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,
S A R A P A N U N Z I and D O N A T E L L A V A L E N T E
Department of Pediatrics and Developmental Neuropsychiatry, Center of Pediatric Sleep Disorders,
University of Rome ÔLa SapienzaÕ, Italy

Keywords
actigraphy, autism spectrum disorders,
cognitive–behavioural therapy, insomnia,
melatonin
Correspondence
Flavia Cortesi MD, Center of Pediatric Sleep
Disorders, Department of Pediatrics and
Developmental Neuropsychiatry, University of
Rome ÔLa SapienzaÕ, via dei Sabelli 108, 00185
Rome, Italy.
Tel.: +390644712293;
fax: +39064957857;
e-mail: flavia.cortesi@uniroma1.it
Accepted in revised form 5 April 2012; received
9 January 2012
DOI: 10.1111/j.1365-2869.2012.01021.x
SUMMARY
Although melatonin and cognitive–behavioural therapy have shown
efficacy in treating sleep disorders in children with autism spectrum
disorders, little is known about their relative or combined efficacy. One
hundred and sixty children with autism spectrum disorders, aged
4–10 years, suffering from sleep onset insomnia and impaired sleep
maintenance, were assigned randomly to either (1) combination of
controlled-release melatonin and cognitive–behavioural therapy;
(2) controlled-release melatonin; (3) four sessions of cognitive–behavio-
ural therapy; or (4) placebo drug treatment condition for 12 weeks in a
1 : 1 : 1 : 1 ratio. Children were studied at baseline and after 12 weeks
of treatment. Treatment response was assessed with 1-week actigraphic
monitoring, sleep diary and sleep questionnaire. Main outcome mea-
sures, derived actigraphically, were sleep latency, total sleep time, wake
after sleep onset and number of awakenings. The active treatment
groups all resulted in improvements across all outcome measures, with
moderate-to-large effect sizes from baseline to a 12-week assessment.
Melatonin treatment was mainly effective in reducing insomnia symp-
toms, 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 effi-
ciency 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

INTRODUCTION
Autism spectrum disorders (ASD) are lifelong neurodevelop-
mental 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
threaten sleep.
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

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2 F. Cortesi et al.
severity and frequency of these disorders 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 neuro-
developmental 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 manage-
ment 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 interven-
tions in children with neurodevelopmental disabilities (Moon
et al., 2011; Weiskop et al., 2005), and as suggested by
Vriend et al. (2011): Ôpromoting positive sleep hygiene when
combined with standard extinction is likely to improve prob-
lems initiating and maintaining sleep in children with ASDÕ.
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 ÔLa SapienzaÕ.
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 ADOS-
G (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 comorbid-
ities 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 ChildrenÕs 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 (CronbachÕs 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
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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 nightÕs data were discarded and a minimum
of 7 nights were necessary to obtain reliable data. Sleep
measurements obtained through actigraphy were SOL (time
from the parentsÕ 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 childÕs sleep in 30-min time blocks.
Trial design
After baseline assessment, participants were assigned ran-
domly to one of four conditions. Randomization was per-
formed 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 exclu-
sively 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
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Efficacy of melatonin singly or with CBT in ASD 3
reduce insomnia in ASD. After the baseline evaluation, each
family receiving CBT attended four weekly individual treat-
ment 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 dysfunc-
tional beliefs and attitudes about sleep. The behavioural and
educational components consisted of a set of oral instruc-
tions about management of a childÕs sleep, identification of
patient-specific maladaptive sleep condition and implemen-
tation of methods for replacing poor sleep habits with more
appropriate behaviours (Table 1).
CBT sessions were led by experienced clinical psycholo-
gists, and all sessions were audiotaped and reviewed with
principal investigators to ensure adherence to protocol. Treat-
ment 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 high-
purity 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.
4 F. Cortesi et al.
1-mg fast-release and 2-mg controlled-release (CR)-melato-
nin 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 multi-
disabled patients who experienced sleep maintenance prob-
lems (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 ÔLa SapienzaÕ 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 statis-
tical 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. PearsonÕs correlation was calculated to determine
the baseline level of association between parent-completed
somnologues and actigraph-generated sleep measures.
Analysis of variance or PearsonÕs 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 devel-
opmental changes, we included also age and sex as
covariates. Post-hoc comparisons between groups were
performed using the Sheffé 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 FisherÕs
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 differ-
ences 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).
Analyses of variance were conducted on the baseline-
dependent actigraphic and CSHQ measures. anovas were
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 Efficacy of melatonin singly or with CBT in ASD 5

