to avoid physical contact
and gradually increase the interval length of their
interventions
Session 3 Entailed reviewing instructions, identification of
individual difficulties, implementation of methods for
replacing the remaining maladaptive sleep behaviours
with more appropriate sleep habits
Session 4 Reviewed therapy instructions and provided
information on prevention of insomnia relapse
Additionally, parents attended twice-monthly individually tailored
CBT sessions. The focus of maintenance sessions was on consolidating
treatment strategies learned during initial therapy and developing
methods for coping for residual insomnia.
1-mg fast-release and 2-mg controlled-release (CR)-melatonin
over a prolonged 6-h period after ingestion (Armonia Retard 3 mg;
Nathura, Montecchio Emilia, Italy). This product has been regularly
registered in the list of food supplements of the Italian Ministry of
Health (cod. 08 29284 Y).
We used CR-melatonin because of its advantage for
multidisabled patients who experienced sleep maintenance
4 F. Cortesi et al.
problems (Garstang and Wallis, 2006; Giannotti et al., 2006;
Wasdell et al., 2008). No behavioural recommendations regarding
sleep were given during these short meetings and the main focus
was on encouraging participation. Participants met at the
outpatient clinic every 2 weeks for a 15-min meeting to report
adverse effects and to obtain the dosage pills for the following 2
weeks.
Placebo
Participants in this group were treated according to a protocol
identical to those receiving active medication. As with melatonin,
the placebo was made in the identical formulation, and there were
no differences in appearance, smell or flavour between the active
and inactive pills. An active treatment was offered after the12-
week assessment.
Combined CBT and melatonin
Participants in this group received both melatonin and CBT.
Parent-reported adherence
To assess compliance with CBT recommendations, parents were
asked how many days per week they followed elements of the CBT
regimen. Children who missed taking more than 20% of the
medication and who did not follow the CBT recommendation were
considered non-compliant. In all groups, an 80% compliance rate
was required for continued participation in the study.
The study protocol was approved by the ethics committee of the
University La Sapienza of Rome.
Outcome measures and clinical significance of changes
The primary outcomes were the between-group differences in the
mean change from baseline to endpoint, including TST, SOL, SE and
WASO, as inferred from the actigraph data.
These variables were averaged over 7 nights for each
assessment phase. Furthermore, to assess the clinical significance
of these changes, we utilized Morin et al. criteria (1999) examining
group differences in rates of percentage of patients achieving a
SOL of 30 min or less, or a reduction of SOL by 50% and a SE in the
normative level of >85%.
Statistical analysis
We coded and computerized all data and performed statistical
analysis using the statistica version 10 package for Windows
(StatSoft Inc., Tulsa, OK, USA).We calculated descriptive statistics
(mean ± SD) for all continuous variables and frequencies which
were generated for non-continuous variables. Pearsons
correlation was calculated to determine the baseline level of
association between parent-completed somnologues and
actigraph-generated sleep measures. Analysis of variance or
Pearsons v2 tests were used to examine demographic and clinical
variables at pre-treatment. Bonferroni adjustments of the P-values
(alpha level of significance set to 0.05) were performed due to the
multiple comparisons. The Bonferroni adjustments were as
follows: nine component measures of both CSHQ 0.05 ⁄ 9 = 0.005,
and four actigraphically derived variables 0.05 ⁄ 4 = 0.01.
Before analysis, log-transformations were performed on
variables to normalize distribution. To reduce the likelihood of type
1 error, Greenhouse–Geisser correction, which adjusts the
numerator and denominator degrees of freedom in repeated-
measures designs, was applied.
A repeated-measure analysis of variance (rm-anova), adjusted
for baseline mean values, was performed to determine whether or
not there was a difference in response among treatments, using
time and treatment (as a predictor of outcome) using the groups
as the between-subject factors comprising four levels and the time
as the within-subject factors comprising two levels to determine
differences over time for the principal outcome measures. Because
of developmental changes, we included also age and sex as
covariates. Post-hoc comparisons between groups were
performed using the Sheffe´ test. Effect sizes were judged
according to the following commonly used cutoffs: r = 0.10 small
effect, r = 0.30 medium effect and r = 0.50 large effect. We also
examined group differences in rates of clinically significant
improvement as assessed by the percentage of participants
achieving a normal sleep status at the 12-week assessment on
actigraphic data using the two-tailed Fishers exact test.
RESULTS
More than 185 children met inclusion criteria. One hundred and
sixty patients were randomized; of these, 144 completed the
study, but only 134 were suitable for analyses (Fig. 1). Thus, the
results are based on the following subjects: 35 in the combined
therapy, 34 in MLT, 33 in CBT and 32 in the placebo condition.
Notably, there were no significant differences in the demographic
or clinical variables between subjects who completed the study
and those who dropped out.
The average reported duration of insomnia was 2.4 years (SD =
1.7) and 72% of the patients had had symptoms for longer than 2
