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: [email protected] (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 . 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.  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 . 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 . 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 . However, Hazell  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 . 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 . 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 . 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 . 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.  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  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. 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 . Similarly, bruxism is reported to be prevalent in children with ASD . 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 . Clonidine was shown to be eﬃcacious in reducing autonomic arousal proceeding bruxism and the bruxism in adults . 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 , 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.  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  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). 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