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CHRNA7 Deletions are Enriched in Risperidone-Treated Children and Adolescents.

ABSTRACT: OBJECTIVE:Aggression is among the most common indications for referral to child and adolescent mental health services and is often challenging to treat. Understanding the biological underpinnings of aggression could help optimize treatment efficacy. Neuronal nicotinic acetylcholine receptors (nAChRs), specifically the ?7 nAChR, encoded by the gene CHRNA7, have been implicated in aggressive behaviors in animal models as well as humans. Copy number variants (CNVs) of CHRNA7 are found in individuals with neuropsychiatric disorders, often with comorbid aggression. In this study, we aimed to determine the prevalence of CHRNA7 CNVs among individuals treated with risperidone, predominantly for irritability and aggression. METHODS:Risperidone-treated children and adolescents were assessed for CHRNA7 copy number state using droplet digital PCR and genomic quantitative PCR. Demographic, anthropometric, and clinical data, including the Child Behavior Checklist (CBCL), were collected and compared across individuals with and without the CHRNA7 deletion. RESULTS:Of 218 individuals (90% males, mean age: 12.3?±?2.3 years), 7 (3.2%) were found to carry a CHRNA7 deletion and one proband carried a CHRNA7 duplication (0.46%). T-scores for rule breaking, aggression, and externalizing behavior factors of the CBCL were higher in the deletion group, despite taking 58% higher dose of risperidone. CONCLUSIONS:CHRNA7 loss may contribute to a phenotype of severe aggression. Given the high prevalence of the deletion among risperidone-treated youth, future studies should examine the therapeutic potential of ?7 nAChR-targeting drugs to target aggression associated with CHRNA7 deletions.

SUBMITTER: Gillentine MA

PROVIDER: S-EPMC5725633 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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CHRNA7 Deletions are Enriched in Risperidone-Treated Children and Adolescents.

Gillentine Madelyn A MA White Janson J JJ Grochowski Christopher M CM Lupski James R JR Schaaf Christian P CP Calarge Chadi A CA

Journal of child and adolescent psychopharmacology 20170817 10

<h4>Objective</h4>Aggression is among the most common indications for referral to child and adolescent mental health services and is often challenging to treat. Understanding the biological underpinnings of aggression could help optimize treatment efficacy. Neuronal nicotinic acetylcholine receptors (nAChRs), specifically the α7 nAChR, encoded by the gene CHRNA7, have been implicated in aggressive behaviors in animal models as well as humans. Copy number variants (CNVs) of CHRNA7 are found in in ...[more]

PMID: 28817303

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Project description:ObjectivePrevious cross-sectional evidence has linked antipsychotic-related weight gain to reduced body iron concentration. Using longitudinal data, we examined the association between changes in weight following risperidone initiation or discontinuation and ferritin concentration.MethodStudy 1: Between April 2004 and September 2007, participants were enrolled from outpatient settings in a prospective randomized clinical trial comparing the efficacy of risperidone monotherapy to the combination of risperidone and behavior therapy in targeting disruptive behavior in 4- to 13-year-old children with DSM-IV-TR-based autism spectrum disorder. Study 2: Medically healthy 7- to 17-year-old participants in long-term open-label risperidone treatment at study entry returned for follow-up 1.5 years later, between July 2007 and July 2011. Available blood samples were used to measure ferritin. Linear multivariable regression analysis tested the association between ferritin concentration and change in age-sex-specific body mass index (BMI) z score between study entry and endpoint, adjusting for relevant confounders.ResultsStudy 1 sample consisted of 73 participants (85% males, mean age: 7.7 ± 2.4 years). After 18.0 ± 2.0 weeks on risperidone, their BMI z score increased by 0.93 ± 0.70 points and ferritin concentration declined by 6.8 ± 13.3 μg/L. After adjusting for age and sex, change in BMI z score was inversely correlated with percent change in ferritin concentration (β = -18.3, P < .003). Study 2 participants had all been receiving risperidone at study entry. At follow-up, 1.5 ± 0.3 years later, risperidone was discontinued in 26 of the 96 who were included in the analysis. Neither change in BMI z score nor in ferritin concentration was different between those who continued versus discontinued risperidone. However, a reduction in BMI z score between study entry and follow-up was associated with higher ferritin concentration at follow-up in participants who discontinued risperidone compared to those who continued it (P = .01).ConclusionsRisperidone-related weight gain is associated with a reduction in body iron reserves, which appears to improve with weight loss following risperidone discontinuation. Preliminary evidence suggests that risperidone may also directly inhibit iron absorption.Trial registrationClinicalTrials.gov Identifier: NCT00080145.

Project description:Aims: Obesity is a significant problem for patients taking atypical antipsychotics. There were two aims of our study. The first aim was to compare the prevalence of overweight and obesity between children and adolescents with autism spectrum disorder (ASD) treated with risperidone with the general pediatric population. The second aim was to investigate the association of the HTR2C -759C>T, ABCB1 1236C>T, ABCB1 2677G>T/A, and ABCB1 3435C>T polymorphisms with risperidone-induced overweight and obesity in children and adolescents with ASD. Methods: Body weight and height were measured in 134 subjects. Overweight and obesity in children and adolescents were classified using the International Obesity Task Force (IOTF) criteria. Genotyping was performed by TaqMan real-time polymerase chain reaction (PCR). Results: Our study found that the prevalence of overweight and obesity was significantly higher in children and adolescents with ASD treated with risperidone compared with healthy individuals (p = 0.01 and p = 0.002). The genetic polymorphisms of HTR2C -759C>T, ABCB1 1236C>T, ABCB1 2677G>T/A, and ABCB1 3435C>T were not associated with overweight/obesity in children and adolescents with ASD treated with risperidone after adjustment for multiple comparisons by the method of Bonferroni. Additionally, haplotype analysis revealed that there was no significant association between ABCB1 3435T-2677T/A-1236T haplotype and overweight/obesity. In multivariate logistic regression, after adjustment by the Bonferroni correction, there was only the duration of risperidone treatment that was significantly associated with overweight/obesity in children and adolescents with ASD. Conclusions: The findings suggest that children and adolescents with ASD treated with risperidone are at a higher risk of obesity, especially patients with extended treatment with risperidone. For the pharmacogenetic factors, -759C>T polymorphism of HTR2C gene and 1236C>T, 2677G>T/A, and 3435C>T polymorphisms of ABCB1 gene were not likely to be associated with the susceptibility to overweight/obesity in children and adolescents treated with risperidone. Due to the small sample size, further studies with a larger independent group are needed to confirm these findings.

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CHRNA7 Deletions are Enriched in Risperidone-Treated Children and Adolescents.

Publications

CHRNA7 Deletions are Enriched in Risperidone-Treated Children and Adolescents.

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