title: Modelling and simulation of placebo effect: application to drug development in schizophrenia.
abstract: 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.
authors: Clinical PKPD, Merck Research Labs, Merck Sharp & Dohme, 5340 BH, Oss, The Netherlands. venkatesh.pilla.reddy@merck.com
authors: Venkatesh
authors: V
authors: Pilla Reddy
authors: Magdalena
authors: M
authors: Kozielska
authors: Rik
authors: R
authors: de Greef
authors: An
authors: A
authors: Vermeulen
authors: Johannes H
authors: JH
authors: Proost
mesh_terms: D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods* / Q000706:statistics & numerical data; D006801:Humans; D008960:Models, Psychological; D064786:Nocebo Effect; D010352:Patient Dropouts / Q000523:psychology; D015990:Placebo Effect; D012559:Schizophrenia / Q000188:drug therapy*
chemical_list: D014150:Antipsychotic Agents