Nocturnal Excretion of 6-Sulphatoxymelatonin in

Children and Adolescents with Autistic Disorder

Sylvie Tordjman, George M. Anderson, Nadège Pichard, Henriette Charbuy, and Yvan Touitou
Background: Many studies in autistic disorder report sleep problems and altered circadian rhythms, suggesting abnormalities in
melatonin physiology. Additionally, melatonin, a pineal gland hormone produced from serotonin, is of special interest in autistic
disorder given reported alterations in central and peripheral serotonin neurobiology.
Latar belakang: Banyak penelitian dalam gangguan autistik melaporkan masalah tidur dan mengubah ritme sirkadian, menunjukkan
kelainan pada fisiologi melatonin. Selain itu, melatonin, hormon kelenjar pineal yang dihasilkan dari serotonin, merupakan minat khusus
pada gangguan autistik mengingat perubahan yang dilaporkan dalam neurobiologi serotonin sentral dan perifer.

Methods: Nocturnal urinary excretion of 6-sulphatoxymelatonin was measured by radioimmunoassay in groups of children and
adolescents with autistic disorder (n = 49) and normal control individuals (n = 88) matched on age, sex, and Tanner stage of
puberty.

Metode: Ekskresi urin malam hari 6-sulphatoxymelatonin diukur dengan radioimmunoassay pada kelompok anak-anak dan remaja dengan
kelainan autistik (n = 49) dan individu kontrol normal (n = 88) yang cocok pada usia, jenis kelamin, dan tahap pubertas Tanner.

Results: Nocturnal 6-sulphatoxymelatonin excretion rate was significantly and substantially lower in patients with autism than
in normal controls (mean ± SEM, .75 ± .11 vs. 1.80 ± .17 µg/hr, p =.0001), and was significantly negatively correlated with
severity of autistic impairments in verbal communication and play (p < .05).

Hasil: Tingkat ekskresi 6-sulfatoksimelatonin nokturnal secara signifikan dan jauh lebih rendah pada pasien dengan autisme dibandingkan
kontrol normal (rata-rata ± SEM, 0,75 ± 0,11 vs 1,80 ± 0,17 μg / jam, p = 0,0001), dan secara signifikan berkorelasi negatif dengan
keparahan gangguan autistik dalam komunikasi verbal dan bermain (p <0,05).

Conclusions: These findings indicate clearly that nocturnal production of melatonin is reduced in autism. Further research is
warranted in order to understand the mechanisms underlying the lower melatonin production, to assess the impact of altered
melatonin on the pathophysiology and behavioral expression of autistic disorder, and to determine the utility of melatonin
administration in individuals with autism.

Kesimpulan: Temuan ini menunjukkan dengan jelas bahwa produksi melatonin pada malam hari berkurang autis.
Penelitian lebih lanjut diperlukan untuk memahami mekanisme yang mendasari produksi melatonin yang lebih rendah,
untuk menilai dampak perubahan melatonin pada patofisiologi dan ekspresi perilaku gangguan autistik, dan untuk
menentukan utilitas administrasi melatonin pada individu dengan autisme.
S. Tordjman et
al
Key Words: 6-Sulphatoxymelatonin, melatonin,
autistic disorder, autism severity, pineal,
circadian sleep-wake rhythm
A
lterations in circadian measures of sleep-
wake rhythm, including reduced total
sleep and longer sleep latency as well as
nocturnal and early morning
awakenings, are
often reported for individuals with autistic
disorder (Honomichl et al 2002; Hoshino et al
1984; Johnson 1996; Patzold et al 1998;
Richdale and Prior 1995; Richdale 1999; Rutter 1968;
Schreck and Mulick 2000). The accumulated
clinical observations and sleep studies strongly
suggest that neuroendocrine functions involved
in the circadian sleep-wake rhythm may be
altered in autism.
lterasi dalam ukuran sirkadian dari ritme
tidur-bangun, termasuk total tidur yang
berkurang dan latensi tidur yang lebih
lama serta kebangkitan malam hari dan
dini hari, adalah sering dilaporkan untuk
individu dengan gangguan autistik
(Honomichl dkk 2002; Hoshino dkk
1984; Johnson 1996; Patzold dkk 1998;
Richdale dan Sebelum 1995; Richdale
1999; Rutter 1968; Schreck dan Mulick
2000). Akumulasi pengamatan klinis dan
studi tidur sangat menunjukkan bahwa
fungsi neuroendokrin yang terlibat dalam
ritme tidur-bangun sirkadian dapat
diubah dalam autisme.
The pineal gland hormone melatonin plays a
key role in regulating human circadian rhythms
including the sleep-wake and body temperature
cycles. In addition, melatonin is produced in the
pineal gland from serotonin and may be of
special interest in autistic disorder given
reported serotonergic alterations in autism
(Anderson 2002; Cook and Leventhal 1996). In
humans, melatonin is secreted almost entirely at
night, with peak secretion typically occurring at
around 2 am. The production of melatonin is
powerfully suppressed by light acting through
the retino- hypothalamic tract. Thus, melatonin
secretion depends upon exogenous factors such
as light and season, and may be also influenced
by endogenous factors such as sex, age and
pubertal stage (Brezinski 1997; Lindblom et al
2002; Sadeh 1997; Touitou 2001; Wetterberg
1999). Many studies have reported that mela-
tonin influences the sleep-wake rhythm. For
instance, an ad- vanced or retarded peak in
melatonin secretion is associated with an
advanced or retarded sleep onset and morning
awakening (Dahlitz et al 1991). Blind
individuals with free-running melato- nin
BIOL PSYCHIATRY 2005;57:134 –138
135
rhythms tend to take naps synchronized with their daytime peaks
in melatonin secretion (Lockley et al 1997). The stabiliza- tion of
the sleep-wake rhythm that is observed around three months of age
in the human infant corresponds to the establish- ment of the
circadian melatonin secretion rhythm (Zhdanova et al 1997).
Hormon kelenjar pineal melatonin memainkan
peran penting dalam mengatur ritme sirkadian
manusia termasuk siklus tidur-bangun dan suhu tubuh.
Selain itu, melatonin diproduksi di kelenjar pineal dari
serotonin dan mungkin menjadi perhatian khusus pada
gangguan autistik mengingat perubahan serotonergik
yang dilaporkan pada autisme (Anderson 2002; Cook
dan Leventhal 1996). Pada manusia, melatonin
disekresi hampir seluruhnya pada malam hari, dengan
sekresi puncak biasanya terjadi sekitar jam 2 pagi.
Produksi melatonin ditekan secara kuat oleh cahaya
yang bekerja melalui saluran retino-hipotalamus.
Dengan demikian, sekresi melatonin tergantung pada
faktor-faktor eksogen seperti cahaya dan musim, dan
mungkin juga dipengaruhi oleh faktor-faktor endogen
seperti jenis kelamin, usia dan tahap pubertas
(Brezinski 1997; Lindblom et al 2002; Sadeh 1997;
Touitou 2001; Wetterberg 1999). Banyak penelitian
telah melaporkan bahwa melatonin memengaruhi
ritme tidur-bangun. Sebagai contoh, peningkatan
lanjutan atau terbelakang dalam sekresi melatonin
dikaitkan dengan onset tidur lanjut atau terbelakang
dan bangun pagi (Dahlitz et al 1991). Individu
tunanetra dengan ritme melato yang berlari bebas
cenderung tidur siang disinkronkan dengan puncak
siang hari dalam sekresi melatonin (Lockley et al
1997). Stabilisasi irama tidur-bangun yang diamati
sekitar tiga bulan pada bayi manusia sesuai dengan
pembentukan irama sekresi melatonin sirkadian
(Zhdanova et al 1997).
The possible therapeutic effects of melatonin in childhood
and adult sleep problems have been examined in a number of
studies (Jan et al 1999; Lewy et al 2001, 2002). Although the
potential utility of melatonin in treating sleep problems in autism
has been discussed (Lord 1998), the available data in this area
are extremely limited (Hayashi 2000; Ishizaki et al 1999).
Efek terapeutik yang mungkin terjadi pada melatonin pada
masalah masa kanak-kanak dan dewasa telah diperiksa dalam
sejumlah penelitian (Jan et al 1999; Lewy et al 2001, 2002).
Meskipun potensi utilitas melatonin dalam mengobati masalah
tidur dalam autisme telah dibahas (Lord 1998), data yang
tersedia di daerah ini sangat terbatas (Hayashi 2000; Ishizaki et
al 1999).
Most of the studies that have examined melatonin production
in developmental disorders have been conducted on children
with disorders associated with mental retardation. Palm and
colleagues (1997) reported that the time of peak serum or urinary
melatonin levels was delayed in seven out of eight mentally
retarded blind children and young adults with circadian sleep-
www.elsevier.com/locate/biopsych
136 BIOL PSYCHIATRY 2005;57:134 – S. Tordjman et al
138
wake disturbances. Zhdanova et al (1997) mengkarakterisasi kemungkinan perubahan
found that 13 children with Angelman melatonin dalam autisme, kami mempelajari
syndrome tended to have lower peak
melatonin levels than those reported for sekresi melatonin nokturnal dalam kelompok
normal children of a similar age range; four of besar individu dengan autisme dan kontrol
the children exhibited a phase delay in normal yang sesuai dengan usia, jenis
nocturnal melatonin secretion. Three studies kelamin dan tahap pubertas, dan meneliti
have examined melatonin secretion in autistic
disorder, either by measuring blood levels
juga hubungan antara melatonin dan tingkat
(Kulman et al 2000; Nir et al 1995) or urinary keparahan dari gangguan autistik.
excretion of melatonin (Ritvo et al 1993). The
studies have been limited by small sample
sizes (10-14 subjects) and the results have not
been entirely consistent. Kulman et al (2000)
and Nir et al (1995) reported decreased
nighttime serum melatonin levels associated
with an abnormal or blunted circadian rhythm
of melatonin secretion, while Ritvo et al
(1993) reported increased daytime urinary
melatonin levels and similar night time values
compared to normal controls.