185 included in
the baseline visit

15 excluded:
not interested,
overwhelmed, too busy

170 completed clinical evaluation

10 excluded:
improved symptoms, lost
contact, unknown reason

160 underwent randomization (immediately after baseline)

40 were assigned 40 were assigned 40 were assigned

40 were assigned
to receive to receive to receive
to receive
combination melatonin CBT
placebo
therapy alone alone

2 dropped 4 dropped
out(Parental out(Parental 4 dropped out 6 dropped out
difficulties in difficulties in (non compliance) (lack of improvement)
administrating medication) administrating medication,
non compliance)

38 36 36 34
completed the 12- completed the 12- completed the 12- completed the 12-
week treatment week treatment week treatment week treatment

3 2 3 2
excluded from excluded from excluded from excluded from
analysis analysis analysis analysis
(actigraph data (actigraph data (actigraph data (actigraph data
missing) missing) missing) missing)

Figure 1. Consort diagram showing partici- 35 included in the 34 included in the 33 included in the 32 included in the
pant flow through the study and reasons for analysis analysis analysis analysis
dropout.

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).
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

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6 F. Cortesi et al.
Table 2 Summary of demographic characteristics for the 160 patients assigned randomly to treatment
COMB
Age, years (SD) 6.4 (1.1)
Male sex (%) 80
Ethnicity
White Causasian (%) 100
Low SES* (%) 24
Primary caregiver sex (female) (%) 96
Mother
Age, years (SD) 33.7 (6.6)
Marital status (married %) 92
Education, years (SD) 13 (4)
*
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.
Ômedium–highÕ range. From covariance analysis, it ap-
peared that neither gender nor age influenced sleep
significantly.
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 12-
week 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.
v2 ⁄ anova
MLT CBT PL P
6.8 (0.9) 7.1 (0.7) 6.3 (1.2) 0.82
82 83 84 0.99
100 100 96 0.34
25 23 26 0.84
92 93 91 0.82
32.9(4.9) 35.7 (6.3) 34.8 (5.7) 0.79
86 93 88 0.76
14 (7) 13 (6) 13 (5) 0.91
Our findings report the efficacy of CR-melatonin in initiating
and maintaining sleep. In this study CBT improved sleep
latency slightly, but it was less effective in reducing impaired
sleep maintenance. However, combining CBT and CR-
melatonin produce additional improvement.
Because the choice of treatment should be based on the
childÕs 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 mela-
tonin 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
inadequate sleep practices and behavioural aspects (Wiggs
and Stores, 2004). In this clinical population, long-standing
sleep problems of settling and night-wakings often become
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 Table 3 Sleep data actigraphically derived for each treatment condition at 2 assessment points

Time · Group
Combination Melatonin CBT PL Time effect effect
Sleep measure
and Time Mean (SD) % Mean (SD) % Mean (SD) % Mean (SD) % F P value ES F value P value

TST

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Baseline 414.03 (45.34) 22.01 410.28 (45.07) 17.31 408.08 (49.03) 9.31 413.00 (45.13) 0.07 474.00 <0.001 74.55 <0.001
12-week 505.01 (31.18) 481.10 (33.15) 445.13 (48.37) 416.23 (43.60) 0.67

SOL
Baseline 85.84 (20.02) 60.75 81.21 (32.35) 44.33 76.34 (31.70) 22.54 78.20 (33.83) )0.02 304.50 <0.001 59.60 <0.001
12-week 33.69 (14.40) 45.21 (23.21) 59.13 (27.60) 79.60 (31.85) 0.61

WASO
Baseline 69.50 (23.35) 57.97 73.71 (45.00) 42.46 68.72 (31.77) 10.29 69.75 (45.21) )0.07 168.00 <0.001 0.53 40.72 <0.001
12-week 29.69 (12.97) 42.21 (22.35) 61.17 (28.93) 70.15 (42.76)

NAPTIME
Baseline 28.26 (49.13) 67.85 33.57 (56.63) 51.51 35.31 (60.17) 37.14 37.33 (56.19) 3.30 26.46 <0.001 0.08 3.32 0.23
12-week 9.20 (22.48) 17.00 (33.11) 12.29 (24.24) 36.10 (33.28)

