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.
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.
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 ␮g/hr, p ⫽.0001), and was significantly negatively correlated with severity
of autistic impairments in verbal communication and play (p ⬍ .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.

Key Words: 6-Sulphatoxymelatonin, melatonin, autistic disorder, an advanced or retarded sleep onset and morning awakening
autism severity, pineal, circadian sleep-wake rhythm (Dahlitz et al 1991). Blind individuals with free-running melato-
nin rhythms tend to take naps synchronized with their daytime
peaks in melatonin secretion (Lockley et al 1997). The stabiliza-

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.
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
From the Center for Scientific Research, Unité de Recherche Mixte 7593,
Vurnérabilité, Adaptation et Psychopathologie, Hôpital Pitié-Salpétrière
(ST, NP), Centre Hospitalier Guillaume Régnier, Faculté de Médecine
Université de Rennes 1; Department of Medical Biochemistry and Molec-
ular Biology (HC, YT), Faculté de Médecine Pitié-Salpétrière, Paris, France;
and the Child Study Center (GMA), Yale University School of Medicine,
New Haven, Connecticut.
Address reprint requests to Sylvie Tordjman, M.D., Ph.D., Centre Hospitalier
Guillaume Régnier, 154 rue de Châtillon, 35200 Rennes, France; E-mail:
lubart@idf.ext.jussieu.fr.
Received May 12, 2004; revised September 14, 2004; accepted November 1,
2004.
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).
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).
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-
wake disturbances. Zhdanova et al (1997) found that 13 children
with Angelman syndrome tended to have lower peak melatonin
levels than those reported for normal children of a similar age
range; four of the children exhibited a phase delay in nocturnal
melatonin secretion. Three studies have examined melatonin
secretion in autistic disorder, either by measuring blood levels
(Kulman et al 2000; Nir et al 1995) or urinary 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.
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

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doi:10.1016/j.biopsych.2004.11.003 © 2005 Society of Biological Psychiatry
S. Tordjman et al BIOL PSYCHIATRY 2005;57:134 –138 135

Table 1. Demographic Characteristics of Study Groups autistic disorder were cognitively impaired (mean full scale IQ ⫾
SD: 42.2 ⫾ 3.2, with a range of 40-58; mean verbal IQ ⫾ SD: 45.5
Group
⫾ 2.2, with a range of 45-57; mean performance IQ ⫾ SD: 45.6
Individuals with Normal Control ⫾ 4.1, with a range of 45-80).
Autistic Disorder Subjects Based on direct clinical observation of the patient by two
Variable (n ⫽ 50) (n ⫽ 88) Statistic t/␹2 P independent child psychiatrists, a diagnosis of autistic disorder
was made according to the criteria of DSM-IV (American Psychi-
Sex M/F 33/17 49/39 1.41 .24
atric Association 1994), ICD-10 and CFTMEA (Classification
Pubertal Statusa 22/20/8 43/33/12 .33 .85
Française des Troubles Mentaux de l’Enfant et de l’Adolescent;
Pre/Pub/Post
Age (years) 11.5 ⫾ 4.5 11.0 ⫾ 4.4 .59 .56
Mises and Quemada 1993), and was confirmed by the ADI-R
Mean ⫾ SD (Autism Diagnostic Interview-Revised) and ADOS-G (Autism
Weight (kg) 39.4 ⫾ 19.8 40.6 ⫾ 17.8 .42 .67 Diagnostic Observation Schedule-Generic) scales (Lord 1997).
Mean ⫾ SD The ADOS-G (Module 1), an extensive observational scale, was
Height (cm) 141.4 ⫾ 24.0 145.1 ⫾ 23.1 .89 .37 administered by one trained child psychiatrist. The severity of
Mean ⫾ SD impairments in the behavioral domains of autism was scored
using the subset of items included in the ADOS (module 1)
The numbers of subjects for Tanner stages 1, 2, 3, 4 and 5 in the group
with austistic disorder were 22, 7, 3, 10 and 8, respectively; numbers of algorithm, following a procedure previously described (Tordj-
subjects in the comparison group were 43, 13, 7, 13 and 12, respectively. M, man et al 2001). Because the ADOS items are scored on an
male; F, female. ordinal scale (from 1 to 3 according to autism severity; the “0”
a
Prepubertal ⫽ Tanner stage 1; Pubertal ⫽ Tanner 2, 3 and 4; Postpuber- coding means that the autistic behavior was not present), we
tal ⫽ Tanner 5. took the median value of all items belonging to the same domain
of autistic impairment according to the ADOS (module 1)
overnight urinary output of the predominant melatonin metabo-
algorithm. This gave a score of central tendency for each of the
lite, 6-sulphatoxymelatonin (6-SM). It is well-established that
four main domains: Reciprocal Social Interaction Total (7 items),
urinary excretion of 6-SM gives an accurate reflection of pineal
Communication Total (5 items), Stereotyped Behaviors and
melatonin secretion (Deacon and Arendt 1994; Markey et al 1985;
Restricted Interests Total (3 items), and Play Total (2 items).
Matthews et al 1991).

