Melatonin for chronic insomnia in Angelman syndrome: a randomized placebo-controlled trial.

Abstract

Previous studies suggested that melatonin improves sleep in insomniac patients with Angelman syndrome. To assess the efficacy of melatonin, a randomized placebo-controlled study was conducted in 8 children with Angelman syndrome with idiopathic chronic insomnia. After a 1-week baseline period, patients received, depending on age, either melatonin 5 or 2.5 mg, or placebo, followed by 4 weeks of open treatment. Parents recorded lights off time, sleep onset time, wake-up time, and epileptic seizures in a diary. Salivary melatonin levels were measured at baseline and the last evening of the fourth treatment week. Melatonin significantly advanced sleep onset by 28 minutes, decreased sleep latency by 32 minutes, increased total sleep time by 56 minutes, reduced the number of nights with wakes from 3.1 to 1.6 nights a week, and increased endogenous salivary melatonin levels. Parents were satisfied with these results. Indications that melatonin dose in Angelman syndrome patients should be low, are discussed.

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Journal of Child Neurology
DOI: 10.1177/0883073808314153
2008; 23; 649 J Child Neurol
Wiebe Braam, Robert Didden, Marcel G. Smits and Leopold M. G. Curfs

Melatonin for Chronic Insomnia in Angelman Syndrome: A Randomized Placebo-Controlled Trial
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649
randomized trials with melatonin in persons with intellectual
disabilities are performed.7In insomniac patients with intel-
lectual disabilities, melatonin decreases sleep latency, but
does not influence sleep maintenance.8-10An open-label trial
of 13 children with Angelman syndrome found that mela-
tonin decreased sleep latency and increased total sleep time
as well.11
Method
Participants
Parents of patients with Angelman syndrome and chronic
idiopathic insomnia that were referred to our sleep center
by local general practitioners, were asked to participate in
a placebo-controlled trial with melatonin. Criteria for par-
ticipation were sleep latency more than 30 minutes, or 2
or more wakes, lasting more than 15 minutes a night, at
least 5 nights a week, during more than 1 year preceding
inclusion. Exclusion criteria were prior use of melatonin,
liver disease, renal failure, chronic pain, and age less than
24 months. Patients were examined by a physician (first
author) for patients with intellectual disabilities who is
specialized in sleep disorders, assessing that behavioral
and social sleep hygiene measures had been attempted
unsuccessfully and no signs for a physical cause for the
insomnia were present. The trial was performed in the
home setting of each individual. It followed the 1983
revised provisions of the 1975 Declaration of Helsinki.
A
with 4 types of chromosomal abnormalities involving the
chromosome 15q11-q13 region (deletions, paternal uni-
parental disomy, methylation imprinting mutations, and
UBE3A and other presumed single gene mutations). Most
individuals with Angelman syndrome exhibit behavioral fea-
tures such as excessive laughter, hyperactivity, noncompli-
ance, speech impairment, and sleep problems.1-3Sleep
problems include settling problems and frequent night wak-
ing.4,5They appear resistant to behavior therapy and con-
ventional sleep medication.5
Melatonin, a hormone synthesized and released by the
pineal gland during darkness, is a chronobiotic drug with
hypnotic properties.6There is increasing evidence that
chronic sleep problems in persons with intellectual disabili-
ties are the result of circadian rhythm disorders and that
melatonin therapy could be effective. However, only a few
ngelman syndrome is characterized by severe intel-
lectual disability, motor impairment, seizures and
subtle dysmorphic facial features and is associated
Original Article
Melatonin for Chronic Insomnia in
Angelman Syndrome: A Randomized
Placebo-Controlled Trial
Wiebe Braam, MD, Robert Didden, PhD, Marcel G. Smits, MD, PhD,
and Leopold M. G. Curfs, PhD
Previous studies suggested that melatonin improves sleep in
insomniac patients with Angelman syndrome. To assess the
efficacy of melatonin, a randomized placebo-controlled study
was conducted in 8 children with Angelman syndrome with
idiopathic chronic insomnia. After a 1-week baseline period,
patients received, depending on age, either melatonin 5 or 2.5
mg, or placebo, followed by 4 weeks of open treatment. Parents
recorded lights off time, sleep onset time, wake-up time, and
epileptic seizures in a diary. Salivary melatonin levels were
measured at baseline and the last evening of the fourth
treatment week. Melatonin significantly advanced sleep onset by
28 minutes, decreased sleep latency by 32 minutes, increased
total sleep time by 56 minutes, reduced the number of nights
with wakes from 3.1 to 1.6 nights a week, and increased endoge-
nous salivary melatonin levels. Parents were satisfied with these
results. Indications that melatonin dose in Angelman syndrome
patients should be low, are discussed.