Sebagian besar studi yang telah meneliti

produksi melatonin pada gangguan
perkembangan telah dilakukan pada anak-
anak dengan gangguan yang terkait dengan
keterbelakangan mental. Palm dan rekan
(1997) melaporkan bahwa waktu serum
puncak atau kadar melatonin urin tertunda
pada tujuh dari delapan anak-anak tunanetra
yang terbelakang mental dan dewasa muda
dengan gangguan tidur-bangun sirkadian.
Zhdanova et al (1997) menemukan bahwa 13
anak-anak dengan sindrom Angelman
cenderung memiliki kadar melatonin puncak
yang lebih rendah daripada yang dilaporkan
untuk anak-anak normal pada rentang usia
yang sama; empat dari anak-anak
menunjukkan penundaan fase dalam sekresi
melatonin nokturnal. Tiga studi telah meneliti
sekresi melatonin pada gangguan autistik, baik
dengan mengukur kadar darah (Kulman et al
2000; Nir et al 1995) atau ekskresi melatonin
urin (Ritvo et al 1993). Studi telah dibatasi
oleh ukuran sampel kecil (10-14 subjek) dan
hasilnya belum sepenuhnya konsisten.
Kulman et al (2000) dan Nir et al (1995)
melaporkan penurunan kadar serum melatonin
malam hari terkait dengan irama sirkadian
abnormal atau tumpul sekresi melatonin,
sementara Ritvo et al (1993) melaporkan
peningkatan kadar melatonin kemih siang hari
dan nilai waktu malam yang serupa
dibandingkan ke kontrol normal.