years. Analyses of sleep diaries show a significant correlation with
actigraph measures of total sleep time (r = 0.75), sleep latency (r =
0.83) and WASO
(r = 0.70).
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Analyses of variance were conducted on the baselinedependent
Figure 1. Consort diagram showing participant
flow through the study and reasons for dropout.
actigraphic and CSHQ measures. anovas were not significant, and
reflected that all the dependent measures were similar across the
conditions at pre-treatment. In addition, demographic variables
were examined with anova and chi-square tests. Again, the four
groups did not vary significantly, indicating that the groups were
equivalent at entry into the study (Table 2).
Using SOL, total sleep time, WASO and sleep efficiency as
dependent measures, rm-anovas yielded significant time effects
and significant group · time interaction effects for all measures
(Table 3). Post-hoc comparisons revealed that subjects in all three
active groups were more improved than those in the placebo
condition at the 12-week assessment (P > 0.01). However, the data
suggest a trend for the combination group to yield greater
improvement rates than either of its single components (Table 3,
Fig. 2).
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Efficacy of melatonin singly or with CBT in ASD 5
The same pattern of results were obtained for CSHQ scores,
which showed all treated children as more improved in most of the
CSHQ subdomains, except for parasomnias and sleep-disordered
breathing scales, than those in the placebo condition (Table 4).
Similarly to the actigraphic results, post-hoc tests confirmed
further that those in the combination group generally improved
more than did those in the melatonin group, followed by the CBT
group.
However, it should be noted that melatonin therapy alone was
more effective than CBT alone in improving bedtime resistance,
sleep onset delay, night-wakings and sleep duration subscales. CBT
alone seemed to be slightly more effective in reducing sleep
anxiety subscale. The effect sizes for all significant comparisons fell
into the medium–high range. From covariance analysis, it
appeared that neither gender nor age influenced sleep
significantly.
6 F. Cortesi et al.
Finally, the percentage of children who met a standard sleep
criterion of SOL 30 min or less or reduction of SOL by 50% at the
12-week assessment was at 84.62% for the combination group,
39.29% for the MLT group and 10.34% for the CBT group. As
expected, none of the children in the placebo group met this
criterion. There were significantly more patients in the
combination group versus the MLT group (P < 0.01) and versus the
CBT group (P < 0.001) who met this criterion, and there were
significantly more participants in the MLT group than in the CBT
group (P < 0.01) that also met the same criterion.
Moreover, the percentage of participants who obtained 85% or
more on SE at post-treatment was 63.38% for the combination
group, 46.43% for the MLT group and10.34% for the CBT alone
group (respectively, <0.001 and <0.01). None of the children in the
placebo group met this criterion.
Melatonin was well tolerated, and no adverse effects were
reported or observed; blood tests and urinanalysis showed no
abnormalities and no one had to discontinue the study because of
side effects. Moreover, none of the parents reported a loss of
response of the child during the treatment period.
DISCUSSION
The results of this large, randomized placebo-controlled 12week
trial show effectiveness of both CR-melatonin and CBT in the
treatment of sleep insomnia in ASD children. Those who received
active treatment were able to maintain sleep more efficiently than
those in the placebo group. However, of the three active
treatments, melatonin in combination with CBT was the most
effective in reducing insomnia symptoms, followed by the MLT
alone and then the CBT group compared to the placebo group.
maintenance. However, combining CBT and CRmelatonin produce
additional improvement.
Because the choice of treatment should be based on the childs
sleep disorders, it is important to identify the causes underlying
the problem. There are multiple hypotheses for intrinsic causes of
sleep disorders in children with ASD. The most robust evidence is
related to abnormal melatonin rhythms and peaks (Bourgeron,
2007). Several investigators have identified abnormal melatonin
levels in individuals with ASD (Kulman et al., 2000; Melke et al.,
2008; Tordjman et al., 2005). According to other studies (Doyen et
al., 2011; Giannotti et al., 2006; Wasdell et al., 2008; Wright et al.,
2011), our results confirm the efficacy of exogenous melatonin in
treatment of sleep disorders in ASD children.
No consensus on the optimal doses of melatonin to promote
sleep in children has been established. In a recent open-label
escalation study, Malow et al. (2011) reported that in most ASD
children 1–3 mg of supplemental melatonin was well tolerated and
also improved sleep latency.
In our study, a dose of 3 mg was effective and safe and no
adverse effect were reported. It is important to note that we used
a CR formulation, which promotes sleep for 6–8 h and was thus
also effective in maintaining sleep. Consistent with previous
studies (Garstang and Wallis, 2006; Giannotti et al., 2006; Wasdell
et al., 2008), our results showed that in all cases melatonin
improved sleep and children showed a more regular and
appropriate bedtime and a longer sleep duration with a significant
reduction of night-wakings.
However, sleep insomnia, which represents the most
predominant sleep disorder in children with ASD (Richdale and
Schreck, 2009; Williams et al., 2004), may also be due to

