Dr. Kolevzon is assistant professor of psychiatry and pediatrics in the Department of Psychiatry at Mount Sinai School of Medicine in New York City.
Disclosure: Dr. Kolevzon receives grant support from the Beatrice and Samuel A. Seaver Foundation, Bristol-Myers Squibb, Johnson and Johnson, the National Institutes of Health, and Neuropharm.
Please direct all correspondence to: Alexander Kolevzon, MD, Assistant Professor of Psychiatry and Pediatrics, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1230, New York, NY 10029; Tel: 212-659-9134; Fax: 212-659-8710; E-mail: email@example.com.
• Methylphenidate and atomoxetine can be useful in the treatment of attention-deficit/hyperactivity disorder (ADHD) symptoms in autism spectrum disorders (ASD).
• Response rates and tolerability may be lower than in typically developing individuals with ADHD.
• Patients with ASD and symptoms of ADHD, aggression, and/or self-injury may benefit from risperidone if cautiously administered and monitored.
Autism is a pervasive developmental disorder defined by social impairment, language impairment, and repetitive patterns of behavior. Symptoms of attention deficit and hyperactivity frequently occur in autism and autism spectrum disorders (ASD), yet current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria prohibit the diagnosis of attention-deficit/hyperactivity disorder (ADHD) in the presence of an underlying pervasive developmental disorder. Autism is characterized by broad heterogeneity in symptoms and associated features and may be a challenge to diagnose clinically. Yet, the accurate identification of ADHD symptoms in ASD has important implications for treatment. There is a significant body of evidence to support the use of medications to treat ADHD in typically developing populations, but a relative dearth of research to explore the effect of pharmacotherapy in populations with ASD and symptoms of ADHD. This article focuses on the medication management of ADHD symptoms in ASD to evaluate the current state of evidence and help guide providers in their clinical judgment.
Autism is a severe neurodevelopmental disorder characterized by social impairment, language impairment, and repetitive patterns of behavior. The autism spectrum, also called pervasive developmental disorders, includes Asperger’s disorder, Rett’s disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified.1 Symptoms of attention deficit, impulsivity, and hyperactivity are extremely common in autism spectrum disorders (ASD), with some surveys reporting estimates of 50%2 to 75%.3 However, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision1 precludes the diagnosis of attention-deficit/hyperactivity disorder (ADHD) if symptoms occur in the context of an underlying pervasive developmental disorder (ie, ASD). Nevertheless, some clinical symptoms of ASD and ADHD clearly overlap and the boundaries between the disorders are sometimes unclear.4
In the absence of biologic markers, clinicians must rely on behavioral characteristics using a variety of diagnostic tools in addition to a comprehensive developmental history to evaluate individuals with ASD. The use of validated diagnostic instruments, cognitive testing, and assessment of adaptive behavior functioning are crucial in developing individualized treatment plans in ASD. Symptoms of ADHD should be specifically explored and rating scales, such as the Conners’ Rating Scale5 can be distributed to parents and teachers both for diagnostic purposes and also as a means to measure improvement from baseline.
The first line of treatment in ASD is behavioral and educational interventions, though their consideration is beyond the scope of this article. Pharmacotherapy in ASD is used to target symptom domains and is not curative. While much evidence supports the use of medications to treat symptoms of ADHD in typically developing children, questions remain as to their utility in patients with developmental delays. There is a paucity of research to examine the effect of pharmacotherapy in populations with co-occurring ASD and symptoms of ADHD, with minimal data to guide providers in their clinical judgment. The following article focuses on the medication management of ADHD-related symptoms in ASD with the goal of providing clinicians with a systematic evaluation of the evidence to date.
Relevant studies were identified by searching the PubMed database for English-language articles on clinical trials of medication in the treatment of autism and autism spectrum disorders, and screening reference lists of original studies. PubMed is a National Library of Medicine service that includes citations from Medline and additional life science journals that date back to the 1950s. For inclusion in this article, identified studies used randomized controlled designs of agent versus placebo or active agent; a well-defined sample of subjects that included children, adolescents, or adults with autism or autism spectrum disorders; and at least one outcome measure with an assessment of inattention, hyperactivity, or impulsivity. Retrospective and open-label studies were also reviewed when relevant to controlled trials.