Keywords:
Angelman syndrome; melatonin; sleep problems
From the Heeren Loo Zuid-Veluwe (WB), the Department of Neurology,
Gelderse Vallei Hospital (WB, MGS), Ede; Radboud University
Nijmegen (RD); and the Department of Clinical Genetics, Academic
Hospital Maastricht/University Maastricht (LMGC), The Netherlands.
Address correspondence to: Wiebe Braam, MD, Heeren Loo Zuid-
Veluwe, PO Box 75, 6710 BB Ede, The Netherlands; e-mail: wiebe.braam@
sheerenloo.nl.
Braam W, Didden R, Smits MG, Curfs LMG. Melatonin for chronic
insomnia in angelman syndrome: a randomized placebo-controlled trial.
J Child Neurol. 2008;23:649-654.
Journal of Child Neurology
Volume 23 Number 6
June 2008 649-654
© 2008 Sage Publications
10.1177/0883073808314153
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Page 3

The local Medical Ethical Committee approved the study.
The patients’ parents gave written informed consent.
The trial consisted of 2 consecutive periods: a 1-week
qualification period and 4 weeks of treatment during
which participants were randomly allocated to melatonin
or placebo therapy. Saliva specimens for measuring mela-
tonin concentrations were collected in the qualification
period (baseline) to examine whether there was a delayed
sleep phase syndrome or another disturbance in mela-
tonin circadian rhythm and at the end of the last week
of the treatment period to examine whether 4 weeks of
treatment had changed endogenous melatonin circadian
rhythm. After the 4-week placebo controlled phase of the
study, all patients received 4 weeks open treatment with
melatonin. At follow-up parents were asked to tell if they
were satisfied with the result of the treatment. Patients
were not allowed to change their co-medication. All inves-
tigators involved in the study were unaware of the treat-
ment allocation. The code was broken when the data of
all patients were recorded in the database.
Treatment
During the 4 treatment weeks, patients 6 years of age and
older received a daily dose of 5 mg of melatonin (Duchefa
Farma BV, Haarlem, The Netherlands) orally at 7 PM, mixed
with carboxymethylcellulose in a fast-release tablet, or an
identically looking placebo. A 5-mg dose was chosen because
most placebo-controlled trials with melatonin used this
dose.12-14Patients under 6 years of age received a daily dose
of 2.5 mg of melatonin orally at 6 PM. Compliance was tested
by comparison of the number of tablets returned with the
number prescribed.
Outcome Measures
Primary outcome measures were the between-group dif-
ferences of sleep latency, sleep onset, wake up time, and
number and length of wakes. Secondary outcome meas-
ures were the between group differences of salivary mela-
tonin concentrations, number of epileptic seizures, as
well as adverse reactions of melatonin. Sleep variables
were assessed by parents and recorded in a sleep diary.
Parents were asked to listen or watch their child every 10
minutes from bedtime until the time they found their
child asleep. Furthermore, they reported the times at
night when they heard or saw that their child was awake.
The parents were encouraged to describe any suspected
adverse effects in the diary. Results were discussed with
parents at the end of the double-blind phase and after 4
weeks of open treatment. At both times, parents were
asked to judge the result as small, moderate, or strong
improvement or unchanged. Because of contradictory
reports of proconvulsant and anticonvulsant effects of
exogenous melatonin,15,24seizure control was asked for at
any visit.
