Treating Irritability in Children and Adolescents With Autism
Treating Irritability in Children and Adolescents With Autism
Owen R, Sikich L, Marcus RN, et al
Pediatrics. 2009;124:1533-1540
The researchers noted that only one drug, risperidone, has been US Food and Drug Administration-approved to reduce irritability in children with autism. The drug evaluated in the current study is another atypical antipsychotic drug, approved for use in schizophrenia and bipolar disorder. This study was a randomized, placebo-controlled multicenter study conducted from 2006 to 2008, but the subjects were only on study protocol for an 8-week period. Each subject child completed a run-in period that lasted 6 weeks, during which the child underwent a screening visit, washout period, and baseline visit. The children completed study visits weekly during the treatment phase. Those assigned to the treatment drug were dosed in a flexible manner, according to investigator assessments, with an initial dose of 2 mg/day, advancing by 2 mg/day (target dosage: 5, 10, or 15 -- the maximum -- mg/day) Dose changes could be made only at the study visits (by single increments and 1 change per week). During the washout, patients were to discontinue all psychotropic medications.
The subjects were between 6 and 17 years old at enrollment, all had a diagnosis of autism, and all had demonstrated aggressive, irritable, or self-injurious behavior. All enrolled children also had significantly elevated scores on the Aberrant Behavior Checklist (ABC), a scale that measures irritability. The ABC assesses the degree to which children exhibit behaviors such as aggression toward other children or adults, irritability, outbursts, depressed mood, or yelling and screaming inappropriately. The primary outcome of interest was the mean change in ABC score, completed by the child's caregiver, from the baseline visit to the end of the study. Other behavioral assessments were also completed, including observations by the investigators. To evaluate the safety of the drug, the investigators collected electrocardiogram readings, laboratory tests, and scales that measured movement to assess for extrapyramidal symptoms.
After enrollment, 51 subjects were randomly assigned to placebo and 15 (29.4%) of these did not complete the study (6 withdrew for lack of efficacy). Forty-seven children were assigned to aripiprazole and 8 (17%) of them did not complete the study (only 1 for lack of efficacy). At the end of the study, 5% of treatment children were receiving 2 mg/day; 33% were receiving 5 mg/day; 41% were receiving 10 mg/day; and 21% were receiving 15 mg/day.
Both placebo and treatment groups experienced a reduction in ABC scores over the treatment phase of the study, but the reduction was greater in the treatment group (ABC score 12.9 vs 5.0 for placebo). Mean clinician scores for subject behavior and quality of life measurements also improved more in the children on study drug compared with placebo. Adverse events were more common among children in the treatment group, occurring in 91.5% of treated children compared with 72% of placebo. Side effects that occurred more commonly in treatment patients were somnolence (17%), sedation (10.6%), drooling or tremor (both 8.5%), vomiting (14.9%), and fatigue (21.3%). Placebo patients were more likely to experience headache (16%) and aggression (8%). Extrapyramidal symptoms (mostly tremors) were more common among treatment patients (14.9% vs 8%), but average scores on the scales to assess extrapyramidal symptoms did not differ greatly between the 2 groups. Treatment group children showed a greater rate of weight gain than the placebo group. Overall, 10.6% of children taking aripiprazole and 5.9% of children taking placebo discontinued their medication due to adverse events. The investigators concluded that aripiprazole was efficacious in reducing symptoms of irritability among children with autism, and this effect was found in parental and clinician assessments.
The findings of this study will no doubt be encouraging to families of children with autism and perhaps to clinicians struggling to find a way to help these children and their families. It is always helpful to have randomized trial data on medications that are not widely used in children, especially those with notable potential side effects such as the antipsychotic medications. This study provides very valuable data to help both parents and clinicians in their decision to place a child on this drug. The study authors point out some very real cautions, and perhaps they should be emphasized here. First, the duration of this study was relatively brief; many of these children would be expected to remain on this medication for longer periods. Second, the study population was narrow, so it is difficult to know how the drug might perform in other autism spectrum disorder populations, such as in children with pervasive developmental disorder or Asperger's syndrome. Finally, there are some clinically significant side effects that must be monitored, including somnolence and the potential for extrapyramidal symptoms in the short term, as well as weight gain in the long term.
