A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders. Risperidone in children with autism and serious behavioral problems. Effects of risperidone on conduct and disruptive behavior disorders in children with subaverage IQs. Risperidone in the treatment of behavioral disturbances in children and adolescents with borderline intellectual functioning: a double-blind, placebo-controlled pilot trial. Risperidone augmentation for treatment-resistant aggression in attention-deficit/hyperactivity disorder: a placebo-controlled pilot study. A randomized, double-blind, placebo-controlled study of risperidone maintenance treatment in children and adolescents with disruptive behavior disorders. Efficacy and tolerability of ziprasidone versus risperidone in patients with acute exacerbation of schizophrenia or schizoaffective disorder: an 8-week, double-blind, multicenter trial. Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence. Efficacy of risperidone versus olanzapine in patients with schizophrenia previously on chronic conventional antipsychotic therapy: a switch study.
Neurobiological research has implicated the dopamine and serotonin systems in the pathogenesis of autism. Open-label reports suggest that the serotonin2A-dopamine D2 antagonist risperidone may be safe and effective in reducing the interfering symptoms of patients with autism.
                Thirty-one adults (age [mean+/-SD], 28.1+/-7.3 years) with autistic disorder (n=17) or pervasive developmental disorder not otherwise specified (n=14) participated in a 12-week double-blind, placebo-controlled trial of risperidone. Patients treated with placebo subsequently received a 12-week open-label trial of risperidone.
                For persons completing the study, 8 (57%) of 14 patients treated with risperidone were categorized as responders (daily dose [mean+/-SD], 2.9+/-1.4 mg) compared with none of 16 in the placebo group (P<.002). Risperidone was superior to placebo in reducing repetitive behavior (P<.001), aggression (P<.001), anxiety or nervousness (P<.02), depression (P<.03), irritability (P<.01), and the overall behavioral symptoms of autism (P<.02). Objective, measurable change in social behavior and language did not occur. Nine (60%) of 15 patients who received treatment with open-label risperidone following the double-blind placebo phase responded. Other than mild, transient sedation, risperidone was well tolerated, with no evidence of extrapyramidal effects, cardiac events, or seizures.
                Risperidone is more effective than placebo in the short-term treatment of symptoms of autism in adults. Atypical antipsychotic agents, which block postsynaptic dopamine and serotonin receptors, have advantages over traditional antipsychotic medications in the treatment of adults with schizophrenia and may be beneficial in children with autistic disorder who have serious behavioral disturbances. However, data on the safety and efficacy of atypical antipsychotic agents in children are limited.
                We conducted a multisite, randomized, double-blind trial of risperidone as compared with placebo for the treatment of autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior in children 5 to 17 years old. The primary outcome measures were the score on the Irritability subscale of the Aberrant Behavior Checklist and the rating on the Clinical Global Impressions - Improvement (CGI-I) scale at eight weeks.
                A total of 101 children (82 boys and 19 girls; mean [+/-SD] age, 8.8+/-2.7 years) were randomly assigned to receive risperidone (49 children) or placebo (52). Treatment with risperidone for eight weeks (dose range, 0.5 to 3.5 mg per day) resulted in a 56.9 percent reduction in the Irritability score, as compared with a 14.1 percent decrease in the placebo group (P<0.001). The rate of a positive response, defined as at least a 25 percent decrease in the Irritability score and a rating of much improved or very much improved on the CGI-I scale, was 69 percent in the risperidone group (34 of 49 children had a positive response) and 12 percent in the placebo group (6 of 52, P<0.001). Risperidone therapy was associated with an average weight gain of 2.7+/-2.9 kg, as compared with 0.8+/-2.2 kg with placebo (P<0.001). Increased appetite, fatigue, drowsiness, dizziness, and drooling were more common in the risperidone group than in the placebo group (P<0.05 for each comparison). In two thirds of the children with a positive response to risperidone at eight weeks (23 of 34), the benefit was maintained at six months.
