Risperidone Treatment of Autistic Disorder: Longer-Term Benefits and Blinded Discontinuation After 6 Months Research Units on Pediatric Psychopharmacology Autism Network

Objective: Risperidone is effective for short-term treatment of aggression, temper outbursts, and self-injurious behavior in children with autism. Because these behaviors may be chronic, there is a need to establish the efficacy and safety of longer-term treatment with this agent. Method: The authors conducted a multisite, two-part study of risperidone in children ages 5 to 17 years with autism accompanied by severe tantrums, aggression, and/or self-injurious behavior who showed a positive response in an earlier 8-week trial. Part I consisted of 4-month open-label treatment with risperidone, starting at the established optimal dose; part II was an 8-week randomized, double-blind, placebo-substitution study of risperidone withdrawal. Primary outcome measures were the Aberrant Behavior Checklist irritability subscale and the Clinical Global Impression improvement scale. Results: Part I included 63 children. The mean risperidone dose was 1.96 mg/day at entry and remained stable over 16 weeks of open treatment. The change on the Aberrant Behavior Checklist irritability subscale was small and clinically insignificant. Reasons for discontinuation of part I included loss of efficacy (N=5) and adverse effects (N=1). The subjects gained an average of 5.1 kg. Part II included 32 patients. The relapse rates were 62.5% for gradual placebo substitution and 12.5% for continued risperidone; this difference was statistically significant. Conclusions: Risperidone showed persistent efficacy and good tolerability for intermediate-length treatment of children with autism characterized by tantrums, aggression, and/or self-injurious behavior. Discontinuation after 6 months was associated with a rapid return of disruptive and aggressive behavior in most subjects. Autistic disorder is characterized by impaired social interaction, abnormal language development, and repetitive and restricted patterns of behavior (DSM-IV), and it affects as many as 20 people per 10,000 (1, 2). Children with autism display broad differences in abilities and needs, but accompanying maladaptive behaviors such as self-injurious behavior, aggression, and tantrums are common and frequently severe enough to limit educational and developmental progress. A variety of treatments, including medication, are employed in the management of these maladaptive behaviors. Controlled trials of medication treatment of autism are limited, but evidence provides support for both conventional and atypical antipsychotic agents (3, 4). Among studies of the conventional antipsychotics, well-controlled trials of haloperidol have revealed statistically significant effects, but only modest clinical benefits, in children with autism, and shortand longer-term side effects are of concern (3, 5). Atypical antipsychotics appear to be preferred by clinicians because of the perception that atypicals have a more favorable side effect profile than typical neuroleptics, but few direct comparison data exist. Atypical agents are also of interest because of possible serotonin (5-HT) abnormalities in some individuals with autism and the high affinity of medicines such as risperidone for 5-HT receptors, especially those of the 5-HT2A and 5-HT2C classes (6). Until 2002, only one placebo-controlled study of risperidone in adults with autism (7) and a handful of open-label studies of children with pervasive developmental disorders (8) had been published. In a prior report, we described the short-term efficacy of risperidone over placebo in an 8-week controlled trial for 101 children and adolescents with autistic disorder (4). Risperidone was chosen for study given the greatest preliminary evidence for its efficacy in this population (6, 8). Although the effects of risperidone on aggression, tantrums, and self-injurious behavior were substantial in our short-term study, the question of whether these improvements would endure over time remained unanswered. In this study, subjects who showed a positive response to risperidone in the short-term trial were enrolled in an additional 4-month open-label trial (total drug exposure= 6 months), which was followed by a placebo-controlled discontinuation protocol lasting up to 8 weeks. The aim of the study was threefold: first, to determine if the short-term efficacy of risperidone is maintained over time; second, to determine if the side effect burden of risperidone remains acceptable over an extended treatment period; and third, to examine the feasibility of risperidone discontinuation after 6 months of treatment. Characteristic Participated in Extension Phase (N =63) Did Not Participate in Extension Phase (N = 38) Mean SD Mean SD Demographic profile Age (years) 8.6 2.8 9.0 2.5 N % N % Male sex 49 77.8 33 86.8 Tanner stage I or II 55 87.3 33 86.8 Race or ethnic group White 44 69.8 23 60.5 Black 6 9.5 5 13.2 Hispanic 3 4.8 4 10.5 Asian or Pacific Islander 4 6.3 4 10.5 Other (mixed race) 6 9.5 2 5.3 Parental annual income (dollars) ≤20,000 6 9.5 7 18.4 20,001–40,000 17 27.0 11 28.9 40,001–60,000 15 23.8 2 5.3 >60,000 23 36.5 18 47.4 Parental education Less than high school 1 1.6 2 5.3 High school 13 20.6 6 15.8 Trade or technical school 4 6.3 2 5.3 At least some college 35 55.6 23 60.5 Advanced degree 10 15.9 5 13.2 Living at home with at least one parent 56 88.9 36 94.7 Educational placement Regular class 4 6.3 4 10.5 Regular school, special education 47 74.6 27 71.1 Special school 11 17.5 4 10.5 Residential school 0 0.0 1 2.6 Other 1 1.6 2 5.3 Developm