Methods and Materials Urine Collection

Subjects
Children and adolescents with autistic disorder (n ⫽ 50) were
matched with normal control individuals (n ⫽ 88) on age, sex
and Tanner stage of puberty assessed by a pediatrician (Tanner
1962). Demographic data are presented in Table 1 and indicate
that the two groups did not differ significantly with respect to
age, sex, pubertal status, weight or height.
All patients with autistic disorder were recruited from French
child psychiatry day hospitals. The control individuals were re-
cruited over a three-month period from a preventive medical center
where they went for a regular check-up. All individuals in both
subject groups were sleeping in their parents’ house and were
attending school or day hospitals on a daily basis from about 9:00 AM
to 4:00 PM. All subjects were Caucasian, nonobese, had no history of
encephalopathy or neuroendocrinological disease, and were deter-
mined to be physically healthy based on an examination by a
pediatrician. Control individuals were unmedicated and did not
show any particular sleep disturbance based on a parental sleep
questionnaire. Twenty of the 50 patients with autistic disorder were
medicated. Nine patients were receiving neuroleptics and seven
were taking benzodiazepines, without dose adjustments, for at least
six months before the urine collection. Nineteen patients had a
history of idiopathic epilepsy, which had been diagnosed by a
neuropediatrician; twelve were receiving anticonvulsive medication
at the time of the study and for at least one year before the urine
collection. The protocol was approved by the ethics committee of
Bicêtre hospital and written informed consent was obtained from
parents.
Cognitive and Behavioral Assessments
Cognitive functioning of patients with autistic disorder was
assessed by two psychologists using the age-appropriate
Weschler intelligence scales and the Kaufman-Assessment Bat-
tery for Children (K-ABC) (Anastasi 1988). All patients with
Nocturnal urine was collected at home by parents during a
12-hour period (from 8:00 PM to 8:00 AM). Subjects were in-
structed to empty their bladder between 7:45 PM and 8:00 PM.
Because of possible effects of season on the secretion of
melatonin, urine was collected for all the patients with autistic
disorder and their comparison subjects in the spring (March-
May). Given that melatonin secretion can be suppressed by
exposure to light, parents were asked to report for the night of
urine collection, as well as for the month before the melatonin
procedure, if their child was sleeping with the light on and if he
or she got up during this night and turned on the light. On the
night of urine collection, all the individuals with autistic disorder
and the comparison subjects went to bed with lights out between
9:00 PM and 10:00 PM, and none of them was exposed to light
until their morning wake-up between 7:00 AM and 7:45 AM. No
bedwetting or accidental loss of urine was reported. One prepu-
bertal boy with autistic disorder was excluded from the study due
to an outlying urine collection volume of only 4 ml. Collected
urines were stored in a refrigerator until delivered to the labora-
tory within 24 hours of the urine collection. The volume of the
urine collection was measured and a portion frozen until ana-
lyzed for creatinine and 6-SM.
Determination of Urinary 6-SM
Blinded analysis of urine 6-sulphatoxymelatonin (6-SM) levels
was performed by radioimmunoassay using an assay kit from
Stockgrand Ltd (Guildford, United Kingdom). The urine samples
were diluted prior to assay (1/250). The intra–assay coefficient of
variation was 6% (n ⫽ 10) for a .030␮g/ml control sample value.
Excretion of 6-SM was expressed as ␮g excreted per hour
(␮g/hr) over the collection period: the urine 6-SM concentration
(␮g/ml) was multiplied by the collection volume in ml and
divided by the 12 hours of collection.

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136 BIOL PSYCHIATRY 2005;57:134 –138
Figure 1. Distribution of nocturnal 6-SM excretion rates (␮g/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.
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 ␮g/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 ␮g/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, benzodiaz-
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S. Tordjman et al
epines, or all medications combined) when compared to un-
medicated patients.
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 ␮g/hr, t ⫽ 5.22,
df ⫽ 134.4, p ⫽ .0001). This result was confirmed when
comparing drug-free individuals with autistic disorder (.77 ⫾ .12
␮g/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.
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 ␮g/hr) compared to
pubertal (1.44 ⫾ .19 ␮g/hr, t ⫽ 2.37, df ⫽ 63.7, p ⫽ .02) or
postpubertal subjects (1.28 ⫾ .18 ␮g/hr, t ⫽ 2.87, df ⫽ 53.9, p ⫽
.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 ␮g/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 ␮g/hr, respectively, t ⫽ 4.82, df
⫽ 50.7, p ⬍ .0001) than in females (.98 ⫾ .23 vs. 1.48 ⫾ .17
␮g/hr, respectively, 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-
S. Tordjman et al
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.
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
BIOL PSYCHIATRY 2005;57:134 –138 137
level was expressed as a urine concentration (moles/liter). This
approach does not account for individual and group differences
in urine volumes.
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.
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).
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).
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
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138 BIOL PSYCHIATRY 2005;57:134 –138
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.
This research was supported by La Fondation de France (ST).
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