Randomized controlled trials in schizophrenia: opportunities, limitations, and trial design alternatives.
Randomized controlled trials in schizophrenia: opportunities, limitations, and trial design alternatives.
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DOI：
10.31887/dcns.2011.13.2/ccorrell
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发表时间：
2011
影响因子：
8.3
通讯作者：
Kane JM
中科院分区：
文献类型：
--
作者：
Correll CU;Kishimoto T;Kane JM
最先进的临床试验设计和方法对于该领域的发展非常重要。相比之下，审判的进行和执行的重要意义只是最近才成为讨论和研究的重点。尽管随机对照试验通常被认为是评估药物和非药物干预的金标准，但试验容易出现并发症和严重影响其成功的影响，与干预措施一样，试验设计和实施也是上下文相关的。它们需要个性化，并适应一些相关的变量，如设置，人口，疾病阶段，干预措施，患者和评估者的期望和偏见，以及调查的总体目标。虽然这意味着不可能有统一的办法，但某些一般原则和准则需要认真考虑。了解基本解决方案和替代方案，认识到需要积极应对的复杂挑战，有助于尽量减少不必要的结果，包括试验失败和无信息或虚假的负面结果。此外，需要探索新的设计替代方案，根据研究问题和相关结果测量精度的提高来富集样本。我们提出了两种新的设计策略，利用最近验证的早期抗精神病药物反应的范例（也被观察到与抗抑郁药和情绪稳定剂）。在“早期应答者随机停药设计”中，所有患者均被分配至活性药物组，只有那些在2周时至少有最小应答的患者入组双盲、安慰剂对照停药试验，从而丰富了安慰剂对照试验部分的真实药物应答者。在镜像“早期无应答者随机剂量增加或增强设计”中，2周时的早期无应答者被分配继续使用药物或使用更高剂量或增强药物。我们希望，通过增加对本文中提出的问题的关注，并进一步完善试验方法和行为，该领域将在精神分裂症的预防和治疗方面取得急需的额外进展。
State-of-the art clinical trial design and methodology are enormously important for the advancement of the field. In contrast, the critical relevance of trial conduct and implementation have only more recently been the focus of discussion and research. Although randomized controlled trials are generally considered the gold standard for the assessment of pharmacologic and nonpharmacologic interventions in medicine, trials are vulnerable to complications and influences that can seriously compromise their success, Like interventions, trial design and conduct are also contextual. They need to be individualized and adapted to a number of relevant variables, such as setting, population, illness phase, interventions, patient and rater expectations and biases, and the overall aims of the investigation. While this means that there is no unified approach possible, certain general principles and guidelines require careful consideration. Knowledge of basic solutions and alternatives, and the recognition of the complex challenges that need to be addressed proactively can help to minimize unwanted outcomes, including trial failure and uninformative or falsely negative outcomes. Moreover, novel design alternatives need to be explored that target sample enrichment according to the study question and enhancement of precision in the measurement of relevant outcomes. We propose two novel design strategies that take advantage of the recently validated early antipsychotic response paradigm (that has also been observed with antidepressants and mood stabilizers). In the “early responder randomized discontinuation design” all patients are assigned to the active drug, and only those who had at least a minimal response at 2 weeks are enrolled in a double-blind, placebo-controlled discontinuation trial, enriching the placebo controlled trial portion with true drug responders. In the mirror image “early nonresponder randomized dose increase or augmentation design,” early nonresponders at 2 weeks are assigned to staying on the medication or going either to a higher dose or an augmentation agent. It is hoped that through increased attention to the issues raised in this article and further refinement of trial methodology and conduct, the field will make much needed additional progress in the prevention and treatment of schizophrenia.