SE
Baseline 70.26 (4.83) 20.00 71.10 (4.91) 15.46 71.37 (4.77) 11.26 71.13 (4.99) 1.12 529.21 <0.001 0.62 59.52 < .0001
12-week 84.46 (4.23) 82.71 (4.00) 79.58 (2.82) 71.93 (4.62)

BEDTIME
Baseline 23.33 (1.35) 6.56 23.45 (1.15) 4.82 23.39 (1.03) 1.85 23.41 (1.19) )0.4 364.60 <0.001 0.63 63.60 <0.001
12-week 22.06 (1.05) 22.30 (1.10) 22.55 (1.01) 23.51 (1.12)

CBT, Cognitive Behavioural Therapy; PL, Placebo; TST, Total sleep time; SOL, Sleep onset latency; SE, Sleep efficiency; NW, Number of night-wakings; ES, Effect size. %, percentage of
improvement.
Efficacy of melatonin singly or with CBT in ASD
7
8 F. Cortesi et al.
Figure 2. Sleep onset latency at baseline and at 12-week assess-
ment repeated-measure analysis of variance (F(3, 109) = 59.632,
P = 0.001. Vertical bars represent 95% confidence intervals.
engrained habits. The presence of unusual and non-func-
tional routines common in children with ASD may result in
bedtime resistance and settling difficulties (Richdale and
Schreck, 2009; Richdale and Wiggs, 2005).
Healthy sleep practices also promote sleep and enhance
sleep regulation by reducing environment stimulation and
behavioural sleep conditioning, which reinforce the associ-
ation of certain activities and environments with sleep, limit
wake-promoting activities and may play a crucial role in
sleep promotion. Consistent with previous studies (Mont-
gomery et al., 2004; Moon et al., 2011; Weiskop et al.,
2005), our results show that behavioural intervention alone,
even though less effective than melatonin, improved sleep
mainly by reducing SOL. As already reported, the action of
behavioural treatment seems to be mainly on the behavio-
ural components of sleep disorders rather than on the
sleep pattern itself. CBT seems to promote good sleep, as
suggested by Jan et al. (2008), entraining intrinsic circa-
dian rhythms to the external environmental and 24-
h day ⁄ night cycle, reducing environmental stimulation and
decreasing anxiety by means of appropriate bedtime
routine activities.
Recently, Henderson et al. (2011) investigated the rela-
tionship between consistent bedtime routine and sleep
quality in children with ASD and showed that the ASD group
had less consistent general routines, lower sleep quality and
higher levels of externalizing behaviour.
A consistent sleep ⁄ wake schedule may be particularly
important for ASD children, as they are vulnerable to both
sleep and circadian rhythm disruptions. However, sleep
hygiene practices and CBT by themselves are not suffi-
cient enough to treat insomnia adequately in these
children.
In our study, there was a significant trend for the combi-
nation group to produce higher improvement on sleep
continuity and efficiency than in either melatonin or CBT
groups with the strongest treatment response. Our results
indicate that the greatest number and percentage of
responders in the combination treatment group achieve a
clinically significant change (63.38% of children with norma-
tive 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 (Montgomery et al., 2004; Moon et al.,
2011; Weiskop et al., 2005) in the treatment of sleep
insomnia in children with ASD. The observed advantage
of combination therapy over either CBT or melatonin alone
suggests that among these effective therapies, combination
therapy provides the best chance for a positive outcome.
Thus, in agreement with Wirojanan et al. (2009), our results
suggest that melatonin can be considered a safe and
effective treatment in combination with behavioural thera-
pies and sleep hygiene practices for the management of
sleep disorders in children with ASD. The superiority of
combination therapy is due most probably to additive or
synergistic effects of the two treatments.
Some limitations of this study should be taken into account.
First, this trial assessed only the effects of the 12-week
treatment, failing to assess mid- and long-term efficacy and
treatment gain after withdrawal. Therefore, we do not know
exactly when the positive response to treatments appeared
and whether or not it would persist during a long-term period.
However, in order to obtain better compliance in this
population, which may display non-compliant or avoidant
behaviour, and whose parents experienced more stress, we
decided to conduct just one post-baseline evaluation. In fact,
this study had a low discontinuation rate of 10%. Moreover,
we did not measure melatonin salivary and plasma level or its
urinary metabolite before and during the treatment; thus, in
this study we cannot correlate the efficacy of melatonin with
the presence of an eventual melatonin deficit. Secondly, the
findings cannot be generalized to patients who have disor-
ders that were excluded from our protocol. Thirdly, parents
had agreed to comply with the treatment regimen, which
implies a motivation that may not be present in all cases.
Therefore, the present results may be biased and could
over- or underestimate the efficacy of the treatments. Finally,
sleep disorders such as obstructive sleep apnoea syndrome
or periodic limb movements were ruled out clinically, but no
pre-screening with gold standard polysomnography was
performed, so we cannot exclude that some of these patients
may have been enrolled into the study.
Limitations notwithstanding, this study confirms that mel-
atonin and CBT in combination or as monotherapies appear
ª 2012 European Sleep Research Society
 Table 4 CSHQ results for each treatment condition at 2 assessment points

