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Brain & Development 30 (2008) 454–460
www.elsevier.com/locate/braindev
Original article
Use of clonidine in children with autism spectrum disorders
Xue Ming a,*, Emily Gordon b, Ning Kang c, George C. Wagner d
a
Department of Neuroscience and Pediatrics, UMDNJ – New Jersey Medical School, 90 Bergen Street,
Doctor’s Oﬃce Center 8100, Newark, NJ 07103, USA
b
Class of 2009, UMDNJ – New Jersey Medical School, Newark, NJ, USA
c
Department of Biostatistics, School of Public Health, University of California, Los Angeles, CA, USA
d
Department of Psychology, Rutgers University, New Brunswick, NJ, USA
Received 20 July 2007; received in revised form 18 November 2007; accepted 14 December 2007
Abstract
Children with autism spectrum disorders (ASD) often exhibit sleep and behavioral disorders. Treatment of sleep disorders can be
diﬃcult in these children. Clonidine, an a2-adrenergic receptor agonist, has been shown to be eﬀective in reducing impulsivity, inattention, and hyperactivity, as well as in serving as a sedative for medial procedures. An open labeled retrospective study of clonidine
in treatment of insomnia, and/or hyperactivity, inattention, mood disorder, and aggressive behaviors was conducted using parent
reports of sleep initiation and maintenance, as well as behaviors prior and during clonidine treatment. Clonidine was eﬀective in
reducing sleep initiation latency and night awakening, to a less degree in improving attention deﬁcits hyperactivity, mood instability
and aggressiveness in this cohort of 19 children with ASD. The side eﬀects were largely tolerable. Further evaluation with placebocontrolled double-blind clinical trial of clonidine use in ASD will provide more insight into the clinical eﬃcacy and safety of the
medicine in ASD.
Ó 2007 Elsevier B.V. All rights reserved.
Keywords: Autism spectrum disorders; Clonidine; Sleep disorders; Attention deﬁcit hyperactivity disorders; Aggression; Mood instability
1. Introduction
Children with autism spectrum disorders (ASD) suffer from medical and psychiatric conditions including
sleep disturbances, gastrointestinal dysfunction, mood
disorders, aggressive behaviors, and attention-deﬁcit
hyperactivity [1–5]. With respect to the sleep disturbances, it has been reported that between 40% and
80% of children with ASD have problematic sleep patterns that are often severe in nature [6–9]. The sleep
problems include diﬃculty in settling to sleep, lengthy
episodes of night waking with or without confusion,
early morning awakening, shortened night sleep, para*
Corresponding author. Tel.: +1 973 972 5204; fax: +1 973 972
9553.
E-mail address: mingxu@umdnj.edu (X. Ming).
0387-7604/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.braindev.2007.12.007
somnia (including bruxism), and irregularities of the
sleep/wake rhythm [1,10–17]. The impact of these sleep
disorders in children with ASD is of particular concern
in light of the increased burden and stress experienced
in parenting a child with ASD. Sleep problems have
been correlated with family or parental distress in normally developing children and in children with an intellectual disability[18,19]. The children with ASD who
had sleep disorders were frequently reported to have
more problems in social relatedness, and other daytime
behavior diﬃculties [20]. Parents reported improvement
of daytime performance following treatment of the sleep
disorders [21–23].
In addition to the sleep disturbances, other behavioral disorders occur with higher frequency in children
with ASD and present still additional problems for their
caregivers. These include mood disorders, aggressiveness
X. Ming et al. / Brain & Development 30 (2008) 454–460
and self-injurious behaviors, obsessive- and compulsivelike behaviors, anxiety, and ritualistic behaviors [3,5,24].
Unfortunately, treatment of these medical and behavioral symptoms associated with ASD has been challenging. Pakyurek et al. [21] reported behavioral and sleep
improvement in two children after tonsillar and adenoidectomy. However, for most children with ASD
whose causes of sleep disorder or behavioral disorders
remain unidentiﬁed, treatment is largely symptombased. Melatonin has been shown to be eﬃcacious in
some ASD children for treatment of sleep onset insomnia. Unfortunately, the beneﬁcial eﬀects of melatonin
diminish over time despite administration of increasing
doses [25]. Traditional hypnotics and sedatives exhibit
various degrees of beneﬁcial eﬀects but present the risk
of side eﬀects such as sedation during daytime. The
other behavioral disorders associated with ASD could
be quite refractory to medication. Atypical neuroleptics,
SSRIs, anti-depressants, anti-convulsants, and other
agents have all been tried in targeting various behavioral
symptoms with variable degree of success, even when
used in conjunction with behavioral therapy [26]. Thus,
there is a need to identify a safe and eﬃcacious treatment for the broad spectrum of medical and behavioral
symptoms associated with ASD.
