EARLY PHARMACOLOGIC INTERVENTION IN AUTISM: FLUOXETINE IN PRESCHOOL CHILDREN

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 孤独症是一种严重的神经发育障碍，其特征在于三个行为领域的质的差异：社会互惠，沟通，以及重复行为或有限兴趣所表现出的兴趣广度。 很少有自闭症患者能够像成年人一样独立生活。 5岁时的语言能力是良好结果的最佳预测因素。这是一个修订后的协议，检查持续早期药物干预的影响，学龄前儿童自闭症。 患有狭义自闭症的年轻（30-58个月）儿童将被随机分配接受为期一年的安慰剂或氟西汀治疗，氟西汀是一种选择性5-羟色胺再摄取抑制剂（SSRI），已被批准用于6岁以下儿童的其他适应症。 主要的结果测量将是在自闭症中表现出特别受损的行为领域的发展模式：特别是互惠的社会互动，务实的沟通，以及有限的兴趣和/或重复行为。 这些核心领域的发展将使用基于广泛性发育障碍行为量表父母报告版本（PDDBIp）的相关子量表的复合测量进行评估，并补充其他更广泛使用的工具，这些工具没有基于年龄的标准或不是专门为自闭症设计的。 每例受试者可参加以下四个研究间隔。 1. 筛选间隔将允许确认诊断和确定随机化治疗的合格性。 在此期间将不提供研究治疗。 预计每例在研究中接受随机化治疗的受试者在此间隔后将有3 - 4例受试者退出。 2. 急性治疗间隔将介于基线至第12周/第3个月评估之间。 3. 延长的治疗间隔将涵盖第3个月评估后至第12个月评估的时间段，这是研究的主要终点。 4. 长期随访间隔将检查第12个月评估后的10年期。 这将是一个观察期，研究不提供任何干预措施，但对受试者接受的干预措施的数量或类型没有限制。 目前，早期强化行为干预被认为是改善自闭症患者整体预后的最有效和最有希望的手段之一。 然而，由于成本和对高技能人员的要求，其中许多干预措施难以广泛实施。 这项研究具有重要意义，因为确定容易实施的干预措施是否可以显着改善一些自闭症儿童的功能的重要性，以及严格确定提供给幼儿的干预措施是否安全和可容忍的重要性。 假设： 1. 与安慰剂治疗的个体相比，氟西汀治疗的个体在一年的过程中表现出复合测量的显著更快的改善速率。 我们估计3个月时的效应量（组间综合评分的标准化差异）为0.35，7个月时为0.4，12个月时为0.5。 2. 治疗12周后，60%的氟西汀组和20%的安慰剂组将显示总体功能的显著改善，其定义为CGI-I“1 -非常改善”或“2 -非常改善”。 3. 治疗12周后表现出临床显著行为变化的个体将具有更大的累积发育增益，因为PDDBIp复合指标的增加大于未表现出临床显著急性行为变化的个体。 4. 父母报告至少有一个一级亲属患有诊断或治疗的双相情感障碍的个体，其PDDBIp复合物的变化比父母没有报告这样的一级亲属的个体更稳健。 我们还假设，具有两个拷贝的5-羟色胺转运蛋白（SERT）基因的短等位基因的个体将比具有至少一个拷贝的长等位基因的个体在PDDBIp复合物中表现出更慢和更不稳健的变化。 此外，我们假设具有细胞色素P450基因CYP 2D 6的低活性形式的个体将比具有该基因的高活性形式的个体具有更多的激活和更多的总副作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Autism is a severe neurodevelopmental disorder characterized by qualitative differences in three behavioral areas: social reciprocity, communication, and the breadth of interests manifest by repetitive behaviors or restricted interests. Very few individuals with autism are able to live independently as adults. Speech by age five years is the single best predictor of good outcome. This is a revised protocol examining the impact of sustained early pharmacologic intervention in preschool children with autism. Young (30-58 months) children with narrowly defined autism will be randomly assigned to yearlong treatment with placebo or fluoxetine, a selective serotonin reuptake inhibitor (SSRI) which is approved for other indications in children as young as six years. The primary outcome measure will be the pattern of development in behavioral domains that appear particularly compromised in autism: specifically reciprocal social interaction, pragmatic communication, and restricted interests and/or repetitive behaviors. Development in these core areas will be assessed using a composite measure based on relevant subscales from the Pervasive Developmental Disorders Behavior Inventory parent report version (PDDBIp) and supplemented with other more widely used instruments that either do not have age-based standards or are not specifically designed for use in autism. Each subject may participate in four study intervals as follows. 1. The screening interval will allow for confirmation of the diagnosis and determination of eligibility for randomized treatment. No study treatment will be provided during this interval. It is expected that three to four subjects will be withdrawn after this interval for every subject that receives randomized treatment in the study. 2. The acute treatment interval will span between the baseline to Week 12/Month 3 assessments. 3. The extended treatment interval will span the period following the Month 3 assessment through the Month 12 assessment, which is the primary endpoint of the study. 4. The long-term follow up interval will examine the ten-year period, which follows the Month 12 assessment. This will be an observational period with no interventions provided by the study, but no limitation placed on the number or type of interventions that the subject experiences. Currently, early intensive behavioral interventions are viewed as among the most effective and promising means to improve the overall prognosis for persons with autism. However, many of these interventions are difficult to implement broadly because of their cost and requirement for highly skilled personnel. This study has great significance both because of the importance of determining whether readily implemented interventions can significantly improve the functioning of some children with autism and because of the importance of rigorously determining whether interventions offered to young children are safe and tolerable. Hypothesis: 1. Individuals treated with fluoxetine will demonstrate a significantly more rapid rate of improvement in the composite measure over the course of one year than individuals treated with placebo. We estimate an effect size (standardized difference in the composite score between groups) of 0.35 at 3 months, 0.4 at 7 months and 0.5 at 12 months. 2. 60% of the fluoxetine group and 20% of the placebo group will show significant improvement in overall functioning as defined by a CGI-I of "1 - very much improved" or "2 - much improved" after 12 weeks of treatment. 3. Individuals who show clinically significant behavior changes after 12 weeks of treatment will have greater cumulative developmental gains as larger increases in the PDDBIp composite measure than those who do not show clinically significant acute behavioral changes. 4. Individuals whose parents report at least one 1st degree relative with diagnosed or treated bipolar affective disorder will show more robust changes in the PDDBIp composite than individuals whose parents do not report such a 1st degree relative. We also hypothesize that individuals with two copies of the short allele of serotonin transporter protein (SERT) gene will demonstrate slower and less robust changes in the PDDBIp composite than individuals with at least one copy of the long allele. Further, we hypothesize that individuals with the low activity form of the cytochrome P450 gene, CYP2D6, will have more activation and a greater number of total side effects than individuals with the high activity form of the gene.