Abstract
Aripiprazole in the Treatment of Irritability in Children and Adolescents with Autistic Disorder
Owen R, Sikich L, Marcus RN, et al
Pediatrics. 2009;124:1533-1540
Study Summary
The researchers noted that only one drug, risperidone, has been US Food and Drug Administration-approved to reduce irritability in children with autism. The drug evaluated in the current study is another atypical antipsychotic drug, approved for use in schizophrenia and bipolar disorder. This study was a randomized, placebo-controlled multicenter study conducted from 2006 to 2008, but the subjects were only on study protocol for an 8-week period. Each subject child completed a run-in period that lasted 6 weeks, during which the child underwent a screening visit, washout period, and baseline visit. The children completed study visits weekly during the treatment phase. Those assigned to the treatment drug were dosed in a flexible manner, according to investigator assessments, with an initial dose of 2 mg/day, advancing by 2 mg/day (target dosage: 5, 10, or 15 -- the maximum -- mg/day) Dose changes could be made only at the study visits (by single increments and 1 change per week). During the washout, patients were to discontinue all psychotropic medications.
The subjects were between 6 and 17 years old at enrollment, all had a diagnosis of autism, and all had demonstrated aggressive, irritable, or self-injurious behavior. All enrolled children also had significantly elevated scores on the Aberrant Behavior Checklist (ABC), a scale that measures irritability. The ABC assesses the degree to which children exhibit behaviors such as aggression toward other children or adults, irritability, outbursts, depressed mood, or yelling and screaming inappropriately. The primary outcome of interest was the mean change in ABC score, completed by the child's caregiver, from the baseline visit to the end of the study. Other behavioral assessments were also completed, including observations by the investigators. To evaluate the safety of the drug, the investigators collected electrocardiogram readings, laboratory tests, and scales that measured movement to assess for extrapyramidal symptoms.
After enrollment, 51 subjects were randomly assigned to placebo and 15 (29.4%) of these did not complete the study (6 withdrew for lack of efficacy). Forty-seven children were assigned to aripiprazole and 8 (17%) of them did not complete the study (only 1 for lack of efficacy). At the end of the study, 5% of treatment children were receiving 2 mg/day; 33% were receiving 5 mg/day; 41% were receiving 10 mg/day; and 21% were receiving 15 mg/day.
Both placebo and treatment groups experienced a reduction in ABC scores over the treatment phase of the study, but the reduction was greater in the treatment group (ABC score 12.9 vs 5.0 for placebo). Mean clinician scores for subject behavior and quality of life measurements also improved more in the children on study drug compared with placebo. Adverse events were more common among children in the treatment group, occurring in 91.5% of treated children compared with 72% of placebo. Side effects that occurred more commonly in treatment patients were somnolence (17%), sedation (10.6%), drooling or tremor (both 8.5%), vomiting (14.9%), and fatigue (21.3%). Placebo patients were more likely to experience headache (16%) and aggression (8%). Extrapyramidal symptoms (mostly tremors) were more common among treatment patients (14.9% vs 8%), but average scores on the scales to assess extrapyramidal symptoms did not differ greatly between the 2 groups. Treatment group children showed a greater rate of weight gain than the placebo group. Overall, 10.6% of children taking aripiprazole and 5.9% of children taking placebo discontinued their medication due to adverse events. The investigators concluded that aripiprazole was efficacious in reducing symptoms of irritability among children with autism, and this effect was found in parental and clinician assessments.
Viewpoint
The findings of this study will no doubt be encouraging to families of children with autism and perhaps to clinicians struggling to find a way to help these children and their families. It is always helpful to have randomized trial data on medications that are not widely used in children, especially those with notable potential side effects such as the antipsychotic medications. This study provides very valuable data to help both parents and clinicians in their decision to place a child on this drug. The study authors point out some very real cautions, and perhaps they should be emphasized here. First, the duration of this study was relatively brief; many of these children would be expected to remain on this medication for longer periods. Second, the study population was narrow, so it is difficult to know how the drug might perform in other autism spectrum disorder populations, such as in children with pervasive developmental disorder or Asperger's syndrome. Finally, there are some clinically significant side effects that must be monitored, including somnolence and the potential for extrapyramidal symptoms in the short term, as well as weight gain in the long term.
Abstract
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