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、更有效的新型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，残疾的成本每年就在300亿美元左右。尽管自闭症患者的攻击性、自残行为（SlB）和易怒症状得到了改善，但现有的药物治疗仍存在显著的不良反应。这些症状包括锥体外系症状（EPS）和迟发性运动障碍，伴有“典型”抗精神病药物，体重明显增加，伴有高脂血症、高甘油三酯血症、糖尿病、肝脏异常，有时伴有“非典型”抗精神病药物死亡。唯一与体重增加无关的非典型抗精神病药齐拉西酮（ziprasidone）已被证明可延长心电图（ECG）校正后的QT间期；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泌乳素血症。此外，到目前为止，还没有针对自闭症核心社会障碍的药物治疗。在这项申请中，a研究I期涉及一项为期8周的随机双盲、安慰剂对照试验，研究新型抗精神病药物阿立哌唑短期治疗6-17岁自闭症儿童和青少年（n=88）的攻击性、SlB和易怒。有反应的受试者将有资格进入为期4个月的阿立哌唑开放标签继续试验（研究a . II期），旨在确定持续治疗是否与维持反应相关。阿立哌唑的潜在不良反应，特别是EPS、体重增加、心电图校正QT间期延长和高泌乳素血症，将在研究a的两个阶段进行监测。研究b是一项试验性联合药物治疗研究，以确定是否添加开放标签d -环丝氨酸，一种谷氨酸受体n-甲基- d -天冬氨酸（NMDA）亚型的部分激动剂，持续的开放标签阿立哌唑改善了被试的社会行为，这些被试的攻击、SlB和易怒在研究a完成后保持稳定。

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).