                Risperidone was effective and well tolerated for the treatment of tantrums, aggression, or self-injurious behavior in children with autistic disorder. The short period of this trial limits inferences about adverse effects such as tardive dyskinesia.
                Copyright 2002 Massachusetts Medical Society To determine whether risperidone is effective in reducing symptoms of disruptive behaviors (such as aggression, impulsivity, defiance of authority figures, and property destruction) associated with conduct disorder, oppositional defiant disorder, and disruptive behavior disorder-not otherwise specified in children with subaverage IQs.
                The trial consisted of a 1-week, single-blind, placebo run-in period and was followed by a 6-week, double-blind, placebo-controlled period. One hundred ten children (aged 5-12 years inclusive) with an IQ of 36-84 with a disruptive behavior disorder and a score of at least 24 on the Conduct Problem subscale of the Nisonger Child Behavior Rating Form (NCBRF) were enrolled. Eighty percent of subjects had comorbid attention-deficit/hyperactivity disorder (ADHD). Risperidone doses ranged from 0.02 to 0.06 mg/kg per day. Subjects were rated on the NCBRF, Aberrant Behavior Checklist, Behavior Problems Inventory, Clinical Global Impressions (CGI), modified California Verbal Learning Test (CVLT), and a continuous performance task (CPT).
                The intention-to-treat analysis of risperidone-treated subjects showed a significant (p < .001) reduction in mean scores (from 33.4 at baseline to 17.6 at end point; 47.3% reduction) versus placebo-treated subjects (mean baseline of 32.6 to 25.8 at end point; 20.9% reduction) on the Conduct Problem subscale of the NCBRF. Between-group differences in favor of risperidone were seen as early as week 1 and were significant at all post-baseline visits. Other subscales showed significant improvement with risperidone compared with placebo. CGI scale ratings of improvement showed highly significant gains for risperidone over placebo. A subanalysis demonstrated that the effect of risperidone was unaffected by diagnosis, presence/absence of ADHD, psychostimulant use, IQ status, and somnolence. Risperidone produced no changes on the cognitive variables (CPT/modified CVLT). The most common side effects included somnolence, headache, appetite increase, and dyspepsia. Side effects related to extrapyramidal symptoms were reported in 7 (13.2%) and 3 (5.3%) of the subjects in the risperidone and placebo groups, respectively (p = .245).
                Risperidone appears to be an adequately tolerated and effective treatment in children with subaverage IQs and severe disruptive behaviors such as aggression and destructive behavior. Risperidone, an antipsychotic agent with combined serotonin (5-HT2A) and dopamine (D2) receptor-blocking properties, is associated with fewer extrapyramidal side effects in adults than conventional neuroleptics. Approved in 1993 for the treatment of schizophrenia, recent studies have highlighted its potential in other conditions, such as the management of behavioral disturbances. This phase II, double-blind, placebo-controlled study evaluated the efficacy and tolerability of risperidone in the treatment of persistent behavioral disturbances in children with borderline intellectual functioning. Thirteen patients (6-14 years) with low IQ (66-85) were enrolled in and completed the 4-week study. Risperidone, in daily doses of > or = 0.01 mg/kg (mean dose at treatment endpoint = 0.05 mg/kg; mean total dose = 1.2 mg/day), was significantly more effective than placebo in improving Aberrant Behavioral Checklist (ABC) symptom cluster scores for irritation (p < 0.05) and hyperactivity (p < 0.01), Clinical Global Impression score (p < 0.05), the Visual Analogue Scale score for individual target symptom (p < 0.001), and Personal Assessment Checklist scores for social relationships (p < 0.05) and occupational attitudes (p < 0.05). In addition, the improvement in total ABC score in the risperidone-treated group was clinically relevant (65% improvement vs. baseline), whereas the placebo-treated patients only improved 7% versus baseline. There was no difference between risperidone- and placebo-treated groups with respect to the occurrence of extrapyramidal side effects, and risperidone was well tolerated. In conclusion, short-term risperidone treatment was well tolerated and significantly more effective than placebo in controlling behavioral disturbances in children with low IQ. To evaluate the effects of risperidone augmentation for treatment-resistant aggression in children with attention-deficit/hyperactivity disorder (ADHD).
