Risperidone for the Core Symptom Domains of Autism: Results From the Study by the Autism Network of the Research Units on Pediatric Psychopharmacology

The study sites included Indiana University, the Kennedy Krieger Institute at Johns Hopkins University, Ohio State University, the University of California at Los Angeles, and Yale University. The protocol was approved by the institutional review board at each site, and written informed consent was obtained from a parent or legal guardian before enrollment.

The details of the study participants are described elsewhere (1, 7). Briefly, they were 101 children and adolescents between the ages of 5 and 17 years (mean age=8.8 years, SD=2.7); 82% were male. They met the DSM-IV criteria for a diagnosis of autistic disorder, which was corroborated by the Autism Diagnostic Interview—Revised (12), and they had impairing behavioral symptoms, such as severe tantrums, aggression, or self-injurious behavior. These subjects were randomly assigned to 8 weeks of risperidone (dose range=0.5–3.5 mg/day, mean=1.8 mg/day, SD=0.7) or placebo in a double-blind trial. On the primary outcome measures, the Aberrant Behavior Checklist irritability subscale and the CGI improvement scale, risperidone was superior to placebo (p<0.001) (1). Thirty-four (69%) of 49 subjects showed a positive response to risperidone during the 8-week double-blind study, and 29 (63%) of 46 subjects responded to risperidone in the 8-week open-label trial for the nonresponders in the placebo group. Thus, a total of 63 subjects entered the 16-week continuation phase. At the beginning of the extension phase, there were no differences between these two groups in the scores on the irritability subscale of the Aberrant Behavior Checklist or in the distribution of CGI severity scores. Therefore, the two groups were combined in the efficacy analysis. A detailed description of the baseline characteristics of this group are described elsewhere (7). Following the 16-week open-label continuation phase, 83% of the subjects continued to be rated as much improved or very much improved (2 or 1 on the CGI improvement scale). The mean daily dose of risperidone for the subjects beginning the 16-week continuation phase was 2.0 mg (SD=1.2). Over the course of the 16-week open-label treatment, there was a modest increase (6%) to a final mean daily dose of risperidone of 2.1 mg (SD=0.8).

This scale was developed to evaluate the effects of treatments on symptomatic behaviors in patients with the syndrome of autism (8). It was designed as a direct observation measure that could be applicable to patients in their natural settings. Direct observation is one way of compensating for a patient’s limited ability to communicate (3). The Ritvo-Freeman Real Life Rating Scale has been used to measure change in behavioral symptoms in controlled drug treatment studies involving children (13), as well as adults (14, 15), with autism. The studies with adults, however, involved only one investigative site and a single rater. For the current study, even with extensive and repeated training and standardization of procedures for the 30-minute observation period, we were unable to attain acceptable reliability across the five study sites for direct observation. We next considered videotaping the 30-minute observation protocol for later coding/rating by reliable raters. However, the validity of videotaping live examinations as a way of recording a representative sample of the subject’s behavior seemed questionable (16). Therefore, we modified the Ritvo-Freeman Real Life Rating Scale to convert it from an observational measure to a parent rating scale. In the adapted version, the original scales were retained and the items were rephrased to allow parents to rate each of the 47 items from 0 to 3 as described in the following.

Like the original instrument, our modified Ritvo-Freeman Real Life Rating Scale included subscales for assessing sensory motor behaviors (e.g., hand flapping, rocking, pacing) (subscale I), social relatedness (e.g., appropriate responses to interaction attempts, initiation of appropriate physical interactions) (subscale II), affectual reactions (e.g., abrupt changes in affect, crying, temper outbursts) (subscale III), sensory responses (e.g., being agitated by noises, rubbing surfaces, sniffing self or objects) (subscale IV), and language (e.g., communicative use of language, initiation of appropriate verbal communication) (subscale V). Each of the five subscales contained a number of individual items that were scored on a 4-point scale: 0 indicated “never,” 1 signified “infrequently (occasionally),” 2 indicated “frequently (daily),” and 3 represented “almost always.” The average of the mean values for each of the five subscale scores was determined to yield an overall score. The score on the Ritvo-Freeman Real Life Rating Scale increases as the number and frequency of symptoms of autism increase. A mathematical sign correction to subtract normal behavior is necessary on subscales II, IV, and V; this could result in negative values on some subscales.

