Risperidone in Children with Autism and Serious Behavioral Problems
McCracken et al. on behalf of the Research Units on Pediatric Psychopharmacology Autism Network
NEJM (New England Journal of Medicine) 347(5):314-321.2002.
Bottom Line Is Risperidone a safe and effective treatment for serious behaviour problems in children with autism?
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Question: Is Risperidone safe and effective in the treatment of serious behaviour problems in children with autistic disorder?
Background: Children with autism often display very difficult behaviours. Their tantrums, extreme irritability, and physical aggression have serious consequences for family life. Their parents are stressed by having to cope with constant disruptions in the household. Siblings may be fearful of the physical aggression directed towards them, or uncomfortable bringing schoolmates home to what can be an unpredictable situation. The family may become more and more isolated as the aggression escalates. Behavioural interventions alone may not be effective for the worst problems. Several psychiatric medications are in use to control difficult behaviours and this study presents results of a trial of a newer treatment.
Design: This was an 8-week trial conducted at multiple university-based medical centres. After being randomly assigned to receive either placebo or drug, children were entered into the trial. Neither parents nor physicians knew whether the child was receiving the active drug or a placebo. After this initial phase, which was followed by 4 months during which the drug was openly prescribed, the child continued in a 2-month placebo-controlled discontinuation phase.
Setting: The study was conducted by the Autism Network of the Research Units on Pediatric Psychopharmacology. The sites were UCLA, Ohio State University, Indiana University, Yale University, and the Kennedy Krieger Institute of Johns Hopkins.
Patients: Children aged 5 to 17 who met DSM-IV diagnostic criteria for autistic disorder, who weighed at least 15 kg, and who had a mental age of at least 18 months were eligible for the study. They also had to be free of co-existing serious medical disorders or psychiatric illnesses requiring medication. Children on medication that was effective in controlling behaviour problems were excluded.
Intervention: 101 children (82 boys and 19 girls with a mean age of 8.8 +/-2.7 years) were randomly assigned to receive either risperidone (49 children) or placebo (52 children).
Main Outcome Measures: Scores on the Irritability subscale of the Aberrant Behavior Checklist Checklist and the Clinical Global Impressions-Improvement (CGI-I) scale.
Main Results: Analysis was by intention to treat, that is, the data of all children who entered the trial, whether they completed it or not, were analyzed. After 8 weeks on risperidone, the treatment group had a 56.9% decrease in the mean irritability score as compared to 14.1% in the placebo group (p<0.001). The positive response rate (i.e., at least 25% improved in the irritability subscale and a rating of much improved or very much improved on the CGI scale) was 69% for the treatment group (34 of 49) and 12% for the placebo group (6 of 52, p<0.001).
Conclusions: Risperidone was found to be safe and effective for short-term treatment of serious behaviour problems in children with autistic disorder. Children in the active treatment group did, however, experience fatigue and weight gain far more frequently than children in the placebo group.
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Commentary Despite the large number of children with ASD who are prescribed medication(s) for behavioural symptoms, as many as 50% in some studies, there have been very few randomized controlled trials to help parents and clinicians decide what treatments are safe and effective. It is very encouraging to see studies that focus specifically on children with autism, and that involve a sufficient number of participants and are designed in such a way to yield meaningful information to guide treatment decisions.
What conclusions can we draw from this study? What is the treatment, who were the children that were treated, and what were the effects of the treatment, both positive and negative?
Risperidone is one of a group of drugs known as the neuroleptics or antipsychotics. Haloperidol (or Haldol), which is an older medication that is also part of this group, has been used to treat individuals with autism since the 1970s. Although haloperidol is very effective in reducing aggressive behaviour, studies in the 1980s indicated that it can cause severe side effects (e.g., 'dyskinesia', or loss of muscle control, especially around the mouth), and its use in children became less frequent. Risperidone is one of a group of 'atypical neuroleptics' (which also includes olanzepine) which were released in the 1990's, and although similar to haloperidol, appear to cause less side-effects, at least in the short-term. Several small, open-label trials (i.e., unblinded studies with no comparison groups) of risperidone had suggested that it was effective in reducing aggressive behaviour and irritability. However, the study reviewed here is the first randomized controlled trial in children with autism.
The children treated in this trial were 5- to 17-year-olds with a confirmed diagnosis of autistic disorder. The group, on the whole, had severe behavioural symptoms, as reflected in extreme scores on parents' ratings of aggression and irritability at baseline, as well as the fact that over 70% had previously been treated with psychotropic medications. Over 80% were intellectually disabled (IQ<70), and most had very limited adaptive functioning (independence in daily living skills) at baseline.
The positive effects of the medication in this group are summarized in the 'Main Results' section above. Remarkably, almost 70% of the children receiving risperidone were considered to be 'much improved', compared to only 12% of the children receiving placebo. The most common side effects in the children receiving risperidone were increased appetite (with an average weight gain of 2.7 kg, or 6 lb, during the 8 wk trial), fatigue (51% of the medication group, compared to 27% of the placebo group), and drooling (27% of the medication group, compared to 6% of the placebo group). Dyskinetic movements were noted in a small number of children in both the medication and placebo groups, with no significant difference that could be attributed to the medication during this 8-week trial. Routine lab tests, including liver enzymes and heart rhythm testing, were essentially normal, and did not differ between the two groups.
What does this trial not tell us? First, we cannot necessarily assume that the medication would be equally effective in children with other diagnoses on the autistic spectrum (e.g., Asperger's) or similarly, in children who are higher functioning or who have milder behaviour problems than the children who were treated in this study. The authors caution that risperidone should be reserved for treatment of moderate-to-severe behavioural problems. Second, this study tells us very little about the effects of risperidone in children who are treated for more than 8 weeks. It is worth noting, however, that most of the children who appeared to have a positive response during the double-blind trial stayed on the medication and were followed for an additional 4 months. Of these children, 23 of the 34 (68%) continued to show some benefit. Third, there are important questions about potential side effects that this study does not answer. We do not know whether the children treated with risperidone continued to gain weight at an excessive rate beyond the 8-week trial, or whether other side effects such as dyskinesia might become more common over a longer period of treatment. The sample is also too small (about 50 children in each treatment group) to detect uncommon but potentially serious side effects. Isolated case reports have indicated that a small number of children taking risperidone can develop increased liver enzymes and/or elevated levels of the hormone prolactin, which can interfere with the menstrual cycle in girls, and cause breast enlargement in boys. Notably, there have been no life-threatening side effects in several years of treatment experience in North America. Finally, we do not know if risperidone is more effective than behavioural interventions, or whether the combination of the two is better than either one alone. We also do not know whether the intensive follow-up (weekly visits with the supervising clinician) is necessary to receive the full benefits of risperidone treatment.
Overall, risperidone appears to be a safe and effective treatment, at least in the short-term, for moderate-to-severe aggression and irritability in children and adolescents with autistic disorder. Further studies will be needed to address whether risperidone continues to be effective beyond 2 to 6 months of treatment and whether side effects become more problematic with longer-term treatment.
Lonnie Zwaigenbaum, M.D., F.R.C.P.(C) |