Acute and Long-Term Safety and Tolerability of Risperidone in Children with Autism

Abstract

Treatment-emergent adverse events (AEs) were monitored during an 8-week, double-blind, placebo-controlled trial of risperidone (0.5-3.5 mg/day) in 101 children and adolescents with a lifetime diagnosis of autistic disorder. In addition, 37 placebo nonresponders received open-label risperidone for another 8 weeks. Of all the risperidone responders (n=65), 63 entered an open extension of another 16 weeks (6 months total risperidone exposure), and 32 of them were rerandomized to either continued risperidone therapy (n=16) or gradual replacement with placebo (n=16) over 8 weeks. We collected the following measures of safety and tolerability: (1) laboratory blood assessments (CBC with differential, electrolytes, and liver function tests) and urinalyses, (2) vital signs, (3) Side Effects Review of AEs thought to be associated with risperidone, (4) sleep records, (5) Simpson Angus Neurological Rating Scale (SARS), (6) Abnormal Involuntary Movement Scale (AIMS), and (7) height and weight. No clinically significant changes were found on the lab tests. During the 8-week acute trial, the most common AEs on the Side Effects Review, scored as moderate or higher, were as follows (placebo and risperidone, respectively): Somnolence (12% and 37%), enuresis (29% and 33%), excessive appetite (10% and 33%), rhinitis (8% and 16%), difficulty waking (8% and 12%), and constipation (12% and 10%). "Difficulty falling asleep" and anxiety actually favored the risperidone condition at statistically significant levels. The same AEs tended to recur through 6 months of treatment, although often at reduced levels. Using Centers for Disease Control (CDC) standardized scores, both weight and body mass index (BMI) increased with risperidone during the acute trial (0.5 and 0.6 SDs, respectively, for risperidone; 0.0 and 0.1 SDs, respectively, for placebo) and into open-label extension (0.19 and 0.16 SDs, respectively), although the amount of gain decelerated with time. Extrapyramidal symptoms, as assessed by the SARS, were no more common for drug than placebo, although drooling was reported more often in the risperidone group. There were no differences between groups on the AIMS. Two subjects had seizures (one taking placebo), but these were considered unrelated to active drug. Most AEs were mild to moderate and failed to interfere with therapeutic changes; there were no unanticipated AEs. The side effects of most concern were somnolence and weight gain.

Effects of risperidone on cognitive-motor performance and motor movements in chronically medicated children

“…Heart rate increases have often been reported with risperidone and other atypical antipsychotics (Tandon, 2002;Stigler, Potenza, & McDougle (2001)). Consistent with the RUPP report and many other investigations (Aman et al, 2005;Martin et al, 2004), we observed significant increases in weight with risperidone.…”

“…However, one detailed analysis of a large sample of children with autism indicated that reports of somnolence usually ceased within 2 weeks of the last dose titration of risperidone (Aman et al, 2005). Most of the participants in the current trial had either a disruptive behavior disorder or autism, and it is reasonable, therefore, to hypothesize that risperidone may have reduced behaviors incompatible with learning performance, such as stereotypy or hyperactivity.…”

“…Aman et al (2005) conducted a thorough analysis of AEs and did not observe significant differences in heart rate activity for 101 subjects with autism in the initial RUPP risperidone study. However, the assessment of heart rate in the current investigation was highly standardized; these participants were more cooperative than the participants in the RUPP autism study, and the conditions of assessment (following a mandatory 4-min of rest while sitting) were quite rigorous.…”

Tolerability, Safety, and Benefits of Risperidone in Children and Adolescents with Autism: 21-Month Follow-up After 8-Week Placebo-Controlled Trial

“…Finally, two children in the predominately risperidone group experienced seizures. In our previous AE study (Aman et al 2005a), we reported two other participants who experienced seizures, one while taking placebo and one with risperidone treatment. Hedges et al (2003) reviewed the evidence on antipsychotic induction of seizures and concluded that clozapine was the second-generation antipsychotic most frequently associated with seizures whereas risperidone appeared to have relatively low risk.…”

“…These included 1) clinical nonfasting laboratory tests for complete blood count (CBC) with differential, blood chemistries, liver functions, triglycerides, glucose, and HgbA1C; 2) urinalysis; 3) ECG; 4) vital signs; and 5) height and weight. Other assessments included 6) a Side Effects Review Form [which included the 28 most common AEs associated with risperidone] (Aman et al 2005a); 7) The Simpson-Angus Rating Scale (Simpson and Angus 1970) for extrapyramidal symptoms; 8) the Abnormal Involuntary Movement Scale (AIMS) (Guy 1976); 9) a physical examination; and 10) a medical history assessing health since departure from the acute trial. To enable the subjects to consume some food before assessment, we developed breakfast and lunch ''Nutrition lists'' that resulted in * 70 g of carbohydrate and a minimum amount of fat (7-10 g).…”