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

描述（由申请人提供）：在过去十年中，非典型抗精神病药（AAP）的处方率增加了几倍。这导致AAP的使用与其在儿科人群中的有效性和安全性的有限科学证据之间形成鲜明对比。利培酮是美国食品和药物管理局根据自闭症和破坏性行为障碍儿童临床试验结果确定的唯一一种儿科适应症。因此，其在青年中的有效性，以及其有效的多巴胺D2受体阻断活性，使其在AAP中独一无二。然而，由于高催乳素血症，其可能阻碍骨矿物质积累，从而增加骨质减少和骨质疏松症的风险，这引起了人们的担忧。此外，AAP显著增加体重并导致代谢异常的倾向已经产生了调查用这些强效药物治疗的青年中血脂异常、葡萄糖耐受不良、胰岛素抵抗和代谢综合征表型的发生的呼吁。通过将回顾性与前瞻性设计相结合，本申请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调查与长期使用利培酮的青年代谢和激素异常。最近完成了对各种临床和实验室数据（包括骨矿物质密度）的回顾性和横断面收集。然而，这些代谢和激素异常的临床影响可能只有在长期接触后才变得显著。因此，在本研究的两年期间，我们建议增加当前的样本量，并在基线入组后15个月重新评估所有患者。随访时，将记录中期临床病史，并收集与假定代谢和激素异常相关的临床和实验室指标。因此，本申请旨在评估长期利培酮治疗对青年骨矿物质积累、体重增加、脂质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诱导的代谢异常的风险。这项工作的结果可能会使这种有效药物的使用更安全。这项工作的结果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引起骨质疏松症和心血管疾病的可能性，为解决儿童和青少年中非典型抗精神病药物的长期安全性的新兴文献增添内容。确定遗传因素，使某些青少年处于更高的风险，这种副作用将最终使临床医生能够通过在选择非典型抗精神病药物处方之前进行基因检测，针对每个儿童的需求和脆弱性进行治疗。

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.