ADHD and AUTISM
Attention difficulties are an inherent aspect of autism spectrum disorders. According to DSM-IV TR criteria, Attention Deficit Hyperactivity Disorder (ADHD) is not supposed to be diagnosed separately among individuals with Autism Spectrum Disorders. However, a recent study concluded “ADHD symptoms are pervasive in clinically referred children and adolescents with ASD” (Lee and Ousley, 2006). Holtmann et. al. (2007) examined co-morbid measures of psychopathology among 182 subjects diagnosed as having PDD, who were divided into high and lower attention problem groups usin
g the median of the Child Behavior Checklist (CBCL). The PDD subjects with more severe attention symptoms exhibited more general psychopathology than those in the PDD subgroup having fewer attention problems. In addition, the PDD-hyperactive subgroup exhibited more impairments on the social interaction scale of the ADI-R as well as more internalizing and externalizing problems.
As a practical matter, not all youngsters with ASDs present the true profile of ADHD, either Inattentive or Hyperactive Type, but some clearly do. There is some evidence that medication treatments that are effective for treating ADHD symptoms among children who do not have ASDs, can also be effective for some youngsters with ASDs who meet ADHD diagnostic criteria. But the question is, “How good is the evidence that ADHD medications are effective in autism, and what are their side effect profiles?”
In routine clinical practice, three groups of ADHD drug s are used in treating children with ASDs who also present with ADHD symptoms: (1) Antihypertensives, such as atenolol or clonidine (2) Stimulants, such as methylphenidate or amphetamines, or (3) Atomoxatine, a norepinephrine reuptake inhibitor originally developed as an antidepressant. Though these medications are widely used, there have been very few controlled clinical studies of their effectiveness and safety in this population. Summarized below are studies of the effects of these medications between 1992 and the present in children with ASDs and ADHD symptoms.
CLONIDINE (Catapres®) is a commonly prescribed medication for symptoms of hyperactivity and inattentiveness of children with ASDs. It is an alpha adrenergic agonist that was originally approved for treating hypertension, which has mild calming effects as well as producing some sedation. Frankenhauser et. al. (1992) evaluated effectivenss of a clonidine transdermal skin patch using a double-blind, placebo-crossover design in nine children and adults with ASDs (aged 5 to 33 years). Subjects received either clonidine (approximately 0.005 mg/kg/day) or placebo by a weekly transdermal patch. Each trial lasted 4 weeks with a 2-week washout period between treatment phases. During clonidine treatment improvements were observed in social relationship to people, affectual responses, and sensory responses of the Ritvo-Freeman Real Life Rating Scale. A patient global rating scale showed clonidine treatment resulted in significant improvement in comparison with placebo. Adverse effects included sedation and fatigue during the first 2 weeks of clonidine treatment. Jaselskis et. al. (1992) tested oral clonidine on 8 male children (8.1 +/- 2.8 years) with autistic disorder, diagnosed by DSM-III-R criteria, using a placebo-controlled, double-blind crossover design. Subjects were included in the study if they had inattention, impulsivity, and hyperactivity that was excessive for their developmental level. Teacher ratings on the Aberrant Behavior Checklist (irritability, stereotypy, hyperactivity, and inappropriate speech) were lower during clonidine treatment than during placebo. Comprehensive Teacher's Rating Scale ratings on hyperactivity were not significantly improved during the study, except for oppositional behavior. Parent Conners Abbreviated Parent-Teacher Questionnaire ratings significantly improved during clonidine treatment. Clonidine led to increased ratings of the side effects of drowsiness and decreased activity. Clinician ratings of videotaped sessions were not significantly different between clonidine and placebo. The researchers concluded clonidine was modestly effective in the short-term treatment of irritability and hyperactivity in some children with autistic disorder.