Time · Group
Combination Melatonin CBT PL Time effect effect
CSHQ
and Time Mean (SD) % Mean (SD) % Mean (SD) % Mean (SD) % F P value ES F P Value

Total score
Baseline 66.11 (5.47) 27.83 66.67 (8.55) 17.83 64.48 (5.48) 0.6 64.20 (4.85) 0.09 570.26 <0.001 0.78 134.67 <0.001
12-week 47.84 (2.94) 54.78 (6.22) 60.06 (4.71) 64.80 (4–52)

Bed resistance
Baseline 14.53 (1.82) 41.77 13.85 (2.23) 24.18 13.44 (2.08) 13.54 13.63 (1.82) )0.03 360.11 <0.001 0.74 104.52 <0.001

ª 2012 European Sleep Research Society

12-week 8.46 (1.39) 10.50 (2.20) 11.62 (2.22) 14.10 (1.93)

SOD
Baseline 2.88 (0.32) 41.31 2.85 (0.35) 26.31 2.89 (0.30) 13.14 2.90 (0.31) )0.01 102.89 <0.001 0.37 21.31 <0.001
12-week 1.69 (0.73) 2.10 (0.68) 2.51 (0.57) 2.93 (0.25)

Sleep anxiety
Baseline 7.95 (1.83) 34.21 8.35 (2.19) 13.65 8.62 (1.98) 16.80 7.66 (1.73) )3.52 163.5 <0.001 0.46 31.11 <0.001
12-week 5.23 (0.95) 7.21 (1.87) 7.17 (1.48) 7.93 (1.99)

Night-wakings
Baseline 7.61 (0.89) 41.91 7.67 (0.94) 34.41 7.62 (0.94) 7.34 7.76 (0.93) )1.28 139.21 <0.001 0.64 66.82 <0.001
12-week 4.42 (0.90) 5.03 (1.10) 7.06 (1.06) 7.86 (0.81)

Sleep duration
Baseline 7.34 (1.35) 40.32 7.17 (1.51) 32.77 7.01 (1.48) 4.70 6.46 (1.25) 0.01 154.31 <0.001 0.53 41.90 <0.001
12-week 4.38 (1.02) 4.82 (0.94) 6.68 (1.16) 6.40 (1.29)

Parasomnias
Baseline 9.15 (1.68) 2.51 9.10 (2.42) )2.74 9.75 (2.11) )0.71 8.96 (1.80) )2.23 4.29 0.61 0.02 6.13 0.82
12-week 8.92 (1.38) 9.35 (1.78) 9.82 (2.25) 9.16 (1.53)

SDB
Baseline 3.18 (0.40) 1.22 3.20 (0.44) 1.56 3.10 0.30) )1.61 3.15 (0.40) )1.58 2.99 0.86 0.02 1.00 0.39
12-week 3.22 (0.35) 3 15 (0.48) 3.20 (0.41) 3.20 (0.44)

DS
Baseline 13.92 (2.86) 22.12 13.35 (3.84) 14.68 13.31 (2.67) 10.14 13.13 (3.11) 1.29 146.7 <0.001 0.39 23.66 <0.001
12-week 10.84 (1.68) 11.39 (2.34) 11.96 (1.97) 12.96 (1.97)

CBT, Cognitive Behavioural Therapy; PL Placebo; % of improvement; SOD, Sleep Onset Delay; SDB, Sleep Disordered Breathing; NW, Night-wakings; DS, Daytime Sleepiness; ES, Effect
size.
Efficacy of melatonin singly or with CBT in ASD
9
10 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 familyÕs
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