Clinical PKPD, Merck Research Labs, Merck Sharp & Dohme, 5340 BH, Oss, The Netherlands.
J Pharmacokinet Pharmacodyn. 2013 Jun;40(3):377-88. doi: 10.1007/s10928-012-9296-7. Epub 2013 Jan 12.
High and variable placebo effect (PE) within and among clinical trials can substantially affect conclusions about the efficacy of new drugs in the treatment of schizophrenia and other neuropsychiatric disorders. In recent years, it has become increasingly difficult to prove drug efficacy against placebo, and one of the reasons is that the placebo response has increased over recent years. The increased placebo response over the years is partly explained by unidentified parallel interventions, patient factors, issues with trial designs, and regional variability or demographic differences. In addition, a nocebo effect, which is undesirable effects a subject manifests after receiving placebo, e.g. extrapyramidal side effects, in placebo arms of antipsychotic trials could also influence the PE and clinical trial outcomes. Placebo effects (PEs) are a natural phenomenon and cannot be avoided completely in clinical trials. However, accounting for the PE via mixed effects modelling approaches could reduce bias in quantifying the overall effect size of the drug treatment. This review article focuses on the PE and its impact on schizophrenia clinical trial outcomes. The authors briefly describe the factors that lead to high and variable PE. Next, pharmacometric approaches to account for the PE and dropouts in schizophrenia clinical trials are described. Finally, some points are provided that could be considered while designing and optimizing antipsychotic trials via simulation approaches.
高且可变的安慰剂效应（PE）在临床试验内和临床试验间都可能极大地影响关于新药物治疗精神分裂症和其他神经精神障碍的疗效的结论。近年来，证明药物疗效优于安慰剂变得越来越困难，其中一个原因是近年来安慰剂反应有所增加。近年来，安慰剂反应增加的部分原因是未确定的平行干预措施、患者因素、试验设计问题以及区域变异性或人口统计学差异。此外，一种称为“反安慰剂效应”的现象也可能影响 PE 和临床试验结果，即受试者在接受安慰剂后表现出的不良作用，例如抗精神病试验中安慰剂组的锥体外系副作用。安慰剂效应（PE）是一种自然现象，在临床试验中无法完全避免。然而，通过混合效应模型方法来考虑 PE 可以减少定量药物治疗总体效果大小的偏差。本文综述了 PE 及其对精神分裂症临床试验结果的影响。作者简要描述了导致高且可变的 PE 的因素。接下来，描述了用于在精神分裂症临床试验中考虑 PE 和脱落的药代动力学方法。最后，通过模拟方法设计和优化抗精神病试验时，提供了一些可以考虑的要点。
