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

描述(申请人提供)：精神病通常首先出现在年轻人，并导致广泛的痛苦，长期残疾，过早死亡，和巨大的经济负担。及早干预是减轻这一负担的重要战略。精神障碍的先兆是痛苦、功能受损和临界值以下的精神病。我们最初的研究在操作性上定义了超高风险或临床高风险(UHR或CHR)状态，该状态预测早期精神病的风险大幅增加。来自11个随机对照试验的证据表明，干预可以将过渡风险降低50%。然而，临床医生仍然不清楚如何选择最佳的治疗顺序来防止病情进展和最大限度地恢复。这项研究将进行一项连续的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。这项研究利用了澳大利亚在对慢性阻塞性肺疾病患者进行随机对照试验方面的丰富经验，以及澳大利亚通过“Headspace”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100,000多名患有新发精神障碍的年轻人提供了护理，其中40%的人CHR呈阳性。自2006年起，Orygen青年健康研究中心在全国范围内设计和实施这一医疗创新，并直接管理4个Headspace中心，每年治疗超过5000名患者。美国CHR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。美国在样本浓缩、临床试验方法学和转化性医疗服务研究方面的专业知识相辅相成，完成了这一美澳合作。500名患者将在两年内被招募，并进入第一步，其中包括为期6周的支持和解决问题(SPS)的开放阶段。在步骤2中，无反应者(50%)将被随机分为阿司匹林+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，这是一种以炎症为潜在机制的新实验治疗方法。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)将提供给步骤2的所有无反应者，并将涉及抗抑郁药和安慰剂的随机比较以及抑郁程度的分层。在步骤3中，12周的无反应者(和中途退出者)将遵循快速失败的途径，并将通过共同的决策过程提供Omege 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跟踪，将SPS和监测与单独监测进行对比。在美国CHR诊所和各种美国利益相关者团体的焦点小组中自然地对阶段性模型进行试点测试将解决与转换到美国医疗保健相关的问题。

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.