In order to better characterize the possible

melatonin alter- ation in autism, we studied
nocturnal melatonin secretion in large groups
of individuals with autism and normal controls
matched on age, sex and stage of puberty, and
examined also the relationship between
melatonin and severity of the autistic disorder. Secretion of melatonin was assessed by measuring the overnight
Dalam rangka untuk lebih
www.elsevier.com/locate/biopsych
S. Tordjman et BIOL PSYCHIATRY 2005;57:134 –138
al 137
urinary output of the predominant melatonin autistic disorder were cognitively impaired (mean full scale IQ ±
metabo- lite, 6-sulphatoxymelatonin (6-SM). It
is well-established that urinary excretion of 6-
SM gives an accurate reflection of pineal SD: 42.2 ± 3.2, with a range of 40-58; mean verbal IQ ± SD: 45.5
melatonin secretion (Deacon and Arendt 1994; ± 2.2, with a range of 45-57; mean performance IQ ± SD: 45.6
Markey et al 1985; Matthews et al 1991).
Indi Norm ± 4.1, with a range of 45-80).
vidu al
Sekresi melatonin dinilai dengan mengukur V als C Statist Metode dan Bahan
output urin semalam dari metabolit a with on ic t/y2 Subjek
r Auti tro
melatonin dominan, 6-sulfatoksimelatonin i stic l
Anak-anak dan remaja
(6-SM). Sudah diketahui bahwa ekskresi a Diso S dengan gangguan autistik
b rder ub (n = 50) dipasangkan
urin 6-SM memberikan refleksi akurat l dengan individu kontrol
(n = je
sekresi melatonin pineal (Deacon dan e 50) ct normal (n = 88) pada usia,
Arendt 1994; Markey et al 1985; Matthews s jenis kelamin dan tahap
et al 1991). (n pubertas Tanner yang
= dinilai oleh dokter anak
Table 1. Demographic Characteristics of Study 88
Groups (Tanner 1962). Data
) demografis disajikan pada
Group Tabel 1 dan menunjukkan
bahwa kedua kelompok
tidak berbeda secara
signifikan sehubungan
dengan usia, jenis
kelamin, status pubertas,
berat badan atau tinggi
badan.
Semua pasien dengan
gangguan autistik direkrut
dari rumah sakit psikiatri
anak Perancis. Individu
kontrol dipulihkan selama
periode tiga bulan dari
pusat medis preventif di
mana mereka pergi untuk
pemeriksaan rutin. Semua
individu di kedua
kelompok mata pelajaran
tidur di rumah orang tua
mereka dan menghadiri
sekolah atau rumah sakit
sehari-hari setiap hari dari
sekitar 9:00 pagi hingga
4:00 sore. Semua subjek
adalah Kaukasia,
nonobese, tidak memiliki
riwayat ensefalopati atau
penyakit
neuroendokrinologis, dan
ditentukan secara fisik
sehat berdasarkan
pemeriksaan oleh dokter
anak. Individu kontrol
tidak diberi obat dan tidak
menunjukkan gangguan
tidur tertentu berdasarkan
kuesioner tidur orang tua.
Dua puluh dari 50 pasien
dengan gangguan autis
diobati. Sembilan pasien
menerima neuroleptik dan
tujuh menggunakan
www.elsevier.com/locate/biopsych
 138 BIOL PSYCHIATRY 2005;57:134 – S. Tordjman et al
138
b ti f D: 45,5 ± 2,2, respect to age, sex, pubertal using the subset of items
e d d dengan kisaran status, weight or height. included in the ADOS (module
n a ( e 45-57; rata-rata All patients with autistic 1) algorithm, following a
z k r n IQ kinerja ± SD: disorder were recruited from procedure previously described
o n a g 45,6 ± 4,1, French child psychiatry day (Tordj- man et al 2001).
d y t a dengan kisaran hospitals. The control Because the ADOS items are
i a a n 45-80). individuals were re- cruited scored on an ordinal scale
a g - over a three-month period from (from 1 to 3 according to
z a r k a preventive medical center autism severity; the “0” coding
e n a i where they went for a regular means that the autistic
p g t s Based on direct check-up. All individuals in behavior was not present), we
i g a aclinical observation of both subject groups were took the median value of all
n u r the patient by two sleeping in their parents’ house items belonging to the same
Sex M/F 33/17 49/39 1.41 .24 and were attending school or
e a as aindependent 43/33/12 child domain of autistic impairment
Pubertal Status 22/20/8 .33 .85 day hospitals on a daily basis
,Pre/Pub/Post
n k npsychiatrists, a
from about 9:00 AM to 4:00 PM.
according to the ADOS
Aget (years)
a a 11.5diagnosis
± 4.5 of11.0autistic
± 4.4 .59 .56 All subjects were Caucasian,
(module 1) algorithm. This
a
Mean u SD l
± 4disorder was made nonobese, had no history of
gave a score of central
n (kg)
Weight ti a 39.40according
± 19.8 to 40.6
the criteria
± 17.8 .42 .67 encephalopathy or
tendency for each of the four
p ±s SD
Mean - of DSM-IV (American neuroendocrinological disease,
main domains: Reciprocal
a (cm)
Height ti p 141.45Psychi-
± 24.0 atric
145.1 ± 23.1 .89 .37 and were deter- mined to be
Social Interaction Total (7
p ±k SD e
Mean 8Association 1994), physically healthy based on an items), Communication Total
e m n ; ICD-10 and CFTMEA examination by a pediatrician. (5 items), Stereotyped
n e u (Classification Control individuals were Behaviors and Restricted
y n h bFrançaise des Troubles unmedicated and did not show Interests Total (3 items), and
e g eMentaux de l’Enfant et any particular sleep disturbance Play Total (2 items).
s a I r de l’Adolescent; Mises based on a parental sleep
u l Q aand Quemada 1993), questionnaire. Twenty of the 50 Berdasarkan pengamatan klinis
a a r and was confirmed by patients with autistic disorder langsung dari pasien oleh dua
i m ± t the ADI-R (Autism were medicated. Nine patients psikiater anak independen,
a i S i Diagnostic Interview- were receiving neuroleptics and diagnosis gangguan autistik
n g D Revised) and ADOS-G seven were taking dibuat sesuai dengan kriteria
d a : I (Autism Diagnostic benzodiazepines, without dose
DSM-IV (American
o n QObservation Schedule- adjustments, for at least six
Psychiatric Association 1994),
s g 4 Generic) scales (Lord months before the urine
i g 2 v1997). The ADOS-G collection. Nineteen patients ICD-10 dan CFTMEA
s u . e(Module 1), an had a history of idiopathic (Klasifikasi Française des
, a 2 r extensive observational epilepsy, which had been Troubles Mentaux de l'Enfant
u n bscale, was administered diagnosed by a et de l'Adolescent; ADOS-G
n k ± aby one trained child neuropediatrician; twelve were (Modul 1), skala pengamatan
t o l psychiatrist. The receiving anticonvulsive yang luas, dikelola oleh
u g 3 severity of impairments medication at the time of the seorang psikiater anak yang
k n . ±in the behavioral study and for at least one year
before the urine collection. The
terlatih. Tingkat keparahan
s it 2 domains of autism was gangguan dalam domain
protocol was approved by the
e i , Sscored perilaku autisme dinilai
ethics committee of Bicêtre
The numbers of Materials hospital and written informed menggunakan subset item yang
subjects for Tanner consent was obtained from termasuk dalam Algoritma
stages 1, 2, 3, 4 and 5 Subjects parents.
in the group with
ADOS (modul 1), mengikuti
Children and prosedur yang dijelaskan
austistic disorder were
22, 7, 3, 10 and 8, adolescents with Cognitive and Behavioral sebelumnya (Tordjman et al,
respectively; numbers of autistic disorder (n = Assessments
2001) .Karena item ADOS
subjects in the 50) were matched Cognitive functioning of
comparison group were with normal control patients with autistic disorder diberi skor pada skala ordinal
43, 13, 7, 13 and 12, individuals (n = 88) was assessed by two (dari 1 hingga 3 sesuai dengan