                Twenty-five children (ages 7-12 years) with attention-deficit/hyperactivity disorder (ADHD) and significant aggressive behaviors were randomized to risperidone or placebo for 4 weeks for this double-blind study. Subjects were already in treatment with a constant dose of psychostimulant medication. The primary efficacy measure was change from baseline in the Children's Aggression Scale-Parent (CAS-P) and -Teacher (CAS-T) total scores.
                The mean risperidone dose at endpoint was 1.08 mg/day. For the CAS-P total score, a significant difference was found (chi(1)(2) = 4.30, p < .05) with 100% of risperidone subjects improving by more than 30% from baseline to endpoint, whereas only 77% of the placebo group reported a similar response. No differences were found on the CAS-T total score. For the CAS-P and CAS-T, no significant interaction was found between treatment group and time. Rates of adverse events did not differ significantly between groups.
                Risperidone treatment appears to be well tolerated and modestly effective when used in combination with psychostimulants for treatment-resistant aggression in children with ADHD. The authors compared the effects of maintenance versus withdrawal of risperidone treatment in children and adolescents with symptoms of disruptive behavior disorder.
                Patients with disruptive behavior disorder (5-17 years of age and a range of intellect) who had responded to risperidone treatment over 12 weeks were randomly assigned to 6 months of double-blind treatment with either risperidone or placebo. The primary efficacy measure was time to symptom recurrence, defined as sustained deterioration on either the Clinical Global Impression severity rating (/2 points) or the conduct problem subscale of the Nisonger Child Behavior Rating Form (/7 points). Secondary efficacy measures included rates of discontinuation due to symptom recurrence, disruptive behavior disorder symptoms, and general function. Safety and tolerability were also assessed. Risperidone dosage was based on weight (patients <50 kg: 0.25-0.75 mg/day; patients /50 kg: 0.5-1.5 mg/day).
                Treatment was initiated in 527 patients, with 335 randomly assigned to a double-blind maintenance condition. Time to symptom recurrence was significantly longer in patients who continued risperidone treatment than in those switched to placebo. Symptom recurrence in 25% of patients occurred after 119 days with risperidone and 37 days with placebo. Secondary efficacy measures also favored risperidone over placebo. Weight increased over the initial 12 weeks of treatment (mean weight z score change=0.2, SD=2.7, N=511), after which it plateaued.
                This study is the first placebo-controlled maintenance versus withdrawal trial of its kind in disruptive behavior disorder and provides evidence that patients who respond to initial treatment with risperidone would benefit from continuous treatment over the longer term. More head-to-head comparisons of antipsychotics are needed to discern the relative efficacy and safety profiles of these compounds. Thus, we compared ziprasidone and risperidone in patients with acute exacerbation of schizophrenia or schizoaffective disorder.
                Patients with DSM-III-R acute exacerbation of schizophrenia or schizoaffective disorder were randomly assigned to double-blind ziprasidone 40 to 80 mg b.i.d. (N = 149) or risperidone 3 to 5 mg b.i.d (N = 147) for 8 weeks. Primary efficacy measures included Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions-Severity of Illness scale (CGI-S) score; secondary measures included scores on the PANSS negative sub-scale, CGI-Improvement scale (CGI-I), and PANSS-derived Brief Psychiatric Rating Scale (BPRSd) total and core items. Safety assessments included movement disorder evaluations, laboratory tests, electrocardiography, vital signs, and body weight. Efficacy analyses employed a prospectively defined Evaluable Patients cohort. Treatment equivalence was conferred if the lower limit of the 95% confidence interval of the ziprasidone/risperidone ratio of least-squares mean change from baseline was > 0.60. Data were gathered from August 1995 to January 1997.