Methylphenidate is a psychostimulant that binds to the presynaptic dopamine transporter decreasing reuptake and increasing synaptic dopamine in the striatum and other brain regions. Several randomized, placebo-controlled trials have explored the use of methylphenidate in ASD. Quintana and colleagues6 used 20–40 mg/day doses in 10 children with ASD and found that methylphenidate produced significant improvement in hyperactivity as compared to placebo. No significant differences in the occurrence of side effects were noted between groups, although higher doses appeared to produce a greater likelihood of insomnia and irritability. Another placebo-controlled trial by Handen and colleagues7 of 13 children with ASD and symptoms of ADHD compared doses of 0.3 and 0.6 mg/kg given 2–3 times/day. Hyperactivity improved significantly as compared to placebo and eight of the 13 children (62%) were considered responders. Five of the 13 (38%) children experienced significant side effects as compared to placebo, including social withdrawal, dullness, sadness, and irritability.
The largest controlled trial8 with methylphenidate to date was done by the Research Units of Pediatric Psychopharmacology (RUPP) Autism Network using a double-blind, placebo-controlled, crossover design in 72 children and adolescents with ASD. Methylphenidate was administered in low (.125 mg/kg), medium (.250 mg/kg), and high (.5 mg/kg) doses TID. Methylphenidate was superior to placebo on measures of inattention and hyperactivity and 49% of subjects were classified as responders. Side effects were significantly more likely to occur in patients on methylphenidate, including decreased appetite, difficulty falling asleep, irritability, and emotional outbursts. A total of 13 out of 72 subjects (18%) withdrew from the study due to adverse events and the most common reason for discontinuation was irritability (six subjects). A follow-up of the RUPP methylphenidate study by Posey and colleagues9 confirmed results from the original study using secondary outcomes to measure core symptoms of ADHD but found that hyperactivity and impulsivity were more likely to improve than inattention. Higher doses (.25–.50 mg/kg) were also more consistently effective than low doses (.125 mg/kg).
Atomoxetine is a non-stimulant, norepinephrine reuptake inhibitor which also enhances prefrontal dopaminergic transmission because the norepinephrine transporter is sensitive to dopamine in the frontal cortex. Retrospective10 and open-label studies11 of atomoxetine found significant effects on measures of hyperactivity and inattention in children and adolescents with ASD. One double-blind, placebo-controlled, crossover study12 examined the safety and efficacy for symptoms of ADHD in 16 children and adolescents with ASD. Atomoxetine was started at doses of .25 mg/kg/day and increased to a maximum dose of 1.4 mg/kg/day given in divided doses. Atomoxetine significantly improved symptoms of hyperactivity and impulsivity as compared to placebo, but results only approached significance on measures of inattention. Patients who received atomoxetine exhibited significantly more side effects, including gastrointestinal distress, fatigue, and tachycardia. Other side effects such as decreased appetite and irritability were reported but rates did not differ significantly from placebo.
Haloperidol is a first-generation antipsychotic that acts by blocking postsynaptic dopamine receptors. Antipsychotics have been used extensively in developmentally disabled populations and typically developing children with ADHD. Aman and Langworthy13 identified 11 clinical trials that evaluated antipsychotics for hyperactivity in children with ASD. Four of these were controlled trials that examined the use of haloperidol.14-17 Haloperidol appears to improve hyperactivity in ASD, although results were not always consistent, depending on the outcome measure utilized.
Risperidone is a second-generation antipsychotic that acts by blocking postsynaptic dopamine and serotonin receptors. The remaining seven studies identified in the article by Aman and Langworthy13 used open-label designs; six were with risperidone18-23 and one examined the use of olanzapine.24 Results of these open-label trials were mostly positive and found that risperidone significantly reduces hyperactivity in ASD.
The RUPP Autism Network later conducted a large placebo-controlled trial25 of risperidone in 101 children and adolescents (5–17 years of age) to examine impact on tantrums, aggression, and self-injury. The Aberrant Behavior Checklist Irritability subscale was the primary outcome measure but the Hyperactivity subscale was also used. Risperidone was initiated at 0.5 mg/day and titrated to a maximum of 2.5 mg/day in divided doses (mean=1.8 mg/day). Risperidone significantly improved hyperactivity as compared to placebo (effect size=1). Irritability also improved significantly (effect size=1.2). Sixty nine percent of patients receiving risperidone were considered responders according to global ratings as compared to 12% of patients who received placebo. Risperidone was significantly more likely to produce side effects, including mild (49%) to moderate (24%) increases in appetite, fatigue (59%), drowsiness (49%), drooling (27%), dizziness (16%), and weight gain (2.7±2.9 kg). There was no evidence of extrapyramidal symptoms and no child required discontinuation due to side effects.