The scale was administered at baseline and at the end of weeks 4 and 8 during the controlled trial and monthly thereafter for subjects who entered the 16-week open-label continuation phase of the study (i.e., 12, 16, 20, and 24 weeks after baseline). The parent or primary caregiver was asked to consider the child’s behavior over the past month.

This scale is a reliable and valid semistructured clinician-rated measure of obsessive-compulsive symptom severity in children and adolescents with obsessive-compulsive disorder (OCD) (9). The Children’s Yale-Brown Obsessive Compulsive Scale is a modified version of the Yale-Brown Obsessive Compulsive Scale, which was developed for adults with OCD (17, 18). Like the adult version, the scale for children is a 10-item clinician-rated, semistructured instrument designed to assess the severity of OCD symptoms over the previous week. The overall structure, anchor points, and scoring of the original instrument were retained in the children’s version, but the wording of the probe questions was modified to make them more developmentally appropriate for children and adolescents.

The severity of the endorsed obsessions is rated on five items: time spent, interference, associated distress, degree of resistance against the thoughts, and degree of control over obsessive thoughts. Each of these five items is rated on a 5-point ordinal scale: 0 indicates “none”; 1, “mild”; 2, “moderate”; 3, “severe”; and 4, “extreme.” The obsessions severity score is obtained by adding the scores for items 1 through 5 (range=0 to 20). There are five comparable severity items for compulsions (items 6 through 10), which are also scored from 0 to 4. The compulsion severity score is obtained by adding the scores on items 6 through 10 (range=0 to 20). Summing the scores for all 10 items yields the total score on the Children’s Yale-Brown Obsessive Compulsive Scale (range=0 to 40). Because many children with autism have limited cognitive and verbal communication abilities, we used only the compulsion subscale of the Children’s Yale-Brown Obsessive Compulsive Scale (range=0–20). These cognitive and communication impairments may also limit the subject’s ability to describe his or her subjective experience concerning resistance and degree of control over repetitive behavior. For these items, we relied on the parent as the primary informant. Children with OCD typically describe distress associated with the performance of their unwanted rituals (19). By contrast, children and adults with autism often engage in self-stimulating or self-soothing stereotypic behaviors and do not appear distressed during the performance of repetitive behavior (20, 21). Because of these observations, the modified Children’s Yale-Brown Obsessive Compulsive Scale did not require the subject’s recognition that the behavior is excessive. To capture stereotypic behaviors, the scale’s symptom checklist was expanded to include repetitive behaviors associated with autism, such as spinning objects, staring, twirling, and repeating words and phrases.

Reliability was established through multiple training sessions and co-rating of videotaped interviews. Each clinical rater had to achieve a criterion of ±15% of the gold standard established by an experienced rater (L.S.). For example, if the gold standard rating total for a videotaped interview was 14, the other raters had to rate the same tape between 12 and 16 to qualify as a rater; if the gold standard was 10, they had to rate the tape between 9 and 11. Anyone who did not meet this criterion on four tapes underwent further training and rated additional tapes until qualified. The Children’s Yale-Brown Obsessive Compulsive Scale was administered by a blinded clinician at baseline and at the end of 2, 4, 6, and 8 weeks of the controlled drug study. This measure was also administered on a monthly basis during the 16-week open-label continuation phase (i.e., 12, 16, 20, and 24 weeks after baseline). The scores determined by the clinical rater were based on the information provided by the subject’s parent or primary caregiver during the interview regarding his or her child’s repetitive behavior over the interval since the last assessment.

