Long-Term Safety and Genetic Risk Factors of Risperdone Treatment in Youth

青少年利培酮治疗的长期安全性和遗传风险因素

• 批准号: 8033328
• 负责人: Chadi A. Calarge
• 金额: $ 8.69万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033328
• 关键词: Address; Adolescent; Adverse effects; Adverse event; Age; Alleles; Antipsychotic Agents; Bone Density; Bone Development; Build-it; Cardiovascular Diseases; Child; Childhood; Chronic; Clinical; Clinical Trials; Collection; Data; Decision Making; Development; Disruptive Behavior Disorder; Dopamine D2 Receptor; Dyslipidemias; Employee Strikes; Enrollment; Evaluation; Functional disorder; Genes; Genetic; Genetic screening method; Glucose Intolerance; Hormonal; Hyperprolactinemia; Insulin Resistance; Laboratories; Leptin; Light; Lipids; Literature; Long-Term Effects; Measures; Medical History; Metabolic; Metabolic syndrome; Minerals; Nature; Observational Study; Osteopenia; Osteoporosis; Patients; Pharmaceutical Preparations; Phenotype; Population; Prevalence; Process; Prolactin; Recording of previous events; Research; Risk; Risperidone; Safety; Sample Size; Sampling; Serotonin; Serotonin Receptor 5-HT2C; Single Nucleotide Polymorphism; System; Testing; Time; United States Food and Drug Administration; Variant; Weight; Weight Gain; Work; Youth; atypical antipsychotic; base; blood glucose regulation; bone; design; follow up assessment; follow-up; genetic analysis; genetic risk factor; genetic variant; glucose metabolism; high risk; prospective; serotonin 5 receptor; serotonin receptor

DESCRIPTION (provided by applicant): Over the last decade, the prescribing rate of atypical antipsychotics (AAPs) for youth has increased by several folds. This has resulted in a striking contrast between the use of AAPs and the limited scientific evidence regarding their efficacy and safety in the pediatric population. Risperidone is the only AAP to have a pediatric indication by the U.S. Food and Drug Administration based on findings from clinical trials in children with autistic and disruptive behavior disorders. Thus, its proven efficacy in youth, in addition to its potent dopamine D2 receptor blocking activity, makes it unique among AAPs. Concerns, however, have been raised regarding its potential to hinder bone mineral accrual due to hyperprolactinemia, thus increasing the risk of osteopenia and osteoporosis. Furthermore, the propensity of AAPs to increase weight significantly and result in metabolic abnormalities has generated calls to investigate the occurrence of dyslipidemia, glucose intolerance, insulin resistance, and the metabolic syndrome phenotype in youth treated with these potent drugs. By combining a retrospective with a prospective design, this application attempts to address these clinically urgent issues. It builds on an ongoing study investigating the metabolic and hormonal abnormalities associated with the chronic use of risperidone in youth. The retrospective and cross-sectional collection of a variety of clinical and laboratory data, including bone mineral density, has recently been completed. However, the clinical impact of these metabolic and hormonal abnormalities is likely to become significant only after prolonged exposure. Thus, during the two-year period of this study, we propose to increase the current sample size and reevaluate all the patients, 15 months after their baseline enrollment. At follow up, the interim clinical history will be documented and clinical and laboratory measures related to the putative metabolic and hormonal abnormalities will be collected. This application, thus, aims to evaluate the effects of long-term risperidone treatment in youth on bone mineral accrual, weight gain, and lipid and glucose metabolism. It will also test whether variants of the serotonin receptor and leptin genes elevate the risk for risperidone-induced metabolic abnormalities. The result of this work will potentially allow the safer use of this effective medication. Findings from this work will add to the bourgeoning literature addressing the long-term safety of atypical antipsychotics in children and adolescents by evaluating the potential for risperidone to cause osteoporosis and cardiovascular disease by inducing hyperprolactinemia, weight gain, and metabolic abnormalities. Identifying genetic factors that place certain youth at higher risks for such side effects would eventually allow clinicians to tailor treatment to the needs and vulnerabilities of each child by conducting genetic testing before selecting an atypical antipsychotic to prescribe.

描述(申请人提供)：在过去的十年里，非典型抗精神病药物(AAPS)的青少年处方率增加了几倍。这导致了AAPS的使用与关于其在儿科人群中的有效性和安全性的有限科学证据之间的鲜明对比。根据对患有自闭症和破坏性行为障碍的儿童的临床试验结果，利培酮是美国食品和药物管理局唯一具有儿科适应症的AAP。因此，它在年轻人中被证明的有效性，以及它强大的多巴胺D2受体阻断活性，使其在AAP中独一无二。然而，人们担心它可能会阻碍高催乳素血症导致的骨矿物质积累，从而增加骨量减少和骨质疏松症的风险。此外，AAPS有显著增加体重和导致代谢异常的倾向，这引发了调查服用这些强效药物的年轻人中血脂异常、糖耐量异常、胰岛素抵抗和代谢综合征表型的发生情况。通过将回顾与前瞻性设计相结合，本应用程序试图解决这些临床紧迫问题。它建立在一项正在进行的研究的基础上，该研究调查了与年轻人长期使用利培酮有关的代谢和激素异常。对各种临床和实验室数据的回顾和横断面收集，包括骨密度，最近已经完成。然而，这些代谢和激素异常的临床影响可能只有在长期暴露后才会变得显著。因此，在这项研究的两年期间，我们建议增加目前的样本量，并在基线登记后15个月重新评估所有患者。在后续行动中，将记录临时临床病史，并收集与假定的代谢和激素异常有关的临床和实验室措施。因此，这项应用旨在评估青年长期服用利培酮对骨矿物质积累、体重增加以及脂肪和葡萄糖代谢的影响。它还将测试5-羟色胺受体和瘦素基因的变异是否会增加利培酮引起的代谢异常的风险。这项工作的结果可能会使这种有效药物的使用更加安全。这项工作的发现将通过评估利培酮通过诱导高催乳素血症、体重增加和代谢异常而导致骨质疏松症和心血管疾病的可能性，增加新兴的非典型抗精神病药物在儿童和青少年中的长期安全性。确定使某些年轻人面临此类副作用风险较高的遗传因素，最终将使临床医生能够在选择非典型抗精神病药物开处方之前，通过进行基因测试，根据每个儿童的需求和脆弱性进行量身定制的治疗。