Overall, there have been at least five additional controlled trials26-30 of risperidone with positive results in patients with ASD, though not all systematically assessed symptoms of ADHD.
Clonidine is an alpha-2 adrenergic agonist that reduces sympathetic discharge and lowers levels of catecholamine production. Several studies31-33 have found clonidine effective in improving inattention, hyperactivity, and impulsivity in children with ADHD. In patients with ASD, clonidine has been examined in two controlled studies34,35 with a total of 15 males. The first study34 did not show improvement on measures of hyperactivity but did find improvement on global ratings of change according to both parents and clinicians. The second study35 found improvement on parent and teacher ratings of hyperactivity, irritability, and oppositional behavior, but not on the clinician ratings. Side effects included sedation and hypotension. Hyperactivity may improve due to initial sedation, and benefit appears to diminish in some cases after 6–8 weeks.35
The efficacy of guanfacine, another alpha-2 agonist, was examined in two open-label studies.36,37 The first study36 was a large retrospective review of 80 children and adolescents with ASD and symptoms of ADHD. Doses ranged from 0.25–9.0 mg/day administered in divided doses (mean=2.6 mg/day) and treatment duration ranged 7–1,776 days. Twenty-seven percent of patients showed improvement in hyperactivity and 21% showed improvement in symptoms of inattention. Twenty-four percent of patients were considered responders based on global improvement scores and there was a small but statistically significant improvement on global severity ratings. Later, Scahill and colleagues37 conducted a prospective open-label trial of guanfacine in 25 children with ASD and hyperactivity with a history of non-response to methylphenidate. Doses ranged from 1–3 mg/day in divided doses. Forty-eight percent of children were considered responders and results from parent and teacher ratings of inattention and hyperactivity showed significant improvement for both symptoms across two different measures, although parent ratings demonstrated a larger effect. Both studies36,37 suggest that guanfacine was well tolerated and no serious adverse events occurred. Side effects included sedation, irritability, increased aggression and self-injury, decreased appetite, sleep disturbance, constipation, headache, and nocturnal enuresis. Heart rate, blood pressure, and electrocardiogram changes were not deemed clinically significant and did not require discontinuation for any cases in either of the studies of guanfacine.
Amantadine is a noncompetitive N-methyl-D-aspartate (NMDA) antagonist indicated for the treatment of Parkinson’s disease. A placebo-controlled study of amantadine by King and colleagues38 in 43 children and adolescents with ASD assessed the impact on behavioral symptoms. Amantadine was started at doses of 2.5 mg/kg/day and increased to 5 mg/kg/day BID. Significant improvement was found on clinician-rated measures of hyperactivity but not on parent-rated measures. Fifty-three percent of patients demonstrated response on measures of global improvement as compared to 25% of patients receiving placebo; however, this difference was not statistically significant. There were no significant differences in side effects between groups but the most common side effects in patients taking amantadine were insomnia and somnolence. There were no reports of hallucinations, which have been associated with higher doses of amantadine.38
Naltrexone is an opiate antagonist studied in children and adolescents with ASD using open-label designs39-41 and is found to effectively reduce autistic symptoms, including hyperactivity and inattention. At least six randomized, placebo-controlled studies have also examined its efficacy,42-47 although results from these trials are mixed. Campbell and colleagues42 found that hyperactivity was significantly improved according to parent and teacher ratings on the Conners Rating Scale, whereas Willemsen-Swinkels and colleagues43 reported no significant improvement according to parent ratings, but teacher ratings did find improvement in hyperactivity. In contrast, Kolmen and colleagues44 found significant improvement on parent ratings, but not on teacher ratings. Both the Willemsen-Swinkels and colleagues45 and Kolmen and colleagues44 also measured activity level using an actometer and no difference was found between the naltrexone and placebo groups. Bouvard and colleagues46 examined the use of naltrexone in 10 children with ASD using a placebo-controlled design and again no significant differences were found. None of the controlled trials with naltrexone reported significant differences in side effect profiles as compared to placebo.