Clonidine is a centrally acting a2-adrenergic agonist
that has been administered to children with ASD for
the treatment of hyperactivity and impulsivity, sleep disorder as well as for sedation, prior to EEG recording
[27–30]. A placebo-controlled, double-blind trial of
transdermal clonidine showed it to be eﬀective in reducing hyperarousal in children with ASD and that this
calming action resulted in improved social relationships,
improved aﬀectual responses, and an overall improvement in Clinical Global Impression scales in some subjects [27]. However, Hazell [29] believed clonidine
along with dexamphetamine, clomipramine, mirtazapine, and ﬂuoxetine are of unlikely beneﬁt in treating
attention deﬁcits and hyperactivity disorder (ADHD)
in children with autism. Our own anecdotal observations indicated that clonidine administration may be
beneﬁcial for the treatment of sleep disorders in children
with or without ASD.
This study is an open-labeled, semi-quantitative pilot
study using parental report to examine the eﬃcacy of
clonidine in the treatment of sleep and behavioral disorders in children with ASD.
2. Methods
Seventeen children with sleep and behavioral disorders, and two children with behavioral disorders only
were treated with clonidine between 1999 and 2002
were recruited for this study (Table 1). A total of 25
ASD children had been prescribed clonidine during this
time period; six were excluded from this study due to
455
Table 1
Demographic Characteristics of the cohort
Number of Subjects
Sex (male:female)
Age
Range
Median
ASD diagnosis (number of subjects)
Autistic disorder
PDD-NOS
Asperger’s disorder
19
14:5
4–16 years
12 years
12
5
2
(1) loss of follow-up, (2) clonidine was discontinued
after only brief period of time as result of side eﬀects,
or paradoxical irritability, or (3) parental refusal of
study participation. The diagnosis of ASD [autistic disorder, pervasive developmental disorder-not otherwise
speciﬁed (PDD-NOS), Asperger’s disorder] was made
based on DSM IV [31]. Four subjects had additional
diagnostic testing by autism diagnostic interviewrevised (ADI-R), or autism diagnostic observation
schedule-generic (ADOS-G). The participants included
14 males and 5 females, which is consistent with the
male dominance of this disorder. Two children had
Asperger’s disorder and ﬁve had PDD-NOS; the rest,
autistic disorder. The ages of the subjects ranged from
4 to 16 years and the racial backgrounds were diverse,
including Caucasian, African, Asian, and Hispanic
American. Clinical comorbic disorders of each subject
are shown in Table 2. These comorbic disorders are largely consistent with the reported comorbidities in ASD
[5]. The cognitive capacity of the subjects were assessed
by psychologists in the Child Study Team of the subjects’ schools. Psychological instruments appropriate
for the subjects’ age at the time of testing were used.
These instruments include Wechsler Intelligence Scale
for Children (WISC), Naglieri Nonverbal Ability Test,
Stanford–Binet IQ test, Woodcock–Johnson Test. Five
subjects were not tested of cognitive capacity due to
their behavioral disorders that testing was deemed difﬁcult or impossible. The results of the cognitive tests
were expressed as greater or less than 50th percentile
of the test. All children were patients of the pediatric
neurologist (XM) at The Autism Center, UMDNJ –
New Jersey Medical School.