respectively. M, male; F, psychologists using the age- tingkat keparahan autisme;
on age, sex and
female.
a
Prepubertal = Tanner stage of appropriate Weschler pengkodean “0” berarti bahwa
Tanner stage 1; puberty assessed by a intelligence scales and the perilaku autistik tidak ada),
Pubertal = Tanner pediatrician (Tanner Kaufman-Assessment Bat- kami mengambil nilai median
2, 3 and 4; 1962). Demographic tery for Children (K-ABC)
Postpuber- dari semua item yang berasal
data are presented in (Anastasi 1988). All patients
tal = Tanner 5. dari domain yang sama dengan
Table 1 and indicate with
penurunan autis menurut
that the two groups
did not differ algoritma ADOS (modul 1). Ini
Methods and memberikan skor
significantly with
www.elsevier.com/locate/biopsych
 S. Tordjman et BIOL PSYCHIATRY 2005;57:134 –138
al 139
kecenderungan bed with lights out sekresi melatonin dapat 030µg/ml control sample
sentral untuk masing- between 9:00 PM ditekan oleh paparan value. Excretion of 6-SM was
masing dari empat and 10:00 PM, and expressed as µg excreted per
none of them was
cahaya, orang tua diminta
domain utama : Total hour (µg/hr) over the
exposed to light untuk melaporkan malam collection period: the urine 6-
Interaksi Sosial
until their morning pengumpulan urin, serta SM concentration (µg/ml)
Timbal-Balik (7
item), Total
wake-up between untuk bulan sebelum was multiplied by the
7:00 AM and 7:45 prosedur melatonin, jika collection volume in ml and
Komunikasi (5 item), AM. No bedwetting divided by the 12 hours of
Perilaku Stereotip, anak mereka tidur dengan collection.
or accidental loss of
dan Total Minat urine was reported. lampu menyala dan jika ia
Terbatas (3 item), dan One prepu- bertal mendapat pada malam ini
Total Play (2 item). boy with autistic dan menyalakan lampu. Penentuan Urin 6-SM
disorder was Pada malam pengumpulan
excluded from the Analisis buta kadar urin 6-
urin, semua individu sulphatoxymelatonin (6-
study due to an
Urine Collection outlying urine dengan gangguan autistik SM) dilakukan oleh
Nocturnal urine collection volume dan subjek pembanding radioimmunoassay
was collected at of only 4 ml. pergi tidur dengan lampu menggunakan kit uji dari
home by parents Collected urines keluar antara jam 21:00 dan
during a 12-hour were stored in a Stockgrand Ltd (Guildford,
period (from 8:00
22:00, dan tidak ada dari Inggris Raya). Sampel urin
refrigerator until
PM to 8:00 AM). delivered to the
mereka yang terpapar diencerkan sebelum
Subjects were in- labora- tory within cahaya sampai pagi mereka pengujian (1/250). Koefisien
structed to empty 24 hours of the bangun antara jam 7 pagi. : variasi intra-assay adalah
their bladder urine collection. 00 pagi dan 7:45 pagi.
between 7:45 PM The volume of the 6% (n = 10) untuk nilai
Tidak dilaporkan sampel kontrol 0,030 μg /
and 8:00 PM. urine collection was
Because of possible measured and a
mengompol atau ml. Ekskresi 6-SM
effects of season on portion frozen until kehilangan urin secara tidak dinyatakan sebagai μg
the secretion of ana- lyzed for sengaja. Seorang anak laki- diekskresikan per jam (μg /
melatonin, urine creatinine and 6- laki pra-bertal dengan
was collected for SM.
jam) selama periode
kelainan autistik pengumpulan: konsentrasi
all the patients with
autistic disorder dikeluarkan dari penelitian 6-SM urin (μg / ml)
Koleksi Urine karena volume
and their dikalikan dengan volume
comparison Urin nokturnal pengumpulan urin hanya 4
dikumpulkan di pengumpulan dalam ml dan
subjects in the ml. Air seni yang dibagi dengan pengumpulan
spring (March- rumah oleh orang terkumpul disimpan dalam
May). Given that tua selama periode 12 jam.
melatonin secretion
lemari es sampai dikirim ke
12 jam (dari jam 8 laboratorium dalam waktu
can be suppressed
by exposure to
malam sampai 8 24 jam dari pengumpulan
light, parents were pagi). Subjek urin. Volume pengumpulan
asked to report for diinstruksikan untuk urin diukur dan sebagian
the night of urine mengosongkan dibekukan sampai dianalisis
collection, as well kandung kemih
as for the month untuk kreatinin dan 6-SM.
mereka antara 19:45
before the
melatonin dan 20:00. Karena
procedure, if their kemungkinan efek
Determination of Urinary 6-
child was sleeping musim pada sekresi SM
with the light on melatonin, urin Blinded analysis of urine
and if he or she got dikumpulkan untuk 6-sulphatoxymelatonin (6-
up during this night SM) levels was performed
and turned on the semua pasien
by radioimmunoassay using
light. On the night dengan gangguan
an assay kit from Stockgrand
of urine collection, autistik dan subjek Ltd (Guildford, United
all the individuals perbandingan Kingdom). The urine
with autistic mereka pada musim samples were diluted prior to
disorder and the assay (1/250). The intra–
comparison
semi (Maret-Mei).
assay coefficient of variation
subjects went to Mengingat bahwa was 6% (n = 10) for a .
www.elsevier.com/locate/biopsych
Figure 1. Distribution of nocturnal 6-SM excretion rates (µg/hr) observed in individuals with autistic disorder and normal control subjects.
Statistical Analysis
Correlations between melatonin excretion rate and age,
weight or height were calculated by Pearson correlation analy-
ses. Group and subgroup comparisons of urine 6-SM levels were
performed using analyses of variance (ANOVA) and two-tailed
Student’s t tests. Relationships between melatonin levels and
autism severity within the major behavioral domains of impair-
ment were studied using Spearman rank-order correlation anal-
yses. In order to balance type I and type II errors in the statistical
analysis of behavioral domains, a hierarchical strategy was used
(Cohen and Cohen 1983). First, the total behavioral domains
were examined. If there was a significant result for an overall
domain, then a further level of analysis occurred on the sub-
scores included in the domain. Group means are reported as
±SEM, unless otherwise indicated; alpha was set at .05 for all
analyses.
Analisis statistik
Korelasi antara tingkat ekskresi melatonin dan usia,
berat atau tinggi dihitung dengan analisis korelasi
Pearson. Perbandingan kelompok dan subkelompok
kadar urin 6-SM dilakukan dengan menggunakan
analisis varians (ANOVA) dan uji t Student dua sisi.
Hubungan antara kadar melatonin dan keparahan
autisme dalam domain perilaku utama dari gangguan
dipelajari dengan menggunakan analisis korelasi rank-
order Spearman. Untuk menyeimbangkan kesalahan tipe
I dan tipe II dalam analisis statistik domain perilaku,
strategi hierarkis digunakan (Cohen dan Cohen 1983).
Pertama, domain perilaku total diperiksa. Jika ada hasil
yang signifikan untuk keseluruhan domain, maka
tingkat analisis lebih lanjut terjadi pada sub-skor yang
termasuk dalam domain. Berarti kelompok dilaporkan
sebagai
± SEM, kecuali dinyatakan sebaliknya; alpha ditetapkan
pada 0,05 untuk semua analisis.
Results
Mean (±SEM) urine collection volumes were similar in the
autistic disorder and control groups (325 ± 77 and 303 ± 15 ml,
respectively). Urinary excretion of creatinine also did not differ
between the autistic disorder and control groups (295 ± 77 and
294 ± 18 mg/collection, respectively). There were no significant
correlations between hourly 6-SM excretion and age, height or
weight in either group or in the combined sample. Among patients