                Equivalence was demonstrated in PANSS total scores, CGI-S scores, PANSS negative subscale scores, BPRSd total and core item scores, and PANSS total and CGI-I responder rates. Both agents were well tolerated. Risperidone exhibited a significantly higher Movement Disorder Burden (MDB) score (p < .05) and higher incidences of prolactin elevation and clinically relevant weight gain. However, compared with current recommendations, study dosing may have been high for some risperidone-treated patients (mean dose = 7.4 mg/day) and low for some ziprasidone-treated patients (mean dose = 114.2 mg/day).
                Both agents equally improved psychotic symptoms, and both were generally well tolerated, with ziprasidone demonstrating a lower MDB score and less effect on prolactin and weight than risperidone. The short-term efficacy and safety of risperidone in the treatment of disruptive behaviors was examined in a well-characterized cohort of children with subaverage intelligence.
                In this 6-week, multicenter, double-blind, parallel-group study of 118 children (aged 5-12 years) with severely disruptive behaviors and subaverage intelligence (IQ between 36 and 84, inclusive), the subjects received 0.02-0.06 mg/kg per day of risperidone oral solution or placebo. The a priori primary efficacy measure was the change in score from baseline to endpoint on the conduct problem subscale of the Nisonger Child Behavior Rating Form.
                The risperidone group showed significantly greater improvement than did the placebo group on the conduct problem subscale of the Nisonger Child Behavior Rating Form from week 1 through endpoint (change in score of -15.2 and -6.2, respectively). Risperidone was also associated with significantly greater improvement than placebo on all other Nisonger Child Behavior Rating Form subscales at endpoint, as well as on the Aberrant Behavior Checklist subscales for irritability, lethargy/social withdrawal, and hyperactivity; the Behavior Problems Inventory aggressive/destructive behavior subscale; a visual analogue scale of the most troublesome symptom; and the Clinical Global Impression change score. The most common adverse effects reported during risperidone treatment were headache and somnolence. The extrapyramidal symptom profile of risperidone was comparable to that of placebo. Mean weight increases of 2.2 kg. and 0.9 kg occurred in the risperidone and placebo groups, respectively.
                Risperidone was effective and well tolerated for the treatment of severely disruptive behaviors in children with subaverage IQ. The objective of the study was to examine whether patients with schizophrenia who were judged to be stable on long-term treatment with conventional antipsychotic medications would further benefit from a switch to an atypical antipsychotic drug. Thirty-six subjects with schizophrenia spectrum disorder, on conventional antipsychotic medication therapy for at least 2 years, were randomized in double-blind fashion to risperidone versus olanzapine. Patients were titrated up to 6 mg risperidone or 15 mg olanzapine as tolerated, followed by tapering and discontinuation of conventional antipsychotic medication. Atypical antipsychotic agents were then administered alone (monotherapy) for 12 weeks. Efficacy and tolerability were assessed using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale, and Simpson Angus Scale. Body weight was measured at each visit. Both treatment groups exhibited marked and similar improvement in the total PANSS score from baseline to study endpoint (22 weeks) [risperidone: baseline=59.3 (SE 3.1), 22 weeks=44.3 (SE 2.3) (p<0.001); olanzapine: baseline=55.9 (SE 3.3), 22 weeks=46.9 (SE 3.2) (p<0.001). Both groups also exhibited significant reductions in PANSS factor scores for positive and negative symptoms and disorganized thoughts. Only risperidone-treated patients exhibited significant decreases in uncontrolled hostility/excitement and anxiety and depression. Of note, while positive factor scores exhibited the majority of change within the first 10 weeks, negative factor scores continued to decline significantly in both treatment groups throughout the study. Tolerability assessments did not differ between groups. The results indicate that both atypical antipsychotic medications provided significant additional improvement in symptom severity in patients with schizophrenia previously on conventional antipsychotic agents.
Risperidone can be beneficial in some features of autism. However there are limited data available from studies with small sample sizes. In addition, there lacks a single standardised outcome measure allowing adequate comparison of studies, and long-term followup is also lacking. Further research is necessary to determine the efficacy pf risperidone in clinical practice.