Table 2 Summary of demographic characteristics for the 160 patients assigned randomly to treatment
v2 ⁄ anova

COMB MLT CBT PL P

Age, years (SD) 6.4 (1.1) 6.8 (0.9) 7.1 (0.7) 6.3 (1.2) 0.82

Male sex (%) 80 82 83 84 0.99

Ethnicity
White Causasian (%) 100 100 100 96 0.34
Low SES* (%) 24 25 23 26 0.84
Primary caregiver sex (female) (%) 96 92 93 91 0.82
Mother
Age, years (SD) 33.7 (6.6) 32.9(4.9) 35.7 (6.3) 34.8 (5.7) 0.79
Marital status (married %) 92 86 93 88 0.76
Education, years (SD) 13 (4) 14 (7) 13 (6) 13 (5) 0.91
*
Low socioeconomic status (SES) was defined as an index of 3 or less on the Hollingshead Two-Factor Index of Social Position, which ranges from 1 to
5, based on the education and occupation of the head of the household. anova, analysis of variance; COMB, combination; MLT, melatonin; PL, placebo;
SD, standard deviation.
Our findings report the efficacy of CR-melatonin in initiating and inadequate sleep practices and behavioural aspects (Wiggs and
maintaining sleep. In this study CBT improved sleep latency Stores, 2004). In this clinical population, long-standing sleep
slightly, but it was less effective in reducing impaired sleep problems of settling and night-wakings often become