Many other medications have been studied in ASD, but few specifically measured symptoms of ADHD, and a list of these trials is beyond the scope of this article. Some studies have shown promise for several selective serotonin reuptake inhibitors, tianeptine, divalproex sodium, lamotrigine, and omega-3 fatty acids, among others. However, to date, no additional randomized controlled trials have found evidence to support their use for symptoms of ADHD in ASD.
Methylphenidate and atomoxetine are both typically used to treat ADHD and are also effective in ASD. Recently, Santosh and colleagues48 conducted a retrospective and an open-label prospective trial to compare response to stimulants (methylphenidate or dextroamphetamine) between children with ASD and ADHD and children with ADHD alone, and found no significant differences in treatment response or side-effect profiles between groups. However, other studies suggest that response rates of methylphenidate may differ in ASD as compared to what is reported in typically developing children with ADHD alone. The National Institute of Mental Health Collaborative Multisite Multimodal Treatment Study of Children with ADHD (MTA) reported response rates of 70% to 80% as compared to the 49% reported in the RUPP Autism Network trial of methylphenidate.8 In terms of tolerability, 18% of subjects in the RUPP trial withdrew, yet discontinuation rates were quite low in the MTA study (1.4%). While methylphenidate may improve irritability in ADHD without ASD, it appears to worsen irritability in some patients with ASD. In the only controlled study of atomoxetine,12 results were significantly better than placebo, but the sample size was small and only seven of 16 children (43%) were considered responders. Overall, both methylphenidate and atomoxetine appear to effectively treat ADHD-related symptoms in ASD. However, response rates may be lower in ASD plus ADHD than in ADHD alone, and symptoms of inattention may be less likely to respond than symptoms of hyperactivity and impulsivity. Finally, treatment success may be limited by tolerability.
Many studies have demonstrated efficacy for antipsychotics, and since the RUPP trial with risperidone25 this medication in particular has consistently shown benefit for hyperactivity in ASD.26,27,49,50 In 2006, The United States Food and Drug Administration approved risperidone for the treatment of irritability in ASD in children and adolescents 5–16 years of age. Symptoms of aggression and self-injury are especially distressing for patients with ASD and their families, and risperidone is an effective pharmacotherapeutic option for this symptom constellation. However, significant concerns about tolerability remain and suggest that benefits of this medication must be carefully weighed against the risks. Metabolic monitoring, nutritional counseling, and a physical activity regimen should be included for all children treated with risperidone.
Evidence from controlled studies of alpha-2 agonists for ADHD-related symptoms in ASD is inconsistent and response rates are relatively low. Open-label studies of guanfacine appear promising but additional controlled studies are needed. alpha-2 agonists may, nevertheless, be a reasonable alternative or augmentation strategy and have the advantage of being relatively benign. Amantadine and other NMDA antagonists are interesting compounds to consider in the treatment of ASD but their use for ADHD-related symptoms is limited by a relative dearth of evidence and only one controlled trial to date. Despite multiple controlled trials, naltrexone appears to exert minimal benefit and inconsistent results indicate that isolated findings should be interpreted with caution.
Regardless of medication choice, treatment of children and adolescents with ASD should be initiated at very low starting dosages using very slow titration schedules. Benefits must be carefully weighed against risks, and future research would benefit from systematic assessment of side effects to clarify safety profiles and identify patients who are most vulnerable. Future studies to specifically examine treatment of ADHD symptoms in ASD should utilize specific outcome measures that clearly assess medication impact on symptoms of inattention, hyperactivity, and impulsivity.
Several weaknesses of this article are important to note. First, its focus is primarily on studies of children and adolescents because inattention and hyperactivity occur more commonly in this population. Second, mental retardation has not been adequately addressed. The presence of mental retardation may play a role in predicting treatment response and some studies suggest a trend for lower response rates for patients with mental retardation. Despite this, many studies have demonstrated the efficacy of stimulant medications, for example, in patients with mental retardation,51-56 though some investigators have suggested that an IQ of ≥45 is required in order to see favorable effects.53,54 However, among the studies reviewed above which specifically examined IQ as a moderator of methylphenidate response, none showed a significant effect.7,8,57 Third, there is limited discussion of methodologic weaknesses of the studies reviewed because the focus has been primarily on randomized controlled trials. This selection bias does not imply that controlled trials are beyond criticism, and is not intended to dismiss the value of case reports, case series, and open-label trials. Finally, and despite best efforts, some relevant studies may not have been included in this article. PP
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