Novel Pharmacological Strategies in Autism

描述(由申请人提供)：本申请的长期目标是通过开发更安全和更有效的新药物治疗策略来改善自闭症的药物治疗。自闭症在美国和全世界都是一个主要的公共卫生问题。据估计，仅在美国，每年因残疾而造成的损失就在300亿美元左右。尽管有了改善的能力来减少自闭症经常发生的攻击性、自残行为(SLB)和易怒，但现有的药物治疗与显著的不良反应有关。这些症状包括锥体外系症状(EPS)和迟发性运动障碍，使用“典型”抗精神病药物，体重显著增加，并伴随高脂血症、高甘油三酯血症、糖尿病、肝脏异常，有时使用“非典型”抗精神病药物会导致死亡。齐拉西酮是唯一一种与体重显著增加无关的非典型抗精神病药物，已被证明可以延长心电图上校正的QT间期；这是一种潜在的致命并发症。典型和非典型抗精神病药物都会引起高催乳素血症。此外，到目前为止，还没有针对自闭症的核心社会损害开发出药物治疗。在这项申请中，研究A阶段I涉及一项为期8周的随机、双盲、安慰剂对照试验，这种新型抗精神病药物阿立哌唑用于短期治疗患有自闭症的儿童和青少年(6-17岁)的攻击性、系统性红斑狼疮和易怒(n=88)。有反应的受试者将有资格参加为期4个月的阿立哌唑开放标签继续试验(研究A阶段II)，旨在确定正在进行的治疗是否与维持反应有关。在研究A的两个阶段，都将监测阿立哌唑的潜在不良反应，特别是EPS、体重增加、心电图上校正QT间期的延长以及高催乳素血症。研究B是一项试验性联合药物治疗研究，旨在确定在正在进行的开放标签阿立哌唑的基础上，增加N-甲基-D-天冬氨酸(NMDA)亚型的部分激动剂D-环丝氨酸是否能改善正在进行的开放标签阿立哌唑的社会行为，这些受试者的攻击性、SLB和易怒在研究A阶段完成后保持稳定(在阿立哌唑单一治疗6个月后)。

DESCRIPTION (provided by applicant): The long-term objective of this application is to improve the pharmacotherapy of autism by developing safer and more efficacious novel drug treatment strategies. Autism is a major public health concern in the U.S. and throughout the world. The cost of the disability is estimated to be in the range of $30 billion annually in the U.S. alone. Despite an improved ability to reduce the aggression, self-injurious behavior (SlB) and irritability that often occur with autism, existing drug treatments are associated with significant adverse effects. These include extrapyramidal symptoms (EPS) and tardive dyskinesia with "typical antipsychotics" and significant weight gain and associated hyperlipidemia, hypertriglyceridemia, diabetes mellitus, hepatic abnormalities, and at times mortality with the "atypical" antipsychotics. The only atypical antipsychotic not linked with significant weight gain, ziprasidone, has been shown to prolong the corrected QT interval on electrocardiogram (ECG); a potentially fatal complication. Both typical and atypical antipsychotics cause hyperprolactinemia. Furthermore, to date, no drug treatment has been developed for the core social impairment of autism. In this application, Study A. Phase I involves an 8-week randomized double blind, placebo-controlled trial of the novel antipsychotic aripiprazole for the short-term treatment of aggression, SlB and irritability in children and adolescents (age 6-17 years) with autism (n=88). Subjects who respond will be eligible to enter a 4-month open-label continuation trial of aripiprazole (Study A. Phase II) designed to determine if ongoing treatment is associated with the maintenance of response. Potential adverse effects of aripiprazole, with particular attention to EPS, weight gain, prolongation of the corrected QT interval on ECG, and hyperprolactinemia, will be monitored throughout both Phases of Study A. Study B. is a pilot combination drug treatment study to determine if adding open-label D-cycloserine, a partial agonist at the N-methyI-D-aspartate (NMDA) subtype of glutamate receptor, to on-going open-label aripiprazole results in improved social behavior in subjects whose aggression, SlB and irritability Iremain stabilized upon completion of Study A. Phase II (following 6 months of aripiprazole monotherapy).