EARLY PHARMACOLOGIC INTERVENTION IN AUTISM: FLUOXETINE IN PRESCHOOL CHILDREN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 自闭症是一种严重的神经发育障碍，其特征是在三个行为领域表现出质的差异：社会互惠、交流和重复行为或受限兴趣所表现出的兴趣广度。很少有自闭症患者能够在成年后独立生活。5岁时的语言能力是预测好结果的唯一最佳指标。这是一项检查持续早期药物干预对学龄前自闭症儿童的影响的修订方案。患有狭义自闭症的幼儿(30-58个月)将被随机分配到安慰剂或氟西汀治疗一年，氟西汀是一种选择性5-羟色胺再摄取抑制剂(SSRI)，被批准用于年幼6岁儿童的其他适应症。主要的结果衡量标准将是行为领域的发展模式，这些领域在自闭症中似乎特别受到损害：特别是互惠的社会互动、务实的交流、受限的兴趣和/或重复的行为。这些核心领域的发展将使用基于普及性发展障碍行为清单家长报告版本(PDDBIp)的相关分量表的综合衡量标准进行评估，并辅之以其他更广泛使用的工具，这些工具要么没有基于年龄的标准，要么不是专门为自闭症设计的。每个受试者可以参加如下四个研究时段。 1.筛查间隔将允许确认诊断和确定随机治疗的资格。在此期间，不会提供任何研究治疗。预计在此间隔之后，对于每个接受随机治疗的受试者，将有三到四名受试者被取消。 2.急性治疗间隔时间为基线至第12周/第3个月评估。 3.延长的治疗间隔将从第3个月评估之后一直持续到第12个月评估，这是研究的主要终点。 4.长期后续行动间隔将审查12个月评估之后的十年期间。这将是一个观察期，没有研究提供的干预措施，但对受试者经历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总体预后的最有效和最有希望的手段之一。然而，其中许多干预措施很难广泛实施，因为它们的成本和对高技能人员的需求。这项研究具有重大意义，既是因为确定随时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，也是因为严格确定向幼儿提供的干预措施是否安全和可容忍。 假设： 1.在一年的时间里，服用氟西汀的患者比服用安慰剂的患者在综合指标上的改善速度要快得多。我们估计效应大小(组间综合评分的标准化差异)在3个月时为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%的安慰剂组患者的总体功能将有显著改善，CGI-I的定义为“1-非常有效”或“2-非常有效”。 3.那些在治疗12周后表现出临床显著行为变化的人将比那些没有表现出临床显著急性行为变化的人有更大的累积发展收益，因为PDDBIp综合测量的增加更大。 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，比父母没有报告此类一级亲属的个体，在PDDBIp综合测验中表现出更强劲的变化。我们还假设，具有两个短等位基因的5-羟色胺转运蛋白(SERT)基因的个体将比具有至少一个长等位基因的个体在PDDBIp复合体中表现出更慢和更不强劲的变化。此外，我们假设细胞色素P450基因的低活性形式的个体将比该基因的高活性形式的个体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.