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

为临床高风险的适应性治疗序列建立证据基础

• 批准号: 9757822
• 负责人: Patrick McGorry
• 金额: $ 60.28万
• 依托单位: ORYGEN YOUTH HEALTH RESEARCH CENTRE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-24 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757822
• 关键词: Address; Administrator; Age; Antidepressive Agents; Antipsychotic Agents; Aspirin; Australia; Behavioral; Biological; Biological Markers; Caring; Case Management; Cessation of life; Clinic; Clinical; Clinical Treatment; Clinical Trials; Cognitive; Collaborations; Development; Distress; Dose; Drops; Early Intervention; Economic Burden; Elements; Ensure; Environment; Evidence based treatment; Family; Family member; Fatty Acids; Fish Oils; Focus Groups; Goals; Health; Health Services Research; Healthcare; Healthcare Systems; Impairment; Inflammation; Inflammatory; International; Intervention; Intervention Trial; Knowledge; Laboratories; Link; Measures; Mental Depression; Mental Health; Mental disorders; Methodology; Modeling; Monitor; Moods; Outcome; Outpatients; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Placebo Effect; Placebos; Problem Solving; Process; Psychotic Disorders; Quality of life; Randomized; Randomized Clinical Trials; Recovery; Relapse; Research; Research Personnel; Risk; Safety; Sample Size; Sampling; Series; Staging; Stratification; Symptoms; Syndrome; Testing; Translating; Translations; United States; Youth; arm; care systems; clinical infrastructure; clinical phenotype; cohort; design; disability; disorder later incidence prevention; efficacy study; evidence base; experience; functional outcomes; health care model; help-seeking behavior; high risk; improved outcome; innovation; intervention program; novel; open label; outcome prediction; patient response; placebo group; predicting response; premature; prevent; primary outcome; programs; prospective; psychologic; public health relevance; recruit; research facility; responders and non-responders; response; shared decision making; treatment strategy

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.

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重要战略。精神障碍之前有一个前驱期的痛苦，受损的功能和阈下精神病。我们最初的研究在操作上定义了超或临床高风险（UHR或EHR）状态，该状态预测了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，干预措施可以将过渡风险降低50%以上。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。该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精神分裂症患者进行随机对照试验方面的丰富经验，结合了澳大利亚通过“顶空”青年心理健康模型建立的国际独特的临床基础设施。Headspace已经为超过10万名患有新出现的精神障碍的年轻人提供了护理，其中40%是HIV阳性。从2006年起，Orygen青年健康研究中心在全国范围内设计和实施了这一医疗保健创新，并直接管理4个顶空中心，每年治疗5000多名患者。美国的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。美国在样本富集、临床试验方法学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一美澳合作。将在两年期间招募500名患者，并进入第1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步中随机分配至阿司匹林+ SPS、阿司匹林+认知行为病例管理（CBCM）、安慰剂+ SPS或安慰剂+ CBCM。这是该设计的关键实验步骤，该设计将研究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。将测量生物标志物和认知脆弱性标志物，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的所有无应答者，并将涉及抗抑郁药和安慰剂的随机比较，并对抑郁水平进行分层。第3步中12周时的无应答者（和脱落者）将遵循“快速失败”途径，并将通过共同决策过程提供Omege 3脂肪酸（鱼油）或低剂量抗精神病药物的选择。将通过随机设计对每个阶段的应答者进行随访，将SPS和监测与单独监测进行对比。在美国的一家诊所自然地对分阶段模型进行试点测试，并与美国的各种利益相关者团体进行焦点小组讨论，以解决与转化为美国医疗保健相关的问题。

项目成果

A Sequential Adaptive Intervention Strategy Targeting Remission and Functional Recovery in Young People at Ultrahigh Risk of Psychosis: The Staged Treatment in Early Psychosis (STEP) Sequential Multiple Assignment Randomized Trial.

• DOI: 10.1001/jamapsychiatry.2023.1947
• 发表时间: 2023-09-01
• 期刊: JAMA PSYCHIATRY
• 影响因子: 25.8
• 作者: McGorry, Patrick D.;Mei, Cristina;Amminger, G. Paul;Yuen, Hok Pan;Kerr, Melissa;Spark, Jessica;Wallis, Nicky;Polari, Andrea;Baird, Shelley;Buccilli, Kate;Dempsey, Sarah-Jane A.;Ferguson, Natalie;Formica, Melanie;Krcmar, Marija;Quinn, Amelia L.;Mebrahtu, Yohannes;Ruslins, Arlan;Street, Rebekah;Wannan, Cassandra;Dixon, Lisa;Carter, Cameron;Loewy, Rachel;Niendam, Tara A.;Shumway, Martha;Nelson, Barnaby
• 通讯作者: Nelson, Barnaby

Baseline data of a sequential multiple assignment randomized trial (STEP study).

• DOI: 10.1111/eip.13263
• 发表时间: 2022-10
• 期刊: EARLY INTERVENTION IN PSYCHIATRY
• 影响因子: 2
• 作者: Hartmann, Jessica A.;Nelson, Barnaby;Amminger, Gunther Paul;Spark, Jessica;Yuen, Hok Pan;Kerr, Melissa J.;Polari, Andrea;Wallis, Nicky;Blasioli, Julie;Dixon, Lisa;Carter, Cameron;Loewy, Rachel;Niendam, Tara A.;Shumway, Martha;McGorry, Patrick D.
• 通讯作者: McGorry, Patrick D.