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8 F. Cortesi et al.
greatest number and percentage of responders in the
combination treatment group achieve a clinically significant
change (63.38% of children with normative SE criterion of >85%
and 84.62% of children with a SOL <30 min). In addition, this group
produced fewer treatment dropouts than under other treatment
conditions.
The results achieved after short-term melatonin treatment
singly or in combination are notable because of the baseline
severity and chronicity of insomnia in the current study group.
Obtaining these remission rates for combination and MLT alone
groups within 3 months is remarkable.
In conclusion, our results extend those of previous
investigations, which studied the efficacy of melatonin alone,
either in fast or in the CR formulation (Garstang and Wallis, 2006;
Giannotti et al., 2006; Wasdell et al., 2008) or CBT alone
Figure 2. Sleep onset latency at baseline and at 12-week assessment (Montgomery et al., 2004; Moon et al., 2011; Weiskop et al., 2005)
repeated-measure analysis of variance (F(3, 109) = 59.632, P = 0.001. Vertical in the treatment of sleep insomnia in children with ASD. The
bars represent 95% confidence intervals.
observed advantage of combination therapy over either CBT or
melatonin alone suggests that among these effective therapies,
engrained habits. The presence of unusual and non-functional
combination therapy provides the best chance for a positive
routines common in children with ASD may result in bedtime
outcome. Thus, in agreement with Wirojanan et al. (2009), our
resistance and settling difficulties (Richdale and Schreck, 2009;
results suggest that melatonin can be considered a safe and
Richdale and Wiggs, 2005).
effective treatment in combination with behavioural therapies
Healthy sleep practices also promote sleep and enhance sleep
and sleep hygiene practices for the management of sleep
regulation by reducing environment stimulation and behavioural
disorders in children with ASD. The superiority of combination
sleep conditioning, which reinforce the association of certain
therapy is due most probably to additive or synergistic effects of
activities and environments with sleep, limit wake-promoting
the two treatments.
activities and may play a crucial role in sleep promotion.
Some limitations of this study should be taken into account.
Consistent with previous studies (Montgomery et al., 2004; Moon
First, this trial assessed only the effects of the 12-week treatment,
et al., 2011; Weiskop et al., 2005), our results show that
failing to assess mid- and long-term efficacy and treatment gain
behavioural intervention alone, even though less effective than
after withdrawal. Therefore, we do not know exactly when the
melatonin, improved sleep mainly by reducing SOL. As already
positive response to treatments appeared and whether or not it
reported, the action of behavioural treatment seems to be mainly
would persist during a long-term period. However, in order to
on the behavioural components of sleep disorders rather than on
obtain better compliance in this population, which may display
the sleep pattern itself. CBT seems to promote good sleep, as
non-compliant or avoidant behaviour, and whose parents
suggested by Jan et al. (2008), entraining intrinsic circadian
experienced more stress, we decided to conduct just one post-
rhythms to the external environmental and 24h day ⁄ night cycle,
baseline evaluation. In fact, this study had a low discontinuation
reducing environmental stimulation and decreasing anxiety by
rate of 10%. Moreover, we did not measure melatonin salivary and
means of appropriate bedtime routine activities.
plasma level or its urinary metabolite before and during the
Recently, Henderson et al. (2011) investigated the relationship
treatment; thus, in this study we cannot correlate the efficacy of
between consistent bedtime routine and sleep quality in children
melatonin with the presence of an eventual melatonin deficit.
with ASD and showed that the ASD group had less consistent
Secondly, the findings cannot be generalized to patients who have
general routines, lower sleep quality and higher levels of
disorders that were excluded from our protocol. Thirdly, parents
externalizing behaviour.
had agreed to comply with the treatment regimen, which implies
A consistent sleep ⁄ wake schedule may be particularly
a motivation that may not be present in all cases. Therefore, the
important for ASD children, as they are vulnerable to both sleep
present results may be biased and could over- or underestimate
and circadian rhythm disruptions. However, sleep hygiene
the efficacy of the treatments. Finally, sleep disorders such as
practices and CBT by themselves are not sufficient enough to treat
obstructive sleep apnoea syndrome or periodic limb movements
insomnia adequately in these children.
were ruled out clinically, but no pre-screening with gold standard
In our study, there was a significant trend for the combination
polysomnography was performed, so we cannot exclude that
group to produce higher improvement on sleep continuity and
some of these patients may have been enrolled into the study.
efficiency than in either melatonin or CBT groups with the
Limitations notwithstanding, this study confirms that melatonin
strongest treatment response. Our results indicate that the
and CBT in combination or as monotherapies appear

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F. Cortesi et al.
to be effective for these commonly occurring sleep disorders in
children with ASD. The results confirm those of previous studies of
melatonin and CBT and, most importantly, show that together
they offer children the best chance of a positive outcome.
Our findings indicate that all three treatment options may be
recommended, taking into consideration the familys treatment
preferences, treatment availability, cost and time burden. Further
analysis of predictors and moderators of treatment response,
assessing a long-term effect, may identify who is the most likely to
respond to which of these effective alternative. The extent and
eventual clinical utility of these approaches should be evaluated
by other studies using long-term follow-up and controlling for
several confounding factors.
DISCLOSURE STATEMENT
No conflict of interest, no financial support.
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ª 2012 European Sleep Research Society