with autistic disorder, there were no differences seen in hourly 6-
SM excretion between patients with and without life- time epilepsy
(.62 ± .13 vs. .93 ± .18 µg/hr, t = 1.40, df = 43.1, p = .17). In
those patients with a lifetime history of epilepsy, no significant
effect of anticonvulsants was seen when medicated and
unmedicated groups were compared (.50 ± .18 vs. .93 ± .18
µg/hr, respectively, t = 1.56, df = 24.9, p = .13). More generally,
medication appeared to have little effect on 6-SM excretion, as
rates were not significantly different in subsets of medicated
patients (anticonvulsants, neuroleptics, benzodiazepines, or all
medications combined) when compared to unmedicated patients.
Hasil
Volume pengumpulan urin rata-rata (± SEM) serupa pada kelompok
autis dan kelompok kontrol (masing-masing 325 ± 77 dan 303 ± 15
ml). Ekskresi kreatinin urin juga tidak berbeda antara gangguan
autistik dan kelompok kontrol (masing-masing 295 ± 77 dan 294 ±
18 mg / pengumpulan). Tidak ada korelasi yang signifikan antara
ekskresi 6-SM setiap jam dan usia, tinggi atau berat badan dalam
kelompok atau dalam sampel gabungan. Di antara pasien dengan
gangguan autistik, tidak ada perbedaan yang terlihat dalam
ekskresi 6-SM setiap jam antara pasien dengan dan tanpa epilepsi
seumur hidup (0,62 ± 0,13 vs 0,93 ± 0,18 μg/jam, t = 1,40, df =
43,1 , p = .17). Pada pasien-pasien dengan riwayat epilepsi seumur
hidup, tidak ada efek antikonvulsan yang terlihat ketika kelompok-
kelompok yang diberi obat dan tanpa obat dibandingkan (0,050 ±
0,18 vs 0,93 ± 0,18 μg/jam, masing-masing, t = 1,56, df = 24,9, p
= 0,13). Lebih umum, pengobatan tampaknya memiliki sedikit
efek pada ekskresi 6-SM, karena tingkat tidak berbeda secara
signifikan dalam himpunan bagian pasien yang diobati
(antikonvulsan, neuroleptik, benzodiazepin, atau semua obat yang
dikombinasikan) bila dibandingkan dengan pasien yang tidak
diobati
A three-way ANOVA including group (autistic disorder,
nor- mal control group), puberty (prepubertal, pubertal and
postpu- bertal) and sex factors showed a significant effect of
group (F = 10.58, df = 1.136, p = .001) and group interacting
with puberty (F = 3.33, df = 1.136, p = .04). There were no
significant effects of puberty or sex alone, or of group
interacting with sex. Patients with autistic disorder had
significantly and substantially lower (42% of control) 6-SM
excretion rates than normal control comparison subjects (.75 ±
.11 vs. 1.80 ± .17 µg/hr, t = 5.22, df = 134.4, p = .0001).
This result was confirmed when comparing drug-free
individuals with autistic disorder (.77 ± .12 µg/hr) to normal
control subjects (t = 5.17, df = 134.6, p =
.0001). The distribution of 6-SM excretion rates in individuals
with autistic disorder and normal controls is shown in Figure 1.
A large proportion of the individuals with autistic disorder
(31/49, 63%) had 6-SM excretion values which were less than
half of the mean excretion rate observed in the control group.
ANOVA tiga arah termasuk kelompok
(gangguan autistik, kelompok kontrol normal),
pubertas (pra-pubertas, pubertas, dan
pascapersalinan) dan faktor jenis kelamin
menunjukkan pengaruh yang signifikan dari
kelompok (F = 10,58, df = 1,136, p = 0,001 ) dan
kelompok yang berinteraksi dengan pubertas (F =
3.33, df = 1.136, p = .04). Tidak ada efek signifikan
dari pubertas atau seks saja, atau interaksi
kelompok dengan seks. Pasien dengan gangguan
autistik memiliki tingkat ekskresi 6-SM yang secara
signifikan dan substansial lebih rendah (42% dari
kontrol) dibandingkan subyek kontrol yang normal
(0,75 ± 0,11 vs 1,80 ± 0,17 μg / jam, t = 5,22, df =
134,4, p = .0001). Hasil ini dikonfirmasi ketika
membandingkan individu bebas obat dengan
gangguan autistik (0,77 ± 0,12 μg / jam) dengan
subyek kontrol normal (t = 5,17; df = 134,6; p =
0.0001). Distribusi tingkat ekskresi 6-SM pada
individu dengan gangguan autistik dan kontrol
normal ditunjukkan pada Gambar 1. Sebagian besar
individu dengan gangguan autistik (31/49, 63%)
memiliki nilai ekskresi 6-SM yang kurang dari
setengah dari tingkat ekskresi rata-rata yang diamati
pada kelompok kontrol.
As seen in Figure 2, no significant puberty-related differences
in 6-SM excretion were found in autistic disorder. However, in
the control group, rates of 6-SM excretion were significantly
higher in prepubertal subjects (2.30 ± .31 µg/hr) compared to
pubertal (1.44 ± .19 µg/hr, t = 2.37, df = 63.7, p = .02) or
postpubertal subjects (1.28 ± .18 µg/hr, t = 2.87, df = 53.9, p
=
.006).
Seperti yang terlihat pada Gambar 2, tidak ada perbedaan
signifikan terkait pubertas dalam ekskresi 6-SM yang
ditemukan pada gangguan autistik. Namun, pada
kelompok kontrol, tingkat ekskresi 6-SM secara
signifikan lebih tinggi pada subjek prapubertas (2,30 ±
0,31 μg/jam) dibandingkan dengan pubertas (1,44 ± 0,19
μg/jam, t = 2,37, df = 63,7, p = 0,02) atau subyek
postpubertal (1,28 ± 0,18 μg/jam; t = 2,87; df = 53,9; p =
0,006).
The lower 6-SM excretion observed in patients with autistic
disorder compared to controls was most marked in prepubertal
subjects (.56 ± .15 vs. 2.30 ± .31 µg/hr, respectively, t = 5.05,
df = 54.8, p < .0001) (see Figure 2) and was more marked in
males (.66 ± .12 vs. 2.20 ± .29 µg/hr, respectively, t = 4.82,
df
= 50.7, p < .0001) than in females (.98 ± .23 vs. 1.48 ± .17
µg/hr, respectively, t = 1.51, df = 63, p = .14).
Ekskresi 6-SM yang lebih rendah diamati pada pasien
dengan gangguan autistik dibandingkan dengan kontrol
yang paling ditandai pada subjek prapubertas (0,56 ± 0,15
vs 2,30 ± 0,31 μg / jam, masing-masing, t = 5,05, df =
54,8, p <. 0001) (lihat Gambar 2) dan lebih ditandai pada
pria (0,66 ± 0,12 vs 2,20 ± 0,29 μg / jam, masing-masing,
t = 4,82; df = 50,7; p <.0001) dibandingkan pada wanita
(0,98 ± 0,23 vs 1,48 ± 0,17 μg/jam, masing-masing, t =
1,51, df = 63, p = .14).
Finally, sleep behavior data obtained on the patients are being
analyzed and will be reported separately; preliminary results do
not indicate that melatonin sulfate excretion was closely associ-
 Discussion
Nocturnal 6-SM excretion rate was significantly and substan-
tially lower in patients with autistic disorder than in normal
comparison subjects, and was significantly negatively correlated
with severity of autistic impairments in verbal communication and
play. The finding of abnormally low nighttime excretion of
melatonin in autism is consistent with two smaller studies of
serum melatonin (Nir et al 1995; Kulman et al 2000). Nir and
colleagues found a mean reduction in nocturnal serum melatonin
of approximately 25% in autistic patients and Kulman et al
reported that none of the 14 patients studied showed a physio-
logical increase of melatonin concentrations during the night. It is
noteworthy that urinary 6-SM, the main melatonin metabolite, has
been reported to be highly correlated with blood melatonin
concentrations in humans (Arendt et al 1985; Markey et al 1985).
Our data and the results of the serum melatonin studies contra-
dict a study reporting no difference in nocturnal levels of urinary
melatonin between patients with autistic disorder and normal
controls (Ritvo et al 1993). However, the study of Ritvo and
colleagues was conducted with adults and the sample size was
relatively small (n = 10). Perhaps more importantly, melatonin

