Placebo response mitigation with a participant-focused psychoeducational procedure: a randomized, single-blind, all placebo study in major depressive and psychotic disorders

Abstract

The remarkably high and growing placebo response rates in clinical trials for CNS indications, such as depression and schizophrenia, constitute a major challenge for the drug development enterprise. Despite extensive literature on participant expectancies and other potent psychosocial factors that perpetuate placebo response, no empirically validated participant-focused strategies to mitigate this phenomenon have been available. This study evaluated the efficacy of the Placebo-Control Reminder Script (PCRS), a brief interactive procedure that educates participants about factors known to cause placebo response, which was administered prior to the primary outcome assessments to subjects with major depressive or psychotic disorders who had at least moderate depression. Participants were informed they would participate in a 2-week randomized clinical trial with a 50% chance of receiving either an experimental antidepressant medication or placebo. In actuality, all participants received placebo. Participants randomly assigned to receive the PCRS (n = 70) reported significantly smaller reductions (i.e., less placebo response) in depression than those who did not receive the PCRS (n = 67). The magnitude of this effect was medium (Cohen’s d = 0.40) and was not significantly impacted by diagnostic status. The number of adverse events (i.e., nocebo effect) was also lower in the PCRS group, particularly in the first week of the study. These findings suggest that briefly educating participants about placebo response factors can help mitigate the large placebo response rates that are increasingly seen in failed CNS drug development programs.

Influence of study characteristics, methodological rigor and publication bias on efficacy of pharmacotherapy in obsessive compulsive disorder: a systematic review and meta-analysis of randomized placebo-controlled trials

“…The copyright holder for this this version posted November 24, 2023. ; https://doi.org/10.1101/2023.11.24.23298989 doi: medRxiv preprint year, amount of intervention arms and study sponsorship were not significant after adjusting for multiple testing. Although a placebo-run in phase has been found to increase efficacy by decreasing placebo response in depression trials, we were unable to demonstrate an effect of placebo-run in, possibly as almost all studies actually used a run-in phase (30). Notably, the European Medicine Agency Guideline on clinical investigation of medicinal products for the treatment of OCD recommends against using a run-in phase as it might impair generalization of the study results (31).…”

Probable effects of polypharmacy and equivalent doses of psychotropic drugs on prevalence of adverse drug events among psychiatric inpatients in a general hospital in Japan

“…In particular, therapeutic effects are exerted by placebos that serve as a control for the investigational drug in clinical trials of antipsychotic drugs in patients with psychiatric disorders. Furthermore, the nocebo effect—the development of ADEs due to a patient's belief that they might occur—is notably high (Alphs et al., 2012; Cohen et al., 2021). Therefore, it is possible that the administration of high‐dose anxiolytics and hypnotics reduced anxiety in patients and decreased the risk of psychogenic ADEs, including those classified as “gastrointestinal disorders,” “nervous system disorders,” and “psychiatric disorders.”…”

Influence of study characteristics, methodological rigour and publication bias on efficacy of pharmacotherapy in obsessive-compulsive disorder: a systematic review and meta-analysis of randomised, placebo-controlled trials

“…Although a placebo-run in phase has been found to increase efficacy by decreasing placebo response in depression trials, we were unable to demonstrate an effect of placebo run-in, possibly as almost all studies actually used a run-in phase. 37 Notably, the European Medicines Agency guideline on clinical investigation of medicinal products for the treatment of OCD recommends against using a run-in phase as it might impair generalisation of the study results. 38 Our meta-analysis is the first study on OCD pharmacotherapy to demonstrate an effect of publication bias on efficacy, using a Copas selection model with a Bayesian approach.…”