The indication for clonidine treatment was sleep initiation and sleep maintenance diﬃculty in 17 children, tic
disorder with ADHD in one child, and ADHD in one
child. Fifteen children had both sleep disorders and
behavioral disorders, such as ADHD, mood disorders,
and/or aggression. We operationally deﬁned sleep initiation diﬃculty as a sleep onset latency of greater than
one hour and sleep maintenance diﬃculty as a failure
to resume sleep within 30 min upon awakening from
sleep at night. ADHD and mood disorder were made
based on DSM IV criteria [31]. Aggressive behaviors
456
Table 2
Eﬃcacy of clonidine on sleep and behavioral disorders in ASD
Subject
A, B, E, G
B, C, I
A, B, C
A, B, C
A, B, F, I
A, B, E
A, B, C
A, B, D, E, G
C, E, H
A, B, E
A, B, E
A, B, D, I
A, B, C, D
A, B, D, E, I
A, C, E
A, C, E
C, E, G, H
A, B, D, E
A, B, C, E
Cognitive
testsb
<50%
NT
<50%
NT
>50%
>50%
>50%
NT
>50%
<50%
>50%
<50%
>50%
NT
<50%
<50%
NT
<50%
>50%
Concurrent medicationsc
None
Topiramate, Aripiprazole
Sertraline, Topiramate
Aripiprazole, Valproate
Fluvoxamine
None
None
Valproate
None
None
Aripiprazole
Topiramate
Valproate, Aripiprazole
Topiramate, Atomoxetine
Risperidone, Sertraline
Melatonin, Risperdal
Risperidone
Valproate
Risperidone
Sleep latencyd (h)
Numbers of night awakeningse
Behavior improvement while receiving
clonidinef
Without clonidine
With clonidine
Without clonidine
With clonidine
Aggressiong
ADHDh
Mood disorderi
5
<0.5
2
3
3
3
3
5
NA
4.5
4.5
2
3
4
3.5
5
NA
5
2
<0.5
<0.5
<0.5
<0.5
1
<0.5
1
1
NA
1
1.2
0.5
<0.5
.05
<0.5
2
NA
0
1
2
1
3
4
1
2
1
2
NA
3
2
2
3
5
0
1
NA
1
1
0
0
0
2
0
0
0
1
NA
0
0
0
1
1
0
0
NA
0
1
1
2
1
2
NAj
3
3
1
1
3
NA
3
3
2
1
1
1
3
3
1
2
2
1
NA
3
3
2
2
2
NA
1
3
1
2
1
2
1
3
1
3
1
2
NA
3
3
2
2
1
NA
2
3
3
1
2
2
1
3
a
Clinical comorbidity include: A, sleep initiation disorder; B, sleep maintenance disorder; C, mood disorder; D, epilepsy; E, attention-deﬁcit hyperactivity disorder; F, anxiety disorder; G,
aggressiveness; H, tic disorder; I, gastrointestinal dysfunction.
b
See Method for details of the cognitive tests. Results are expressed as greater or less than 50th percentile of the corresponding test. NT, not tested.
c
The concurrent medications the subjects received in addition to clonidine. Clonidine was administered once daily on regular basis, except Subject 19 who received clonidine intermittently on an as
needed basis.
d
The values in the columns are the estimated duration of sleep latency as measured by the number of hours from the subjects were put in bed (light out) to sleep initiation with and without
clonidine. p < 0.0001 (sign rank test).
e
The numbers of episodes of night awakening from sleep that lasted more than 30 min with and without clonidine. p < 0.0001 (sign rank test).
f
Behavioral improvement while the subjects were receiving clonidine treatment. The measurement was made by using a symptoms improvement scale: 1 = no improvement in behavior,
2 = behavior improved but still present, and 3 = complete resolution of the behavior.
g
Aggression was signiﬁcantly improved (p < 0.0001, sign test).
h
Symptoms of ADHD was signiﬁcantly improved (p < 0.0001, sign test).
i
Symptoms of mood disorder was signiﬁcantly improved (p < 0.0001, sign test).
j
NA: not applicable.
X. Ming et al. / Brain & Development 30 (2008) 454–460
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Clinical
comorbiditya
X. Ming et al. / Brain & Development 30 (2008) 454–460
were deﬁned as unprovoked kicking, biting, pinching,
hitting, or head banging toward self or others that
occurred on a daily basis and were persistent for an estimate of 6 months or more. The use of clonidine was ‘‘as
needed” in two children and ‘‘once daily” in 17 children.
Fourteen children were on clonidine for more than
2 years. The rest of the children used clonidine for more
than 6 months. The initial dose of clonidine was 0.05 mg
and gradually advanced to 0.1 mg at bedtime. Seven
children were prescribed a transdermal clonidine patch
at dose of 0.1 mg per day but only two of these children
remained on patch form; the other ﬁve were switched to
oral tablets due to either skin irritation and/or behavioral sensory hypersensitivity to adhesives on skin. Of
the children who were on tablets, eight took additional
daytime clonidine for their behavioral disorders.
The caregivers were asked to provide, in a typical
week, an average estimate of sleep onset time (lights
out to sleep onset) and number of night awakenings with
diﬃculty in resuming sleep (sleep resumption did not
occur within 30 min), both prior to and during the clonidine treatment. The average sleep initiation time and
the number of night awakenings were recorded as part
of the clinical record that the caregivers were asked to
provide during clinical visits prior to start of clonidine.
The same sleep parameters were then collected while
the child was on clonidine treatment. These were
obtained during follow-up clinical visits after clonidine
had been administered for at least 1 month.
Finally, the behavioral disorders that clonidine was
used to treat included ADHD, aggression, mood disorder, and tic disorder. Some subjects exhibited combinations of these behavioral disorders. Improvements in
behavioral symptoms after initiation of clonidine were
rated by parents or caregivers as 1 (no improvement),
2 (some improvement) or 3 (complete resolution of the
symptoms).
