Project 4 ACISR

项目4 ACISR

• 批准号: 8110783
• 负责人: CHRISTOPH U CORRELL
• 金额: $ 4.71万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-27 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110783
• 关键词: Adverse event; Age; Antipsychotic Agents; Blood; Body mass index; C-reactive protein; Cardiovascular system; Characteristics; Chronic; Clinical; Clozapine; Coronary heart disease; Data; Development; Effectiveness; Health; Insulin Resistance; Intercellular adhesion molecule 1; Intervention; Knowledge; Lead; Life Expectancy; Lipids; Mediator of activation protein; Metabolic; Metabolic Marker; Patients; Pharmaceutical Preparations; Placebos; Plasminogen Activator Inhibitor 1; Refractory; Relapse; Risk Marker; Schizophrenia; Supplementation; Symptoms; Testing; Weight; Youth; adiponectin; aripiprazole; clinical practice; comparative efficacy; early onset; evidence base; functional outcomes; improved; meetings; placebo controlled study; risk benefit ratio; secondary outcome; sound; treatment response

Schizophrenia is still all too frequently associated with a chronic relapsing course, poor functional outcome, and decreased life expectancy. The chronicity and refractoriness of this illness is particularly pronounced in early onset schizophrenia (EOS=onset <18 years). Although the limited data suggest that clozapine is the most efficacious option for youth with refractory EOS (Kumra et al. 1996; Shaw et al. 2006; Kumra et al. 2008a,b) it is still underutilized, in part due to a profound negative impact on weight and metabolic parameters. To improve the benefit/risk ratio of clozapine in refractory youth, the development of concurrent interventions to limit cardiometabolic effects and enhance effectiveness is sorely needed. For this reason, other medications, often a second antipsychotic, are commonly combined with clozapine in clinical practice. However, a sound evidence base for this clinical strategy is absent, particularly in youth. To fill this critical gap in knowledge, we propose a 12-week, placebo-controlled trial of clozapine supplementation with aripiprazole in 50 youths (age 10-18 years) with refractory schizophrenia. This study aims to: Specific Primary Aim 1: To test whether the concurrent initiation of clozapine with aripiprazole will result in the reduction of key metabolic adverse events compared to cotreatment with placebo. Primary Hypothesis 1: Compared to placebo, augmentation of clozapine with aripiprazole will lead to significantly less increase in weight and BMI z-score, insulin resistance, and lipid levels. Secondary Hypothesis 1: Compared to placebo, augmentation of clozapine with aripiprazole will lead to significantly less increase in risk markers of coronary heart disease (i.e., C-reactive protein, plasminogen activator inhibitor-1, soluble intercellular adhesion molecule-1, and adiponectin). Specific Secondary Aim 1: To test whether the concurrent initiation of clozapine with aripiprazole will result in greater efficacy compared to cotreatment with placebo. Secondary Hypothesis 1: Compared to placebo, augmentation of clozapine with aripiprazole will lead to significantly greater improvement in BPRS total, positive and negative symptom scores. Secondary Hypothesis 2: Compared to placebo, augmentation of clozapine with aripiprazole will lead to a significantly greater number of patients meeting the criteria for a positive treatment response (i.e., at least a 30% reduction in the BPRS total score AND a score of no more than "mildly ill" on the CGI). Exploratory Aim 1: To identify mediators and moderators of changes in primary and secondary outcomes, such as patient characteristics, antipsychotic blood levels, and markers of metabolic and cardiovascular health.

精神分裂症仍然与慢性复发过程，功能不良和预期寿命降低相关。这种疾病的慢性和难治性在精神分裂症的早期发作（EOS =发作<18年）中特别明显。尽管有限的数据表明，氯氮平是难治性EOS青年的最有效的选择（Kumra等，1996; Shaw等，2006; Kumra etal。2008a，b）仍然未充分利用，部分原因是对体重和代谢参数的深远影响。 为了提高氯氮平在难治性青年中的益处/风险比率，迫切需要开发并发干预措施以限制心脏代谢效应并提高有效性。因此，在临床实践中，其他通常是第二种抗精神病药的其他药物通常与氯氮平相结合。但是，这种临床策略的合理证据基础是不存在的，尤其是在青年中。为了填补知识的这一关键空白，我们提出了为期12周的安慰剂对照试验，对氯氮平补充氯氮平在50名青年（10-18岁）中，患有难治性精神分裂症。这项研究的目的是： 特定的主要目的1：测试与安慰剂的共同治疗相比，氯氮平同时开始与阿立哌唑的启动是否会导致关键代谢不良事件的减少。 原发性假设1：与安慰剂相比，用阿立哌唑增加氯氮平将导致体重和BMI Z得分，胰岛素抵抗和脂质水平的增加显着降低。 次要假设1：与安慰剂相比，氯氮平与阿哌取吡唑的增强将导致冠状动脉疾病的危险标志物的增加显着降低（即C反应蛋白，纤溶酶原激活剂抑制剂-1，溶胶细胞间粘附分子1，以及脂肪素）。 特定的次要目的1：与安慰剂进行测试相比，氯氮平与阿立哌唑的并发启动是否会产生更大的功效。 次要假设1：与安慰剂相比，氯氮平与阿替哌唑的增强将导致BPRS总，正症状和阴性症状评分的改善显着改善。 次要假设2：与安慰剂相比，用阿立哌唑的增强氯氮平将导致符合阳性治疗反应标准的患者数量明显更大（即，BPRS总分至少降低了30％，而CGI上的分数至少降低了30％的评分）。 探索目的1：确定原发性和次要结果变化的介体和主持人，例如患者特征，抗精神病药水平以及代谢和心血管健康的标志。