Endogenous Melatonin
On the last night of the baseline week and the last night of
the fourth treatment week (at which night no melatonin was
given) salivary samples were collected hourly during 5 con-
secutive hours. In children 2–4 years of age from 5 PM, in
children 5 and 6 years of age from 6 PM, and in older chil-
dren from 7 PM. To prevent suppression of melatonin secre-
tion by bright light16the children remained indoors with
curtains closed during that period. Dim light (<50 lux) was
allowed. Saliva was collected in a cotton plug either chewed
on by the patient or by sweeping the cavity of the patients’
mouth by 1 of the parents. The limit of detection of the
assay, which had to contain at least 0.5 mL of saliva, was
0.39 pg/mL with an intra-assay variation of 14.5%/mL.17
The maximum detection level was 50 pg/mL.
Statistical Analyses
Results of a 1-sample Kolmogorov-Smirnov analysis
showed that data of each variable were normally distributed.
Unpaired t-tests were conducted to test differences in
change between melatonin versus placebo treatment on
the sleep variables. Statistical significance was accepted at
P < .05.
Results
A total of 13 children and adults with Angelman syn-
drome and chronic sleep problems were referred to our
sleep center. Four of them were not included because
their sleep problems did not meet criteria for inclusion.
After receiving information on the design of the trial, the
parents of 1 patient decided not to participate because
they thought that the trial was too burdensome for their
child. The remaining 8 patients were randomly assigned
to melatonin or placebo conditions. Thus, the melatonin
and the placebo group each consisted of 4 patients.
Seven patients showed sleep onset as well as sleep
maintenance problems, and 1 patient suffered from sleep
onset problems only (Table 1). There were no statistically
significant differences between patients who were allo-
cated to melatonin and placebo group on all parameters
during baseline week.
During melatonin treatment, sleep latency decreased by
32 minutes, sleep onset advanced by 28 minutes, and total
sleep time increased by 56 minutes on average. The mean
number of nights with wakes decreased from 3.1 to 1.6 a
week on average. These changes significantly differed from
those during placebo treatment (Table 2). There was no sig-
nificant change in lights out time and sleep offset time.
The parents of 2 children (#4 and 8) who received mela-
tonin considered the treatment outcome as a moderate
improvement, and 2 (#2 and 5) as a strong improvement.
After 4 weeks of open treatment with melatonin, the par-
ents of 2 children (#2 and 8) decided upon continuation of
650
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the treatment. The parents of 1 child (#5), however, reported
an increase of the number of night wakes and stopped treat-
ment. The parents of the fourth child (# 4) did not want to
continue treatment, because they were disappointed with
the treatment result.
The parents of the 4 children who received placebo
reported that the sleep problems of their children did not
change. After 4 weeks of open melatonin treatment, the
parents of 3 children (#1, 3, and 6) wanted to continue
melatonin treatment because of the strong improvement
of the sleep of their child, whereas the parents of 1 child
(#7) stopped treatment because the sleep problems in
their child remained unchanged.
In 35 of 80 salivary samples, the amount of saliva was too
low for a melatonin analysis. Visual inspection of the data on
the remaining 45 samples (Table 3) shows that salivary mela-
tonin concentrations, on a day no study medication was
given, increased substantially after melatonin treatment (ie,
child 2, 4, 5, and 8), whereas melatonin concentrations after
placebo treatment (ie, child 1, 3, 6, and 7) did not change.
In patients 4 and 8, salivary melatonin concentrations were
above 50 pg/mL at the first evening after discontinuation of
4 weeks of melatonin treatment. In patient 5, the first sam-
ple (collected at 5 PM) contained more than 50 pg/mL.
Of 4 patients receiving melatonin in the melatonin
group, 2 used antiepileptic drugs (ie, child 5 and 8; see
Table 1). Last reported seizure was, respectively, 3 months
and 2 years before entering the study. No seizures were
reported by their parents during the present study, or by par-
ents of the other 6 patients.