Figure 2. Nocturnal 6-SM excretion rates (mean ± SEM) observed in

indi- viduals with autistic disorder and normal control subjects
grouped by pu- bertal status. ** Prepubertal individuals with autistic
disorder are signifi- cantly different (p < .0001) from prepubertal
normal control individuals; * Prepubertal normal control individuals
are significantly different (p < .01) from pubertal normal control
individuals or postpubertal normal control individuals.

ated with degree of sleep disturbance. However, 6-SM levels

were significantly and negatively correlated with severity of
autistic impairment in total communication (Spearman rho
=
- .45, p = .02), verbal communication (Spearman rho = - .40, p
= .04) and play (Spearman rho = - .41, p = .04). In addition, 6-
SM levels were significantly and positively correlated with
verbal IQ scores (Pearson r = .45, p = .0015), but not with total
IQ or performance IQ.

Akhirnya, data perilaku tidur yang diperoleh pada

pasien sedang dianalisis dan akan dilaporkan secara
terpisah; hasil awal tidak menunjukkan bahwa ekskresi
melatonin sulfat terkait erat dengan tingkat gangguan
tidur. Namun, level 6-SM secara signifikan dan negatif
berkorelasi dengan keparahan gangguan autistik dalam
komunikasi total (Spearman rho = -0,45; p = 0,02),
komunikasi verbal (Spearman rho = -0,40; p = 0,04) dan
mainkan (Spearman rho = - 0,41, p = 0,04). Selain itu,
level 6-SM secara signifikan dan positif berkorelasi
dengan skor IQ verbal (Pearson r = 0,45; p = 0,0015),
tetapi tidak dengan total IQ atau kinerja IQ.
level was expressed as a urine concentration (moles/liter). This
approach does not account for individual and group differences
in urine volumes.
Diskusi
Tingkat ekskresi 6-SM pada malam hari secara
signifikan dan substansial lebih rendah pada pasien
dengan gangguan autistik dibandingkan pada subyek
perbandingan normal, dan secara signifikan
berkorelasi negatif dengan tingkat keparahan
gangguan autistik dalam komunikasi verbal dan
bermain. Temuan ekskresi melatonin rendah pada
malam hari yang abnormal rendah pada autisme
konsisten dengan dua penelitian serum melatonin yang
lebih kecil (Nir et al 1995; Kulman et al 2000). Nir
dan rekannya menemukan pengurangan rata-rata
melatonin serum nokturnal sekitar 25% pada pasien
autis dan Kulman et al melaporkan bahwa tidak ada
dari 14 pasien yang diteliti yang menunjukkan
peningkatan fisiologis konsentrasi melatonin pada
malam hari. Perlu dicatat bahwa 6-SM kemih,
metabolit melatonin utama, telah dilaporkan sangat
berkorelasi dengan konsentrasi melatonin darah pada
manusia (Arendt et al 1985; Markey et al 1985). Data
kami dan hasil penelitian melatonin serum
bertentangan dengan penelitian yang melaporkan tidak
ada perbedaan dalam level malam hari melatonin urin
antara pasien dengan gangguan autistik dan kontrol
normal (Ritvo et al 1993). Namun, penelitian Ritvo
dan rekannya dilakukan dengan orang dewasa dan
ukuran sampel relatif kecil (n = 10). Mungkin yang
lebih penting, kadar melatonin dinyatakan sebagai
konsentrasi urin (mol / liter). Pendekatan ini tidak
memperhitungkan perbedaan individu dan kelompok
dalam volume urin.
This decrease of nocturnal 6-SM excretion was observed
especially in males with autistic disorder, which may be of
interest considering the high male prevalence reported in
autistic disorder (Bryson 1997). The effect of puberty on 6-SM
excretion observed in the control group is consistent with
previous reports suggesting that 6-SM excretion rate and
melatonin secretion rate are higher in prepubertal healthy
children than in pubertal or young adult individuals (Cavallo
and Ritschel 1996; Silman et al 1979), but this effect is not
found in all studies (Bojkowski and Arendt 1990; Griefahn et
al 2003). Our results raise the issue of abnormally low
melatonin excretion in prepubertal individuals with autism.
Indeed, the 6-SM excretion rate observed in the prepubertal
autistic group is seen to be greatly reduced even when
compared to the mean values observed in the older control
subjects (Figure 2). The markedly reduced nocturnal
melatonin production in younger autistic subjects may be of
special interest in terms of neurodevelopmental
consequences.
Penurunan ekskresi 6-SM malam ini diamati terutama pada
pria dengan gangguan autistik, yang mungkin menarik
mengingat tingginya prevalensi pria yang dilaporkan dalam
gangguan autistik (Bryson 1997). Efek pubertas pada ekskresi
6-SM yang diamati pada kelompok kontrol konsisten dengan
laporan sebelumnya yang menunjukkan bahwa tingkat
ekskresi 6-SM dan tingkat sekresi melatonin lebih tinggi pada
anak-anak sehat prapubertas daripada pada individu pubertas
atau dewasa muda (Cavallo dan Ritschel 1996; Silman et al
1979), tetapi efek ini tidak ditemukan dalam semua studi
(Bojkowski dan Arendt 1990; Griefahn et al 2003). Hasil
kami meningkatkan masalah ekskresi melatonin rendah yang
abnormal pada individu prapubertas dengan autisme.
Memang, tingkat ekskresi 6-SM yang diamati pada kelompok
autis prapubertas terlihat sangat berkurang bahkan jika
dibandingkan dengan nilai rata-rata yang diamati pada subjek
kontrol yang lebih tua (Gambar 2). Produksi melatonin
nokturnal yang sangat berkurang pada subjek autis yang lebih
muda mungkin menjadi perhatian khusus dalam hal
konsekuensi perkembangan saraf.
Our finding of negative correlations between 6-SM excretion
and severity of autistic impairment in verbal communication and
play suggests that reduced melatonin secretion is associated with
greater severity of autistic disorder. The significant positive
correlation between verbal IQ scores and 6-SM levels found in
our patients with autistic disorder goes in the same direction,
although the range of IQ scores in the patients was too narrow to
thoroughly test the relationship between IQ scores and 6-SM
levels. The observed correlations between severity of communi-
cation impairments and decreased 6-SM excretion might be
related to previous reports of an association between communi-
cation impairments and problems with sleep onset in low-
functioning children (Quine et al 1991).
Temuan kami tentang korelasi negatif antara 6-SM ekskresi
dan tingkat keparahan gangguan autistik dalam komunikasi dan
permainan verbal menunjukkan bahwa penurunan sekresi
melatonin terkait dengan keparahan gangguan autistik yang lebih
parah. Korelasi positif yang signifikan antara skor IQ verbal dan
level 6-SM yang ditemukan pada pasien kami dengan gangguan
autis berjalan dalam arah yang sama, meskipun kisaran skor IQ
pada pasien terlalu sempit untuk menguji secara menyeluruh
hubungan antara skor IQ dan 6-SM. level. Korelasi yang diamati
