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型药物治疗策略来改善自闭症的药物治疗。自闭症是美国和全世界的一个主要公共卫生问题。据估计，仅在美国，残疾的成本每年就在300亿美元左右。尽管改善了减少自闭症经常发生的攻击性，自我伤害行为（SIB）和易怒的能力，但现有的药物治疗与显著的不良反应有关。这些包括“典型抗精神病药”引起的锥体外系症状（EPS）和迟发性运动障碍，以及“非典型”抗精神病药引起的显著体重增加和相关的高脂血症、高胆固醇血症、糖尿病、肝脏异常，有时还有死亡率。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，已被证明可延长心电图（ECG）上的校正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均可引起高泌乳素血症。此外，迄今为止，尚未开发出针对自闭症核心社交障碍的药物治疗方法。在本申请中，研究A. I期包括一项为期8周的随机双盲、安慰剂对照试验，该试验研究了新型抗精神病药阿立哌唑对患有自闭症的儿童和青少年（6-17岁）的攻击性、SIB和易怒的短期治疗（n=88）。应答的受试者将有资格进入阿立哌唑的4个月开放标签持续试验（研究A。II期），旨在确定正在进行的治疗是否与缓解维持相关。将在研究A的两个阶段监测阿立哌唑的潜在不良反应，特别注意EPS、体重增加、ECG校正QT间期延长和高泌乳素血症。研究B。是一项试验性组合药物治疗研究，以确定将开放标记D-环丝氨酸（谷氨酸受体的N-甲基-D-天冬氨酸（NMDA）亚型的部分激动剂）添加到正在进行的开放标记阿立哌唑中是否导致在研究A完成后攻击性、SIB和易怒性I保持稳定的受试者的社会行为改善。II期（阿立哌唑单药治疗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).