Discussion
Four weeks of melatonin treatment in Angelman syn-
drome children with chronic insomnia was more effective in
decreasing sleep latency, advancing sleep onset, and increas-
ing total sleep time than placebo. Furthermore, the number
of nights per week with wakes decreased more during mela-
tonin treatment. The reduction in sleep latency and the
Melatonin in Angelman Syndrome / Braam et al
651
Table 1.
Participant Characteristics and Medication Use During the Study
Patient
12345678
Type of Angelman syndrome
Age, y:mo
Gender
Weight, kg
Sleep onset problem
Nighttime awakening
Antiepileptic drug use
Present sleep medication
Deletion
4:10
Male
20
Yes
Yes
cbz,clb,vpa
mid
Deletion
12:10
Female
48
Yes
Yes
–
pip
Disomy
6:7
Female
26
Yes
Yes
vpa
–
Deletion
5:7
Male
22.5
Yes
No
–
–
Deletion
8:10
Female
31
Yes
Yes
esm
–
Disomy
9:2
Female
37
Yes
Yes
–
–
Deletion
20:11
Male
56
Yes
Yes
vpa
–
Deletion
13:4
Female
40
Yes
Yes
clb,vpa
–
NOTE: cbz = carbamazepin; clb = clobazam; esm = ethosuximide; vpa = valproate; mid = midazolam; pip = pipamperon.
Table 2.
Difference in Sleep Parameters From Baseline to Week 4
BaselineIntervention (4 weeks)
Melatonin
Mean (SD)
Placebo
Mean (SD)
Melatonin
Mean (SD)
Placebo
Mean (SD)
t dfPt dfP
Lights out timea
Sleep onset timea
Sleep latencyb
Sleep offset timea
No. of nights/week
with wakes
No. of wakes/night
Duration of wakesb
Total sleep timea
20:10 (0:55)
21:00 (1:10)
50.00 (17.49)
07:49 (0:36)
20:09 (1:12)
21:05 (1:30)
56.50 (21:17)
07:02 (0:33)
.011
–.096
–.473
1.715
6
6
6
5
.99
.93
.65
.15
20:14 (0:52)
20:32 (0:56)
17.5 (5.74)
07:42 (0:38)
20:14 (1:12)
21:10 (1:31)
55.75 (20.64)
07:02 (0:02)
0
–.715
–3.570
1.768
6
6
6
5
1
.02c
.01c
.14
3.1 (2.95)
1.5 (1.41)
39.50 (35.25)
10:08 (1:22)
5.9 (1.41)
1.7 (0.69)
55.00 (37.53)
9:40 (0:37)
–1.724
–.127
–.602
.545
6
6
6
5
.14
.9
.57
.61
1.6 (2.01)
0.9 (0.61)
11.75 (9.87)
11:04 (0:46)
5.6 (1.24)
1.8 (0.79)
60.75 (45.02)
9:31 (0:28)
–3.357
–1.926
–2.126
2.996
6
6
6
5
.01d
.1
.08
.03c
a. Hours:minutes.
b. Minutes.
c. P < .05.
d. P < .01.
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Page 5

advance of sleep-onset is consistent with earlier findings
in studies with melatonin in children with chronic sleep
onset.14,18The beneficial effect on night waking and total
sleep time differed from findings in earlier studies showing
that melatonin does not influence sleep maintenance.8-10,19
An average of half an hour earlier getting to sleep and
sleeping 1 hour longer is a statistically significant differ-
ence. However, one might ask whether this is of a mean-
ingful benefit to the patients and their parents. When
asked whether they were satisfied with the results after 4
weeks of melatonin (or in the case of placebo after 4 weeks
of open melatonin use), parents responded positively.
