Minimizing placebo responses in clinical trials

Over the past decades, a growing number of clinical trials in neurologic conditions have failed to demonstrate superiority of active treatments over placebo. A key question in this context is whether an increase in placebo response can explain these trial failures, potentially hindering the development and approval of new therapies. Within this discussion, an underlying assumption appears to be that it is both feasible and beneficial to minimize the placebo responses in clinical trials and thereby improve the drug-placebo ratio. This chapter explores the predominant suggestions occurring in the literature on our opportunities to minimize placebo responses in clinical trials and evaluates the supporting evidence. Furthermore, we discuss whether reducing placebo responses necessarily enhances drug responses and promote successful trials. Finally, we propose leveraging insights from placebo mechanism research to refine RCT methodologies, for example, by incorporating patients' perceptions, emotional feelings, and expectations toward treatments and treatment effects. This approach may yield more ecologically valid trial outcomes for both pharmacological and nonpharmacological treatments in neurologic conditions.