antara keparahan gangguan komunikasi dan penurunan ekskresi
6-SM mungkin terkait dengan laporan sebelumnya tentang
hubungan antara gangguan komunikasi dan masalah dengan
onset tidur pada anak-anak yang berfungsi rendah (Quine et al
1991).
The abnormally low group mean excretion of 6-SM found in
patients with autistic disorder could be related to a dysregulation
in circadian rhythms. The hypothesis of dysregulation in neu-
roendocrine functions involved in circadian rhythms is also
supported by Kulman and collaborators (2000) who report that
none of their patient with autistic disorder had a normal mela-
tonin circadian rhythm (10/14 showed no circadian variation and
4/14 showed an inverted circadian rhythm associated with more
pronounced sleep disturbance) and by reports of abnormalities
 in the circadian rhythm of cortisol secretion observed in
individ- uals with autistic disorder (for review, see Tordjman et
al 1997). It can be also speculated that the present findings
might be related to altered serotonin neurobiology. Melatonin is
synthe- sized directly from serotonin, and peripheral and central
abnor- malities in serotonin physiology have been described in
autism (Anderson 2002; Cook and Leventhal 1996).
Ekskresi rata-rata kelompok rendah yang tidak normal dari
6-SM yang ditemukan pada pasien dengan gangguan autis
dapat dikaitkan dengan disregulasi dalam ritme sirkadian.
Hipotesis disregulasi dalam fungsi neokendendrin yang terlibat
dalam ritme sirkadian juga didukung oleh Kulman dan
kolaborator (2000) yang melaporkan bahwa tidak ada pasien
mereka dengan gangguan autistik yang memiliki ritme
sirkadian melanin normal (10/14 tidak menunjukkan variasi
sirkadian dan 4/14 menunjukkan ritme sirkadian terbalik terkait
dengan gangguan tidur yang lebih jelas) dan oleh laporan
kelainan pada ritme sirkadian sekresi kortisol diamati pada
individu dengan gangguan autistik (untuk ulasan, lihat
Tordjman et al 1997). Dapat juga berspekulasi bahwa temuan
ini mungkin terkait dengan neurobiologi serotonin yang
berubah. Melatonin disintesis langsung dari serotonin, dan
kelainan perifer dan sentral dalam fisiologi serotonin telah
dijelaskan dalam autisme (Anderson 2002; Cook dan Leventhal
1996).
Our results, taken together with the prior studies, indicate
clearly that nocturnal secretion of melatonin is reduced in
autism, especially in the more severely affected children. In the
absence of 6-SM excretion data throughout a 24-hour cycle
(due to the inherent difficulties of obtaining complete urine
collection in low functioning children with autistic disorder),
the mechanisms underlying this result remain to be ascertained.
Is there a general decrease in melatonin secretion during the
whole 24-hour cycle, or is the melatonin circadian rhythm
altered, inverted or phase- shifted in autistic disorder? Further
research is necessary to determine whether the diurnal pattern
of melatonin secretion is altered, whether the nocturnal
reduction is influenced by the level of intellectual functioning,
and whether this nocturnal reduction is important in problems
of sleep-wake rhythm often associated with autism. The
significant relationship found in this study between melatonin
levels and severity of autistic impair- ments indicates that
abnormalities in melatonin physiology may play a role in or be
closely linked to the pathophysiology and behavioral
expression of autistic disorder. The biochemical and neuronal
pathways governing pineal melatonin production are well-
characterized and offer promising avenues for investigation.
Given the greatly diminished 6-SM excretion seen in the prepu-
bertal individuals with autism, research may be most fruitfully
focused on younger patients. Finally, there is the prospect that
administration of melatonin could serve, at least in some
autistic individuals, to normalize physiological, developmental
and be- havioral processes that are influenced by this pineal
hormone. Randomized clinical trials would be necessary to
establish po- tential therapeutic efficacy of melatonin in autistic
disorder.
Hasil kami, diambil bersama dengan penelitian
sebelumnya, menunjukkan dengan jelas bahwa sekresi
melatonin di malam hari berkurang dalam autisme,
terutama pada anak-anak yang lebih parah. Dengan tidak
adanya data ekskresi 6-SM sepanjang siklus 24 jam
(karena kesulitan yang melekat dalam memperoleh
pengumpulan urin lengkap pada anak-anak yang berfungsi
rendah dengan gangguan autistik), mekanisme yang
mendasari hasil ini masih harus dipastikan. Apakah ada
penurunan umum dalam sekresi melatonin selama seluruh
siklus 24 jam, atau apakah ritme sirkadian melatonin
diubah, terbalik atau bergeser fase dalam gangguan
autistik? Penelitian lebih lanjut diperlukan untuk
menentukan apakah pola diurnal sekresi melatonin diubah,
apakah reduksi nokturnal dipengaruhi oleh tingkat fungsi
intelektual, dan apakah reduksi nokturnal ini penting dalam
masalah ritme tidur-bangun yang sering dikaitkan dengan
autisme. Hubungan signifikan yang ditemukan dalam
penelitian ini antara kadar melatonin dan keparahan
gangguan autis menunjukkan bahwa kelainan dalam
fisiologi melatonin dapat memainkan peran atau terkait
erat dengan patofisiologi dan ekspresi perilaku gangguan
autistik. Jalur biokimia dan neuron yang mengatur
produksi melatonin pineal ditandai dengan baik dan
menawarkan jalan yang menjanjikan untuk diselidiki.
Mengingat ekskresi 6-SM yang sangat berkurang terlihat
pada individu pra-bertal dengan autisme, penelitian
mungkin paling bermanfaat berfokus pada pasien yang
lebih muda. Akhirnya, ada prospek bahwa pemberian
melatonin dapat berfungsi, setidaknya pada beberapa
individu autis, untuk menormalkan proses fisiologis,
perkembangan dan perilaku yang dipengaruhi oleh hormon
pineal ini. Uji klinis acak akan diperlukan untuk
membangun kemanjuran terapi potensial melatonin pada
gangguan autistik.
This research was supported by La Fondation de France (ST).
American Psychiatric Association (1994): Diagnostic and Statistical Manual
of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Press.
Anastasi A (1988): Psychological Testing, 6th ed. New York: Macmillan.
Anderson GM (2002): Genetics of childhood disorders: XLV. Autism, Part 4:
Serotonin in autism. J Amer Acad Child Adolesc Psychiatry 41:1513–1516.
Arendt J, Bojkowski C, Franey C, Wright J, Marks V (1985): Immunoassay
of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of
the urinary 24-hour rhythm with atenolol. J Clin Endocrinol Metab 60:1166
–
1172.
Bojkowski CJ, Arendt J (1990): Factors influencing urinary 6-sulpha-
toxymelatonin, a major melatonin metabolite, in normal human sub-
jects. Clin Endocrinol 33:435– 444.