Half an hour earlier, getting to sleep meant that parents
needed less time-consuming efforts to try to let their child
stay in bed. A mean increase in total sleep time by approx-
imately 1 hour, meant less or not waking up anymore in
the middle of the night and waking up by parents and sib-
lings. But next to this, parents reported that their chil-
dren’s behavior was easier to manage and that they were
less sleepy and more attentive at daytime. This latter find-
ing is consistent with another placebo-controlled study
showing that melatonin improved health status.18
Diary measures have measurement error, but are fre-
quently used in nonclinical settings. Sleep diaries based
on observations by others, however, yield more satisfac-
tory data compared with actigraphy than sleep diaries
based on self-report.20Besides, parents of sleep-disturbed
infants were accurate reporters of actigraphically assessed
sleep onset and sleep duration.21Sadeh et al22showed an
85.3% agreement rate between actigraphic sleep–wake
scorings compared with those of polysomnography.
Measures were only used to compare between the results
of the 2 consecutive periods and not used to determine
sleep parameters per se.
Melatonin levels in the baseline week were low. It is
possible that in our patients melatonin levels increased
after the last sampling time. Late melatonin onset is a
key characteristic of the delayed sleep phase syndrome.18
Consequently, sleep onset insomnia in Angelman syndrome
could be the result of a delayed sleep phase syndrome.
Delayed sleep phase syndrome is defined as an abnormally
delayed sleep–wake rhythm. The major symptoms of this
syndrome are extreme difficulty to initiate sleep at a con-
ventional hour of the night and great difficulty to wake up
on time in the morning. Delayed sleep phase syndrome is
associated with late dim light melatonin onset.12This circa-
dian rhythm disorder responds very well to melatonin treat-
ment. Zhdanova et al11also found low melatonin levels in
children with Angelman syndrome in the baseline week.
They attributed these low levels, in part, to the use of val-
proate. Sodium valproate is known to suppress plasma
melatonin levels.23In our study, 4 children used valproate,
but their melatonin levels in the baseline week were not
lower than those of children who did not use valproate.
The question whether melatonin influences seizure
frequency remains a matter of discussion. Melatonin may
increase seizure frequency.15However, melatonin also has
anticonvulsant effects.24The melatonin treatment period
in our patients was perhaps too short to draw conclusions
about the influence of melatonin on seizure frequency.
In 3 of the 4 children who received melatonin, salivary
melatonin levels were extremely high after 4 weeks of treat-
ment. The parents of these children reported the return or
increase of night wakes when visiting the clinic after week
652
Journal of Child Neurology / Vol. 23, No. 6, June 2008
Table 3.
Melatonin in Saliva at Baseline and the Last Day of the Fourth Treatment Weeka
Patient
1
P
2
M
3
P
4
M
5
M
6
P
7
P
8
MMelatonin or placebob
Time (PM)
Baseline week5
6
7
8
9
<0.5
<0.5
0.6
#
#
<0.5
1.4
#
3.3
#
4.9
4.0
4.7
#
#
3.7
3.1
4.2
#
#
<0.5
#
#
#
#
0.6
0.7
1.6
#
#
1.4
<0.5
<0.5
#
#
#
<0.5
#
9.1 10
11
5
6
7
8
9
10
11
Week 4
>50
>50
>50
>50
>50
>50
2.5
1.1
#
#
#
2.7
#
#
4.6
#
6.1
#
9.5
19.2
<0.5
<0.5
2.2
#
#
22.7
#
#
#
#
<0.5
1.3
4.2
#
#
#
34.0
>50
>50
>50
a. Pound signs indicate that not enough saliva was collected.
b. Study medication during weeks 1–4 double-blind phase: P = placebo; M = melatonin.
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4 of the open melatonin treatment phase, or at the next
evaluation 1 month later.
The postmelatonin high levels of salivary melatonin
could be due to a supraphysiological dose of exogenous
melatonin. However, the elimination half-life of mela-
tonin has been reported as 0.8 hours with an absorption
half-life of 0.4 hours, while melatonin levels ranged from
350 to 10 000 times those occurring physiologically.25
Furthermore, in children 6–12 years of age who partici-
pated in a study using 5 mg of melatonin in a similar
study design as in the present study, salivary melatonin
levels measured 24 hours after the last exogenous mela-
tonin intake, were normal and only showed a phase
advance.14,18If there were a large advance of the endogenous
melatonin rhythm, so that endogenous melatonin started to
increase largely before 5 PM, patients should have been
sleepy in the afternoon. Parents did not report this. Another
explanation for the high salivary melatonin levels approxi-
mately 24 hours after the last intake of melatonin is that the
melatonin metabolism is disturbed in Angelman syndrome.