METHYLPHENIDATE (Ritalin®) is the most widely used drug to treat ADHD symptoms in non-autistic children. Quintana et. al. (1995) examined effects of placebo and 10 mg or 20 mg twice daily of MPH on 10 children ages 7-11, with a DSM-III-R diagnosis of autistic disorder using a double-blind crossover study using. Subjects showed modest but statistically significant improvement on MPH over placebo. No significant side effects including occurred on either dose. Handen et.al. (2000) tested effects of MPH (0.3 and 0.6 mg/kg) on thirteen children (ages 5.6 to 11.2 years) with autism and symptoms of attention-deficit hyperactivity disorder (ADHD) in a double-blind, placebo-controlled crossover study. Eight (of 13) subjects decreased their Conners Hyperactivity Index by at least 50%. Ratings of stereotypy and inappropriate speech also decreased. However, no changes were found on the Child Autism Rating Scale. Social withdrawal and irritability, especially at the 0.6 mg/kg dose were observed in some children. Di Martino et. al. (2004) used a two phase protocol to examine effects of methylphenidate in children with ASD and ADHD symptoms. Participants included 13 subjects (mean age of 7.9 years) with PDD and moderate to severe hyperactivity/ impulsivity. One hour after a single oral MPH dose (0.4 mg/kg), 5 (of 13) subjects exhibited increased hyperactivity, stereotypes, dysphoria, or motor tics and were rated as minimally or much worse on the CGI Global Improvement Scale. They received no further treatment with MPH. Four of the remaining 8 subjects were rated as improved, and four as unchanged; they proceeded to a 12-week open trial of MPH. Two (of the remaining 8) children remained unchanged: they discontinued treatment after 1 week. Measures of hyperactivity and impulsivity improved significantly, while autism core symptom measures were unaffected. No significant adverse effects were observed in any of the 8 subjects. Santosh et. al. (2006) administered methylphenidate (Ritalin) to 226 children with ASD and attention deficit hyperactivity disorder (ADHD), and children with ADHD without ASD. They found statistically significant improvements in 'hyperactivity', 'impulsivity', 'inattention', 'oppositionality', 'aggression' and 'intermittent explosive rage' in both groups. Neither tics nor repetitive behavior worsened in either group. Children in the 'ADHD-only' experienced significant 'nausea', 'giddiness', 'headaches' and 'sleep difficulties', while sleep difficulties were the only side effect in children in the ASD with ADHD group.
ATOMOXETINE (Strattera®) is another widely prescribed drug for treating ADHD symptoms in non-autistic children. Posey et.a. (2006) examined effects of atomoxetine (1.2 mg/day) on 16 children and adolescents (mean age 7.7, range 6-14 years) with autistic disorder (n = 7), Asperger's disorder (n = 7), or PDD not otherwise specified (n = 2). Twelve (of 16) participants were rated as "much" or "very much improved" on the Clinical Global Impressions-Improvement scale on ADHD symptoms. Improvements of lesser magnitude were seen in irritability, social withdrawal, stereotypy, and repetitive speech. Atomoxetine was well tolerated with the exception of 2 participants (13 %) who stopped medication due to irritability. Weight decreased by an average of 0.8 kg during the 8-week trial. Arnold et. al. (2006) evaluated effects of atomoxetine on children ages 5 to 15 with ASD and prominent ADHD symptoms. Children were randomly assigned ATX and placebo first, 6 weeks each, separated by 1-week washout, and then 6 weeks of the opposite treatment. 12 boys and 4 girls (7 with autistic disorder, 1 Asperger's, 8 pervasive developmental disorder not otherwise specified) completed at least 3 weeks of each condition (i.e. 3 of 6 weeks). On the primary outcome, the Hyperactivity subscale of the Aberrant Behavior Checklist, ATX was superior to placebo. It was also superior on nine DSM-IV ADHD hyperactive/impulsive symptoms, but did not produce significant improvements in nine inattentive symptoms. One youngster was re-hospitalized for recurrent violence on ATX. Adverse events were otherwise tolerable, with no tendency to stereotypy.
Summary: ADHD symptoms can co-exist with autism spectrum disorders, including a range of emotional and behavioral symptoms often associated with ADHD. Evidence for effectiveness of FDA approved medications for treating ADHD within ASD is limited. The best evidence is for methylphenidate, which appears to reduce ADHD symptoms (but not core autism symptoms) for some children. Methylphenidate appears to have side effects for some children and youth with ASDs, including increased irritability, social withdrawal and sleep problems. Benefits of atomoxetine and clonidine appear less clear and are limited. In a recent review, Hazell (2007) concluded atypical antipsychotics such as risperidone and quetiapine can be beneficial, however, most of the evidence is from uncontrolled studies or studies with inadequate standardized measures of ADHD symptoms. Moreover, atypical antispychotics can have serious side effects, including inducing Type II diabetes, raising questions about their appropriateness for long term treatment of children.
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