The maladaptive behavior domain of the Vineland Adaptive Behavior Scales (10) was completed by trained clinicians by means of a parent interview. The maladaptive behavior domain is divided into two subscales: part 1 consists of 27 items, and part 2 consists of nine items. Each item is scored on a 3-point scale where 0 indicates “no, never,” 1 indicates “sometimes or partially,” and 2 signifies “yes, usually.” Thus, the range of scores for part 1 was 0 to 54, the range for part 2 was 0 to 18, and the range for the total score was 0 to 72. Part 1 includes mood- and anxiety-related symptoms, along with hyperactivity, lying, cheating, bed-wetting, and others. Part 2 contains more severe symptoms, including psychosis, self-injury, and property destruction. These subscales have previously been shown to be sensitive to change with medication in pharmacological studies involving subjects with autism (14, 22). Ratings on this secondary outcome measure were obtained by interview at baseline, at week 8 of the placebo-controlled phase, and at the end of the 16-week open-label continuation phase of the study (i.e., 24 weeks after baseline).

The data were analyzed according to the intent-to-treat principle. The statistical tests were two-tailed, and p values of 0.05 or less were considered to indicate statistical significance. Bonferroni correction for multiple tests was not done because the different instruments measured different domains of functioning. For the 8-week controlled trial, the monthly and biweekly scores on the Ritvo-Freeman Real Life Rating Scale and the Children’s Yale-Brown Obsessive Compulsive Scale, respectively, were analyzed with the use of mixed-effects linear models in which the study group and site were the fixed effects and the outcome and time were the random effects (23). The mixed-effects approach makes full use of available data and allowed us to combine subject-specific scores on the Ritvo-Freeman Real Life Rating Scale and Children’s Yale-Brown Obsessive Compulsive Scale in order to estimate the slope of the regression line for each group over time. A strong downward trend in scores in the risperidone group, as compared with the placebo group, would indicate a statistically significant interaction between treatment and time. Site-by-treatment interactions that were not significant were removed from the final model. The parameters of the mixed-effects model were estimated with the use of SAS Proc Mixed software (24). Because the Vineland maladaptive behavior domain scales had insufficient data points for the mixed-effects model, analysis of covariance was used to compare groups during the placebo-controlled phase.

For the 16-week open-label continuation phase, the monthly scores on the Ritvo-Freeman Real Life Rating Scale and the Children’s Yale-Brown Obsessive Compulsive Scale were analyzed with mixed-effects linear regression models in which time, site, and the site-by-time interaction were the fixed effects. The average slope of the regression line was calculated for each individual across time. Paired t tests of scores on the Vineland maladaptive behavior domain scales were used to compare the values at the beginning of the 16-week open-label continuation phase with the scores at the end (week 24).

Risperidone significantly decreased the overall score on the Ritvo-Freeman scale and the scores on the subscales for sensory motor behaviors (subscale I), affectual reactions (subscale III), and sensory responses (subscale IV), but it had no statistically significant effect on the score on the subscale for social relatedness (subscale II) or language (subscale V). Table 1 shows the mean scores at baseline, the end of week 4, and the end of week 8, as well as the effect size, for each of the five subscales and the overall Ritvo-Freeman Real Life Rating Scale in each study group during the 8-week controlled phase of the study. The scores are also shown for the monthly measurements in the 16-week open-label continuation phase. There was no significant change in any of these measures over the course of the continuation phase.

Figure 1 shows the mean scores at baseline and at the end of weeks 2, 4, 6, and 8 on the modified compulsion scale of the Children’s Yale-Brown Obsessive Compulsive Scale for each study group during the 8-week controlled phase of the study. The mean score went from 15.51 (SD=2.73) to 11.65 (SD=4.02) in the risperidone group compared to 15.18 (SD=3.88) to 14.21 (SD=4.81) in the placebo group. There was a significant interaction between study group and time (F=8.21, df=1, 243, p=0.005); the effect size (Cohen’s d) was 0.55. The mean values are also shown for the 16-week open-label continuation phase. There was no significant change in this measure during the continuation.

Table 2 shows the mean scores at baseline and the end of week 8 for part 1, part 2, and the total maladaptive behavior domain for the risperidone and placebo groups. The mean values for these measures are also shown for the end of the 16-week open-label phase (week 24 of the study). There was a significant interaction between treatment and time for each of these scores during the 8-week controlled phase of the study. There was no significant change in these measures over the 16-week continuation phase.