Statistical analysis was performed on the parameters
with and without clonidine. Due to non-normal distribution and small number of cases, sign test, the nonparametric analog of the single-sample t-test, was
chosen and performed for each of the three behavioral
disorder variables; sign rank, the nonparametric analog
of the paired t-test was carried out for each of the two
sleep disorder variables. In cases of sleep latency less
than 0.5 h, 0.5 was used to calculate the statistical
signiﬁcance.
This study was approved by the Institutional Review
Board of our institute and informed consent was
obtained from parents or guardians.
3. Results
Seventeen of the 19 subjects were prescribed clonidine
for sleep disorder. All 16 children who had prolonged
sleep initiation exhibited a reduction in sleep initiation,
457
and 16 of the 17 children with sleep maintenance diﬃculty had reduction in the frequency of awakening during the nights. The range of average sleep initiation prior
to clonidine treatment was 2–5 h with the exception of
one child whose sleep initiation was within 30 min.
The range of average sleep initiation during clonidine
treatment was less than 30 min–2 h. Subject #2 did not
have sleep initiation diﬃculty and clonidine was given
for the lengthy night awakening. Clonidine did slightly
reduce his sleep initiation time as well. Although two
subjects still suﬀered from prolonged sleep initiation
(>1 h), the caregivers of both subjects expressed satisfaction with the eﬀect of clonidine. In regard to sleep maintenance, 16 children responded favorably while one
child continued to have similar frequency of night awakenings. This child (subject 19) did beneﬁt from clonidine
in reducing sleep initiation time. There were ﬁve subjects
who still experienced night awakenings while on clonidine. The eﬀect of clonidine in improving sleep disorders
was almost immediate, within the ﬁrst week of administration, despite the fact that all subjects were initiated at
a lower dose. However, the dose of clonidine had to be
increased after prolonged use (after approximately
1 year).
All 19 children had one or more behavioral diﬃculties. Two children were taking clonidine exclusively for
behavioral causes, one for ADHD, the other for tic disorder with comorbic ADHD. The parents reported various improvements of the behaviors after the clonidine.
There was no uniform improvement of one speciﬁc
behavior consistently among the subjects. However, four
subjects had complete resolution of their behavioral disorders while on clonidine. Subject 1 had no improvement
of behaviors although this subject did experience the
beneﬁcial eﬀects of clonidine in the management of the
sleep disturbances. The majority of subjects had some
improvement in their behavioral symptoms while on clonidine. Nonetheless, the overall parental satisfaction was
less favorable for the behavioral improvements while
taking clonidine as compared to that of the sleep
disorders.
The frequency of adverse reactions to clonidine was
rare. Skin irritation to transdermal patches was, however, frequent and in all cases leading to discontinuation
of the transdermal patches. When clonidine tablets were
administered during the daytime, sedation was the most
frequent complaint. Other side eﬀects such as pallor,
lethargy, tachycardia, or hypotension during examination were rare. However, side eﬀects such as dizziness
or mild depression may have been under-reported
because the language and expression impairment in
these children could be a potential barrier in detecting
these side eﬀects. One child who was not enrolled in this
study had signiﬁcant pallor and clonidine was discontinued after just one dose. Another child, aged 15 years,
developed paradoxical irritability that the parents attrib-
458
X. Ming et al. / Brain & Development 30 (2008) 454–460
uted to clonidine use. Again, this child was not enrolled
in this study due to the brief use of the medicine.
The use of concurrent medications for comorbic disorders in each subject is shown in Table 2. Fourteen of
the 19 children used other medications during clonidine
treatment period; 11 of these 14 children were on the
same medications and the same doses of the concurrent
medication during this study period, therefore clonidine
was the only variant of treatment in these 11 children.
However, three children had other variants of treatment,
in addition to clonidine administration. One child initiated aripiprazole, one child initiated sertraline, and a
third child had a decreasing dose of topiramate, during
the clonidine treatment period.
4. Discussion
Clonidine is an a-adrenergic agonist that acts on presynaptic neurons predominantly of brainstem to inhibit
norepinephrine activity. As a result, sympathetic outﬂow is inhibited, leading to decrease in peripheral resistance, heart rate, and blood pressure. Such a mechanism
could explain the therapeutic beneﬁt of clonidine in the
treatment of sympathetic hyper-arousal states associated
with ADHD, aggressiveness, tic disorder etc. The sedative eﬀects of clonidine are well recognized and are listed
as ‘‘adverse eﬀects” in the Physician’s Desk Reference
[32].
