RUPP Risperidone Study
The RUPP (Research Units on Pediatric Psychopharmacology) Autism Network has just completed its first study, a randomized controlled trial of risperidone in 101 children with autistic disorder. The data were presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry, October 23-28, 2001 in Honolulu by Dr. Benedetto Vitiello of the National Institute of Mental Health. The study sites were Indiana University, Ohio State University, Johns Hopkins University (Kennedy Krieger Institute), UCLA, and Yale University. Risperidone, an atypical antipsychotic, has a favorable balance of affinities for selected subclasses of serotonin and dopamine receptors that is believed to lessen the risk of extrapyramidal side effects. The critical data derive from the first phase of a three phase study. Phase 1 was an 8 week period of treatment with risperidone or placebo. Phases 2 and 3 are currently in progress. (Phase 2 is a 4 month open label trial for those who improved after receiving risperidone in Phase 1, to monitor for late side effects, durability of response, etc. Phase 3 will be a randomized double blind placebo controlled discontinuation of treatment. There were two different dosing schedules, based on weight. For children weighing more than 20 kg but less than 45 kg, the initial dose was 0.5 mg at bedtime. The dose was increased to 0.5 mg twice a day and gradually titrated to 1.0 mg in the morning and 1.5 mg at bedtime by the end of the 4th week. For children weighing 45 kg or more, the dose was titrated up to 1.5 mg in the morning and 2.0 mg at bedtime, by the end of the 4th week.
Diagnosis and assessment to assure reasonable uniformity and comparability of study groups was done using a battery of rating scales. Outcome measures used observations of both a parent and a blinded clinician. The blinded clinician interviewed the parent and completed the Irritability Subscale of the Aberrant Behavior Checklist (ABC), as a secondary outcome measure, along with two other interview instruments. The primary outcome measure used by the blinded clinician was an assessment of degree of improvement (rated as "much improved" or "very much improved") on the Global Improvement Item of the Clinical Global Impression Scale (CGI-I). Improvement was referenced against a baseline severity scale. Targeted behaviors included tantrums, aggression, and self-injury. A positive response was defined as a 25% decline on the Irritabilty Subscale of the ABC and a rating of "much improved" or "very much improved" on the CGI-I scale.
There were 82 boys and 19 girls, with ages ranging between 5 and 17 years (mean age, 8.8 years). The risperidone dose ranged between 0.75 and 3.5 mg per day. The group receiving risperidone had a statistically significant decrease in targeted behaviors: positive response in 34 of 49 (69.4%) receiving risperidone versus improvement in 6 of 52 (11.5%) receiving placebo. The average weight gain at the end of 8 weeks was 2.2 kg (risperidone) versus 0.1 kg (placebo). The risperidone group had a significantly higher rate of increased appetite, drowsiness, drooling, tremor, and dyskinesia compared to the placebo group. These side effects were considered to be mild.
The above data and conclusions should be considered preliminary until the publication of the final, peer-reviewed paper. The design of this study is a model for psychopharmacotherapy research. Behavioral changes following treatment are difficult to quantify. Each child has a unique behavioral profile and detecting a treatment effect requires a controlled study design and measures sensitive enough to discern treatment-related effects. The threshold of change on the ABC Irritability Subscale was set at a 25% decrement which may be enough to result in significant benefit in terms of challenging behavior. Such treatment would not be expected to be uniformly effective but a rate of efficacy of up to 70% is a major contribution toward the management of especially challenging aggressive outbursts.
Ronald J. Kallen, MD