Risperidone in Children with Autism and Serious Behavioral Problems

McCracken, James T.; McGough, James J.; Shah, Bhavik; Cronin, Pegeen; Hong, Daniel; Aman, Michael G.; Arnold, L. Eugene; Lindsay, Ronald L.; Nash, Patricia; Hollway, Jill A.; McDougle, Christopher J.; Posey, David J.; Swiezy, Naomi B.; Kohn, Arlene E.; Scahill, Lawrence; Martin, Andrés; Koenig, Kathleen; Volkmar, Fred R.; Carroll, Deirdre; Lancor, Allison; Tierney, Elaine; Ghuman, Jaswinder K.; Gonzalez, Nilda M.; Grados, Marco A.; Vitiello, Benedetto; Ritz, Louise; Davies, Mark; Robinson, James A.; McMahon, Don

doi:10.1056/nejmoa013171

Cited by 1,282 publications

(631 citation statements)

References 23 publications

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“…Although both are approved for the treatment of irritability, an associated ASD symptom, both have shown efficacy in reducing core symptoms as well. Specifically, randomized controlled trials of risperidone in individuals with ASD found significant reductions in challenging behaviors, such as irritability and hyperactivity [596-600], and significant improvement in core autism symptoms [601-604]. Randomized controlled trials of aripiprazole have also found a decrease in irritability and hyperactivity and decreased instances of repetitive behaviors in children with ASD over the course of treatment [604,605].…”

Section: Reviewmentioning

confidence: 99%

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Dichter

Damiano

Allen

2012

J Neurodevelop Disord

245

207

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This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.

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Section: Reviewmentioning

confidence: 99%

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Dichter

Damiano

Allen

2012

J Neurodevelop Disord

245

207

View full text Add to dashboard Cite

show abstract

“…1 According to a recent survey, 31% of children with autism spectrum disorders take an antipsychotic medication, 2 with risperidone one of the most popular atypical antipsychotics prescribed. Several open trials of risperidone in autism (reviewed in 3,4 ) and three placebo double-blind randomized controlled trials, [5][6][7] reported significant improvements in at least half of the patients evaluated. 4,8 Risperidone was shown to be well tolerated and effective in treating aggressiveness, hyperactivity, irritability, self-injurious behaviours, stereotipies, social withdrawal and lack of interest.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

Almeida²,

et al. 2009

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Little has been reported on the factors, genetic or other, that underlie the variability in individual response, particularly for autism. In this study we simultaneously explored the effects of multiple candidate genes on clinical improvement and occurrence of adverse drug reactions, in 45 autistic patients who received monotherapy with risperidone up to 1 year. Candidate genes involved in the pharmacokinetics (CYP2D6 and ABCB1) and pharmacodynamics (HTR2A, HTR2C, DRD2, DRD3, HTR6) of the drug, and the brain-derived neurotrophic factor (BDNF) gene, were analysed. Using the generalized estimating equation method these genes were tested for association with drug efficacy, assessed with the Autism Treatment Evaluation Checklist, and with safety and tolerability measures, such as prolactin levels, body mass index (BMI), waist circumference and neurological adverse effects, including extrapyramidal movements. Our results confirm that risperidone therapy was very effective in reducing some autism symptoms and caused few serious adverse effects. After adjusting for confounding factors, the HTR2A c.-1438G4A, DRD3 Ser9Gly, HTR2C c.995G4A and ABCB1 1236C4T polymorphisms were predictors for clinical improvement with risperidone therapy. The HTR2A c.-1438G4A, HTR2C c.68G4C (p.C33S), HTR6 c.7154-2542C4T and BDNF c.196G4A (p.V66M) polymorphisms influenced prolactin elevation. HTR2C c.68G4C and CYP2D6 polymorphisms were associated with risperidone-induced increase in BMI or waist circumference. We thus identified for the first time several genes implicated in risperidone efficacy and safety in autism patients. Although association results require replication, given the small sample size, the study makes a preliminary contribution to the personalized therapy of risperidone in autism.

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“…The approval was largely based on the findings from two randomized, controlled trials in 79 and 101 children with autistic disorder and severe behavioral problems. 4,5 In the larger study, children in the risperidone group had a 57% reduction in irritability compared to only a 14% reduction among children in the placebo group (p Ͻ 0.001). 4 A second atypical antipsychotic, aripiprazole, was approved in late 2009 for the same indication (irritability) in children with ASD, based on the results from two 8-week randomized, placebo-controlled trials in 98 and 218 patients.…”

Section: Introductionmentioning

confidence: 86%

“…4,5 In the larger study, children in the risperidone group had a 57% reduction in irritability compared to only a 14% reduction among children in the placebo group (p Ͻ 0.001). 4 A second atypical antipsychotic, aripiprazole, was approved in late 2009 for the same indication (irritability) in children with ASD, based on the results from two 8-week randomized, placebo-controlled trials in 98 and 218 patients. 6,7 In the larger study, irritability improved 14% to 21% over 8 weeks, but side effects, including sedation, tremor, drooling, and weight gain, were common.…”

Section: Introductionmentioning

confidence: 86%

“…4 However, even in a carefully recruited study population of children with severe tantrums, aggression, or self-injurious behavior, approximately one third of the enrolled children did not have a positive response to therapy. 4 Because significant side effects (i.e., increased appetite, fatigue, drowsiness, dizziness, drooling) were noted with risperidone, and because the long-term safety of this drug in children is not known, it would be useful to have a more reliable method of identifying children who are most likely to benefit from therapy.…”

Section: Genomics: Using Genes To Predict Response To Risperidonementioning

confidence: 98%

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Improving the Prediction of Response to Therapy in Autism

Bent

Hendren

2010

Neurotherapeutics

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Summary: Autism is a heterogeneous disorder involving complex mechanisms and systems occurring at diverse times. Because an individual child with autism may have only a subset of all possible abnormalities at a specific time, it may be challenging to identify beneficial effects of an intervention in double-blind, randomized, controlled trials, which compare the mean responses to treatments. Beneficial effects in a small subset of children may be obscured by the lack of effect in the majority. We review the evidence for several potential model systems of biochemical abnormalities that may contribute to the etiology of autism, we describe potential biomarkers or treatment targets for each of these abnormalities, and we provide illustrative treatment trials using this methodology. Potential model systems include immune over and under reactivity, inflammation, oxidative stress, free fatty acid metabolism, mitochondrial dysfunction, and excitotoxicity. Including potential biomarkers and targeted treatments in clinical trials for autism provides a potential method for limiting the heterogeneity of enrolled subjects, which may improve the power of studies to identify beneficial effects of treatments while also improving the understanding of the disease.

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Risperidone in Children with Autism and Serious Behavioral Problems

Abstract: 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.

Cited by 1,282 publications

References 23 publications

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

Improving the Prediction of Response to Therapy in Autism

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