Objective. The objective of this study was to investigate the long-term safety and efficacy of risperidone in disruptive behavior disorders in children with subaverage IQs. Disruptive behavior disorders were defined as oppositional defiant disorder, disruptive behavior disorder, and conduct disorder as per the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Methods. This was a 48-week open-label (OL) extension study of risperidone in 77 children diagnosed with a disruptive behavior disorder, and either borderline intellectual function or mild or moderate mental retardation who had participated in a previous 6-week, double-blind (DB) study and completed at least 2 weeks of DB therapy. Children, aged 5 to 12 years inclusive, who had: 1) a DSM-IV Axis I diagnosis of conduct disorder, oppositional defiant disorder, or disruptive behavior disorder-not otherwise specified; 2) a parent-assessed rating of greater than or equal to 24 in the Conduct Problem Subscale of the Nisonger-Child Behavior Rating Form(28); 3) aDSM-IV Axis II diagnosis of mild or moderate mental retardation or borderline intellectual functioning with an IQ greater than or equal to 36 and less than or equal to 84; and 4) a score of less than or equal to 84 on the Vineland Adaptive Behavior Scale. Participants received oral solution risperidone given at a once daily dose of between 0.02 and 0.06 mg/kg for a maximum of 48 weeks. Participants in the DB study who had been randomized would have had a maximum of 54 weeks of risperidone therapy. Study visits were scheduled at entry, weekly for the first month, and monthly for the remaining 11 months. Results. Baseline scores on the conduct problem subscale at the start of the previous DB study were similar for both treatment groups: mean values of 33.5 and 33.3 were recorded for placebo- and risperidone-treated participants, respectively. At the time of the OL baseline visit, mean Conduct Problem Subscale scores were lower in those who had been treated with risperidone than in those who remained risperidone-naive (17.5 and 26.1, respectively). Within 1 week of receiving daily risperidone therapy (mean daily dose: 1.38 mg), those participants who had been risperidone-naive at OL entry showed a rapid improvement in the Conduct Problem Subscale score. At the week 1 assessment, the mean change from baseline for those who had been risperidone-naive at OL entry was similar in magnitude to the change from DB baseline recorded for participants who had received risperidone in the DB study. This mean improvement was sustained in both groups throughout the remainder of the OL study. At study endpoint, those participants who had been risperidone-naive at OL entry experienced a highly significant mean decrease from OL baseline in the mean Conduct Problem Subscale score of 10.6 +/- 2.18. The response to risperidone in the OL trial remained stable in those participants who had been treated with risperidone in the previous DB trial; in this group, the mean change at study endpoint from OL baseline was a nonsignificant decrease of 1.26 +/- 1.45. At DB baseline, 68% of participants had a Clinical Global Impression assessment rated as marked, severe, or extremely severe. By DB study endpoint, only 17% of participants (15% of whom had received placebo and 19% of whom had been treated with risperidone in the previous study) had this severe an assessment; 63% of participants had symptoms rated as either none, very mild, or mild. Similarly, highly significant decreases from baseline in the Vineland Adaptive Behavior Scale rating of the most troublesome symptom (often identified as either aggression (hitting, fighting, or temper tantrums) were observed by study endpoint after 48 weeks of risperidone therapy. For those participants who had received placebo in the previous study, a mean decrease of 47.1 +/- 4.87 mm from a DB baseline of 79.4 +/- 2.69 mm was observed. In those who had received risperidone, a mean decrease of 43.5 +/- 4.57 mm from a DB baseline of 79.3 +/- 3.66 mm was observed. Five subgroup analyses of the primary efficacy outcome were performed. These included analysis by diagnosis (conduct disorder, oppositional defiant disorder, and disruptive behavior disorder-not otherwise specified), degree of mental retardation (borderline, mild, moderate), and presence or absence of somnolence, attention-deficit/ hyperactivity disorder, and psychostimulants. The results showed that the efficacy of risperidone was not affected by type of disorder, level of retardation, presence/absence of somnolence or attention-deficit/ hyperactivity disorder, or use of psychostimulants. Adverse events were reported for 76 participants; none were serious and most were mild/moderate in severity. Somnolence (52%), headache (38%), and weight gain (36%) were the most common adverse events. The degree of sedation was mild and not associated with cognitive deterioration. In fact, for most parameters assessed on the modified California Verbal Learning Test (a test for verbal learning and memory), there were statistically significant improvements relative to both OL and DB baselines in the mean scores. In addition, statistically significant improvements over baseline were also seen for some Continous Performance Task (which is a test for attention and impulsivity) parameters. Overall, no deterioration of cognitive function was observed while participants were treated with risperidone. Almost half of the 8.5 kg gained was attributable to normal growth. Asymptomatic peak prolactin levels were observed within 4 weeks of beginning risperidone treatment and declined over time to within normal range. At study endpoint, mean prolactin levels were statistically significantly greater than baseline only in male participants but still <20 ng/mL, which is within the normal range. Twenty participants experienced mild or moderate extrapyramidal symptoms, although none withdrew for this reason. Conclusions. Risperidone, administered as an oral solution at a mean dose of 1.38 mg/ d (range: 0.02-0.06 mg/ kg/d) for 1 year, was well tolerated, safe, and showed maintenance of effect in the treatment of disruptive behavior disorders in children aged 5 to 12 years with subaverage IQs.