Bojkowski CJ, Arendt J, Shih MC, Markey SP (1987): Melatonin secretion
in humans assesses by measuring its metabolite, 6-
sulphatoxymelatonin. Clin Chem 33:1343–1348.
Brezinski A (1997): Melatonin in humans. New Engl J Med 336:186 –
195. Bryson SE (1997): Epidemiology of autism: overview and issues
outstanding.
In: Cohen DJ, Volkmar FR (editors). Handbook of autism and pervasive
developmental disorders, 2nd ed. New York: John Wiley and Sons Inc,
pp 41– 46.
Cavallo A, Ritschel WA (1996): Pharmacokinetics of melatonin in
human sexual maturation. J Clin Endocrinol Metab 81(5):1882–
1886.
 Cohen J, Cohen P (1983): Applied Multiple/correlation Analysis for the
Lewy AJ, Bauer VK, Hasler BP, Kendall AR, Pires ML, Sack RL (2001):
Behav- ioral Sciences, 2nd ed. Hillsdale, NJ: Erlbaum.
Capturing the circadian rhythms of free-running blind people with
Cook BH, Leventhal BL (1996): The serotonin system in autism. Curr
0.5 mg melato- nin. Brain Res 918:96 –100.
Opin Pediatr 8:348 –354.
Lewy AJ, Emens R, Sack RL, Hasler BP, Bernert RA (2002): Low but not
Dahlitz M, Alvarez B, Vignau J, English J, Arendt J, Parkes JD (1991):
high doses of melatonin entrained a free-running blind people
Delayed sleep phase syndrome. Lancet 337:1121–1124.
person with a long circadian period. Chronobiol Int 19:649 – 658.
Deacon SJ, Arendt J (1994): Phase shifts in melatonin, 6-
Lindblom N, Heiskala H, Kaski M, Leinonen L, Laakso ML (2002): Sleep
sulphatoxymelato- nin and alertness rhythms after treatment with
frag- mentation inmentally retarded people decreases with
moderately bright light at night. Clin Endocrinol 40:413– 420.
increasing day length in spring. Chronobiol Int 19:441– 459.
Griefahn B, Brode P, Blaszkewicz M, Remer T (2003): Melatonin
Lockley SW, Skene DJ, Tabandeh H, Bird AC, Defrance R, Arendt J (1997):
production during childhood and adolescence: a longitudinal study
Relation- ship between napping and melatonin in the blind. J Biol
on the excre- tion of urinary 6-hydroxymelatonin sulfate. J Pineal
Rhythms 12:16–25.
Res 34:26 –31.
Lord C (1997): Diagnostic instruments in autism spectrum disorder. In:
Hayashi E (2000): Effect of melatonin on sleep-wake rhythm: The sleep
Co- hen DJ, VolkmarFR (editors). Handbook of autism and pervasive
diary of an autistic male. Psychiatry Clin Neurosci 54:383–384.
devel- opmental disorders, 2nd ed.New York: John Wiley and Sons Inc,
Honomichl RD, Goodlin-Jones BL Burnham M, Gaylor E, Anders T
pp 460 – 483.
(2002): Sleep patterns of children with pervasive developmental
Lord C (1998): What is melatonin? Is it useful treatment for sleep
disorders. J Autism Dev Disord 32:553–561.
problems in autism? J Autism Dev Disord 28:345–346.
Hoshino Y, Wanatabe H, Yashima Y, Kaneko M, Kumashiro H
Markey SP, Higa S, Shih M, Danforth DN, Tamarkin L (1985): The
(1984): An investigation on the sleep disturbance of autistic children.
correlation between human plasma melatonin levels and urinary 6-
Folia Psychiatr Neurol Jpn 38:45–51.
hydroxymelato- nin excretion.Clin Chim Acta 150:221–225.
Ishizaki A, Sugama M, Takeuchi N (1999): Usefulness of melatonin for
Matthews CD, Guerin MV, Wang X (1991): Human plasma melatonin
developmen- tal sleep and emotional/behaviour disorders—studies of
and urinary 6-sulphatoxymelatonin: Studies in natural annual
melatonin trial on 50 patients with developmental disorders. No To
photoperiod and in extended darkness. Clin Endocrinol 35:21–27.
Hattatsu 31:428–437
Mises R, Quemada N (1993): CIM-10 (ICD-10) et Classification Française
Jan J, Freeman RD, Fast DK (1999): Melatonin treatment of sleep-wake
des Troubles Mentaux de l’Enfant et de l’Adolescent [CFTMEA, French
cycle disorders in children and adolescents. Dev Med Child Neurol 41:491–
Classifica- tion of Child and Adolescent Mental Disorders], 3rd ed.
500.
Vanves: Center Technique National d‘Etudes et de Recherches sur
Johnson CR (1996): Sleep problems in children with mental retardation
les Handicaps et les Inadaptations (CTNERHI), Presses
and autism. Child Adolesc Psychiatr Clin N Amer 5:673– 683.
Universitaires de France.
KulmanG,LissoniP,RovelliF,RoselliMG,BrivioF,SequeriP(2000):Evidenceofpineal
Nir I, Meir D, Zilber N, Knobler H, Hadjez J, Lerner Y (1995): Brief
endocrine hypofunction in autistic children. Neuroendocrinol Lett 20:31–
report: circadian melatonin, thyroid-stimulating hormone, prolactin,
34.
and corti- sol levels in serum of young adults with autism. J Autism
Dev Disord 25:641– 654.
Palm L, Blennow G, Wetterberg L (1997): Long-term melatonin treatment
in blind children and young adults with circadian sleep-wake
disturbances. Dev Med Child Neurol 39:319 –325.
Patzold LM, Richdale AL, Tonge BJ (1998): An investigation into sleep
char- acteristics of children with autism and Asperger’s disorder. J
Paed Child Health 34:528 –533.
Quine L (1991): Sleep problems in children with mental handicap. J
Ment Defic Res 35:269 –290.
Reiter RJ, Barlow-Walden L, Poeggeler B, Heiden SM, Clayton RJ
(1996): Twenty-four hour urinary excretion of 6-hydroxymelatonin
sulfate in Down syndrome subjects. J Pineal Res 20:45–50.
Richdale AL (1999): Sleep problems in autism : prevalence, cause, and
inter- vention. Dev Med Child Neurol 41:60 – 66.
Richdale AL, Prior MR (1995): The sleep-wake rhythm in children with
autism.
Eur Child Adolesc Psychiatry 4:175–186.
Ritvo ER, Ritvo R, Yuliwer A, Brothers A, Freeman BJ, Plotkin S (1993):
Elevated daytime melatonin concentration in autism. Eur Child Adolesc
Psychiatry 2:75–78.
Rutter M (1968): Concepts of autism-a review of research. J Child
Psychol Psychiatry 9:1–25.
Sadeh A (1997): Sleep and melatonin in infants : A preliminary study.
Sleep 20:185–191.
Schreck KA, Mullick JA (2000): Parental reports of sleep problems in
children with autism. J Autism Dev Disord 30:127–135.
Silman RE, Leone RM, Hooper RJL, Preece MA (1979): Melatonin, the
pineal gland and human puberty. Nature 282:301.
Tanner JH (1962): Growth of Adolescents. Oxford: Blackwell Scientific
Publi- cations.
Tordjman S, Anderson GM, McBride PA, Hertzig M, Snow M, Hall L,
et al (1997): Plasma beta-Endorphin, Adrenocorticotropin Hormone
and Cor- tisol in Autism. J Child Psychol Psychiatry 38(6):705–716.
Tordjman S, Gutknecht L, Carlier M, Spitz E, Antoine C, Slama F, et al
(2001): Role of the serotonin transporter gene in the behavioral
expression of autism. Mol Psychiatry 6:434 – 439.
Touitou Y (2001): Human aging and melatonin. Clinical relevance. Exp
Ger- ontol 36:1083–1100.
Wetterberg L (1999): Melatonin and clinical application. Reprod Nutr
Dev
39:367–382.
Zhdanova I, Lynch H, Wurtman R (1997): Melatonin: a sleep-
promoting hormone. Sleep 20:899 –907.