The results presented suggest that clonidine is a viable
option for clinicians treating ASD patients with insomnia and/or behavioral problems such as aggression,
mood disorder, and ADHD. Almost all the children
with ASD and sleep disorders beneﬁted from clonidine
treatment, although the degree of improvement was
individualized. Sleep initiation time was the most dramatically improved parameter in our subjects; the group
mean sleep initiation time decreased from 3.19 to 0.6 h.
The mean frequency of interruptions in sleep of the
group also decreased greatly. Clonidine enabled many
of our subjects to sleep through the night for the ﬁrst
time in years. The improvements in behavioral disorders
were less dramatic and more variable. It is not clear why
the four subjects had dramatic response to clonidine.
Two subjects (Subjects 6 and 7, both girls) who exhibited complete resolution of the behavioral diﬃculties
were not on any other concomitant medication. Another
child (Subject 19, a girl) had intermittent use of clonidine, and the parents reported a positive correlation
between the use of clonidine and the behavioral
improvement. The fourth child (Subject 13, a boy) with
the resolution of his behavioral diﬃculty had been on
Depakote and Abilify prior to and during clonidine
treatment and his parents attributed the improvement
to clonidine because the improvement occurred following clonidine administration while the other medicines
were kept constant in dosages.
The use of clonidine in pediatric population has been
increasing. Schnoes et al. [33] reported that clonidine
was ranked second by pediatricians for treatment of
sleep disorders, including sleep onset, sleep schedule,
nighttime awakening, early morning awakening, and
parasomnias. Ingrassia and Turk [34] found clonidine
to be eﬀective in treating severe and intractable sleep
problems in children with neurodevelopmental disorders. Clonidine was reported to improve nocturnal hypoxemia and obstructive sleep apnea, possibly due to
suppression of REM sleep[35]. This ﬁnding could possibly explain the improvement in night awakening exhibited by some of our children with ASD, because three of
16 children with sleep maintenance diﬃculty in this
study were documented by overnight polysomnographic
study to have sleep disordered breathing [36]. Similarly,
bruxism is reported to be prevalent in children with
ASD [13]. Four children with ASD in this cohort had
historical bruxism as documented by parental report;
one child from this cohort, who was also a participant
in our sleep disorder research, exhibited bruxism during
the sleep study [36]. Clonidine was shown to be eﬃcacious in reducing autonomic arousal proceeding bruxism and the bruxism in adults [37]. Therefore, it is
possible that clonidine improved sleep in our subjects
by improvement of bruxism and its associated autonomic arousals.
Clonidine has been reported to be eﬃcacious as a
monotherapy or adjunct therapy in the treatment of
sleep disorders alone [30,38], sleep disorder with comorbic ADHD [39], behavioral disorders such as ADHD
[29,40,41], ADHD with comorbic aggression, oppositional deﬁant or conduct disorders [42,43], or ADHD
with tic disorder [44,45]. Jaselskis et al. [28] reported a
double-blind, placebo-controlled cross-over trial of clonidine in eight children with autism and comorbic
behavioral disorders. Irritability, stereotypy, hyperactivity, and inappropriate speech, were improved while on
clonidine based on teachers’ and parents’ rating, but
not on clinician’s rating. However, Hazell [29] reviewed
the eﬀects of clonidine in treatment of ADHD in autism
and concluded that clonidine is unlikely to be of any
beneﬁt. Finally, clonidine premedication has been
reported to reduce pain and improve hemodynamic
variables during anesthesia in pediatrics and adults
[46,47].
Based on the experience with seven children, clonidine patches were more favorable over the tablets in
terms of increased eﬃcacy and reduced side eﬀects.
Unfortunately the high incidence of skin irritation combined with the high prevalence of sensory hypersensitive
and/or obsessive–compulsive behavior in ASD children
limited the use of the transdermal patches. The adverse
eﬀects of clonidine in this study in the age group were
rare and largely tolerable, with the exception of two children whose were younger (5 and 7 years old).
X. Ming et al. / Brain & Development 30 (2008) 454–460
This study has its inherent limitations. First, the
study was retrospective and open-labeled. Second, the
outcome measure was semi-quantitative, largely based
on parental estimation. Despite these limitations, our
data show that clonidine is an option for ASD. Where
other medications have failed, clonidine may provide a
route to resolution of some particularly troubling symptoms, including sleep disorders, ADHD, aggression, and
disordered mood. Further evaluation with placebo controlled double-blind clinical trial of clonidine in ASD
will provide more insight into the clinical eﬃcacy and
safety of the medicine in ASD.
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