Melatonin is metabolized in the liver by cytochrome P450
1A2 to its main primary metabolite 6-hydroxymelatonin.
Exogenous melatonin has a half-life between 30 and 50
minutes. Genetic variations influence the expression of spe-
cific cytochrome P450 isoenzymes in individuals and this
finding influences their capacity to metabolize certain
drugs.26Assuming that exogenous melatonin does not stim-
ulate endogenous melatonin secretion, it is likely that the
high melatonin levels after 4 weeks of treatment with mela-
tonin in 3 of 4 children in this study, found 24 hours after
the last oral melatonin dose, were caused by a low activity
of cytochrome P450 1A2 or another disturbance in the
metabolism of melatonin. However, the possibility that the
elevated levels were the result of down-regulation of
endogenous melatonin or enzyme inhibition by antiseizure
medication can in some cases not be ruled out. Only 3–4%
of the white population is a poor metabolizer of cytochrome
P450 1A2. That 3 of 4 children with Angelman syndrome in
the melatonin group had elevated melatonin levels after 4
weeks of treatment raises the question whether a low activ-
ity of cytochrome P450 1A2 is part of the Angelman syn-
drome phenotype.
We are studying the above-discussed explanations for
a possible disturbed melatonin metabolism in Angelman
syndrome patients. Until the results are published, we
suggest testing melatonin metabolism in each individual
Angelman syndrome patient before considering (long-
term) melatonin treatment, for instance by measuring
salivary melatonin hourly during 24 hours after melatonin
administration. Consequently, the best pharmacothera-
peutic dose can be determined, taking into account the
individually measured elimination half-life of melatonin.
If salivary melatonin levels do not reach basal values
within 12 hours after melatonin administration, consider
lowering the dose with at least 50%.
This first placebo-controlled study of melatonin in
insomniac Angelman syndrome patients has several short-
comings. The number of patients (ie, n = 8) was low. Many
parents referred to our sleep clinic, when asked for permis-
sion to let their child participate in this study, refused to do
so because they only wanted immediate help for their child’s
problems instead of risking the possibility of another 4
weeks of disturbed sleep due to placebo treatment. In this
study, sample size was very small and the power of the t-test
was low. Despite low power, significant and meaningful dif-
ferences were found between placebo and melatonin condi-
tions. It should be noted that a randomized controlled trial
with a larger sample size would have a larger statistical
power. However, it is extremely difficult if not impossible to
include a large number of participants with Angelman syn-
drome in any randomized controlled trial, because Angelman
syndrome is a relatively rare genetic disorder.
We relied on parental sleep diaries rather than more
objective measures, such as actigraphy. Melatonin levels
would better have been measured more than 24 hours,
for example, 48 hours, after the last intake of exogenous
melatonin. The sample was biased by referrals to a highly
specialized outpatient clinic for insomniac patients with
intellectual disabilities. These shortcomings threaten the
validity of our conclusions. Nevertheless, the results show
that melatonin treatment may help insomniac Angelman
syndrome patients. However, further studies need to be
performed on melatonin metabolism in Angelman syn-
drome to establish the best dose. This study indicates that
it is possible that melatonin dose in Angelman syndrome
should be lower than generally prescribed.
Acknowledgments
This study was supported by a research grant from Heeren
Loo Zorggroep Steunfonds. We thank the parents and their
children for their participation; L. Slagman for her help in
the organization of the trial; I.M. van Geijlswijk, PharmD
for preparation of the study medication; and the personnel
of the Gelderse Vallei hospital lab for measuring salivary
melatonin.
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