Building the Evidence Base for Adaptive Treatment Sequences in Clinical High Risk

描述（由申请人提供）：精神疾病通常首先出现在年轻人中，并导致广泛的痛苦，长期残疾，过早死亡和巨大的经济负担。早期干预是减轻这一负担的一项重要战略。精神障碍之前有一个前驱期的痛苦，功能受损和阈下精神病。我们最初的研究在操作上定义了超或临床高风险（UHR或CHR）状态，这预示着早期精神病的风险大幅增加。来自11项随机对照试验的证据表明，干预措施可将转变风险降低50%。然而，临床医生仍然不清楚如何选择最佳的治疗顺序，以防止进展和最大限度地恢复。本研究将进行一项顺序多阶段随机临床试验（SMART），以建立个性化的“适应性”治疗策略，以降低一系列结果的风险。本研究利用澳大利亚在CHR患者中开展随机对照试验的丰富经验，结合澳大利亚通过“顶空”青少年心理健康模式建立的国际独特的临床基础设施。Headspace已经为10万多名患有新发精神障碍的年轻人提供了护理，其中40%为CHR阳性。从2006年起，Orygen青年健康研究中心设计并在全国范围内实施了这一创新的医疗保健，并直接管理4个顶空中心，每年治疗5000多名患者。美国人权研究中心目前还没有这种级别的访问权限。Orygen是澳大利亚最大的心理健康研究机构，专门从事年轻人的早期干预。美国在样品富集、临床试验方法和转化卫生服务研究方面的专业知识的互补融合完成了这次美澳合作。将在两年的时间内招募500名患者，并进入第一步，其中包括为期6周的支持和问题解决（SPS）开放阶段。无应答者（50%）将在第2步随机分为阿司匹林+ SPS、阿司匹林+认知行为病例管理（CBCM）、安慰剂+ SPS或安慰剂+ CBCM。这是本设计的关键实验步骤，将研究CBCM和阿司匹林的疗效，这是一种新的针对炎症的实验治疗方法，可能的机制。将测量生物标记物和认知脆弱性标记物，并研究它们与反应的关系。步骤3（估计n=125）将提供给所有对步骤2无反应的患者，包括抗抑郁药和安慰剂的随机比较，并对抑郁水平进行分层。在第3步中，12周无反应者（和退出者）将遵循“快速失败”途径，并通过共享决策过程提供omega - 3脂肪酸（鱼油）或低剂量抗精神病药物的选择。每个阶段的应答者将通过随机设计进行随访，对比SPS和监测与单独监测。在美国CHR诊所自然地对分阶段模型进行试点测试，并与各种美国利益相关者团体进行焦点小组讨论，将解决与美国医疗保健相关的翻译问题。

DESCRIPTION (provided by applicant): Psychotic illnesses usually first emerge in young people and result in widespread suffering, protracted disability, premature death, and a huge economic burden. Early intervention represents a vital strategy to reduce this burden. Psychotic disorders are preceded by a prodromal period of distress, impaired functioning and subthreshold psychosis. Our original research operationally defined the Ultra or Clinical High Risk (UHR or CHR) state, which predicts a substantially increased risk of incipient psychosis. Evidence from 11 RCTs indicates that interventions can reduce the risk of transition by >50%. However, clinicians remain unclear how to select the best sequence of treatments to prevent progression and maximize recovery. This research will conduct a sequential multistage randomized clinical trial (SMART) to build individualized "adaptive" treatment strategies to reduce the risks for a range of outcomes. The study capitalizes on extensive Australian experience in conducting RCTs in CHR patients combined with internationally unique clinical infrastructure constructed in Australia through the "headspace" youth mental health model. Headspace has already delivered care to over 100,000 young people with emerging mental disorders, of whom 40% are CHR positive. From 2006, Orygen Youth Health Research Centre designed and implemented nationally this innovation in health care and directly manages 4 headspace centres treating over 5000 patients per annum. US CHR research centres do not at present have this level of access. Orygen is Australia's largest mental health research facility, and specializes in early intervention in young people. A complementary blend of US expertise in sample enrichment, clinical trial methodology and translational health services research completes this US- Australian collaboration. 500 patients will be recruited over a two year period and enter step 1 which involves a 6 week open stage of Support and Problem Solving (SPS). Non-responders (50%) will be randomized in step 2 to Aspirin + SPS, Aspirin + Cognitive-Behavioural Case Management (CBCM), Placebo + SPS or Placebo + CBCM. This is the key experimental step of the design which will study the efficacy of CBCM and aspirin, a new experimental treatment targeting inflammation as a potential mechanism. Biomarkers and cognitive vulnerability markers will be measured and their relationship to response will be studied. Step 3 (estimated n=125) will be offered to all non-responders to step 2 and will involve a randomized comparison of antidepressants and placebo with stratification for level of depression. Non-responders at 12 weeks (and drop outs) in step 3 will follow a "fast fail" pathway and will be offered a choice of Omege 3 fatty acids (fish oil) or low dose antipsychotic medication via a shared decision making process. Responders at each stage will be followed through a randomized design contrasting SPS and monitoring with monitoring alone. Pilot testing of the staged model naturalistically in a US CHR clinic and focus groups with various US stakeholder groups will address issues related to translation to US healthcare.