Disconnection of drug-response and placebo-response in acute-phase antipsychotic drug trials on schizophrenia? Meta-regression analysis

Abstract

Differences in efficacy between antipsychotics and placebo in schizophrenia trials have decreased over the past decades. Previous studies have tried to identify potential explanatory factors focusing on response to placebo; however, it is still not clear which factors, if any, specifically moderate drug-response, as they may be different from those moderating placebo-response. Therefore, in this meta-regression analysis we explore whether there is an interaction between drug-response and placebo-response in terms of effect size. We systematically searched multiple electronic databases, ClinicalTrials.gov, and the US Food and Drug Administration website for randomized, placebo-controlled trials investigating the efficacy of antipsychotics in patients with acute schizophrenia (last update: October 2016). The main outcome was the change on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale score from baseline to endpoint after at least 3 weeks of treatment. Multiple patient-, design-, and drug-related potential predictors of response were analyzed by meta-regressions, as predefined in the study protocol. Overall, 167 trials with 28,102 participants were included. Publication year, the number of participants and sites, mean dose, minimum severity threshold as an inclusion criterion, chronicity, industry sponsorship, type of rating scale, diagnostic criteria, and number of medications had a different impact on drug and placebo response. By contrast, baseline severity, duration of wash-out, study duration, and study region affected drug and placebo response in a similar way without a net effect on effect sizes. No other factors had a significant effect on either drug-response or placebo-response. In conclusion, as individual moderators may have different impact on placeboresponse and drug-response, it is important to consider also the specific factors influencing drug-response in order to fully understand the difference between antipsychotics and placebo. These results shed further light on the phenomenon of decreasing effect size of antipsychotics for schizophrenia over time and should help design future randomized controlled trials in the field (Prospero registration number CRD42013003342).

Placebo Response and Its Predictors in Attention Deficit Hyperactivity Disorder: A Meta-Analysis and Comparison of Meta-Regression and MetaForest

“…Because ADHD is more frequently diagnosed and treated in the United States than in the rest of the world and research is also more prevalent in this country, expectations regarding the efficacy of pharmacological treatment may also be higher, resulting in higher placebo response. Nevertheless, it must be stressed that some studies on disorders other than ADHD have found placebo response to be lower in the United States ( Mallinckrodt et al, 2010 ; Welten et al, 2015 ; Leucht et al, 2018 , 2019 ), and other studies have found no effect of location on placebo response ( Bridge et al, 2009 ; Agid et al, 2013 ). Altogether, these results suggest that the true effect of location might be small or near zero and, for this reason, some studies find a positive, others a negative, and others a null effect.…”

Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis

“…Sample size and number of sites have been suggested as predictors of placebo response [ 50 , 51 , 92 ]. We also found that a larger sample size was associated with a larger placebo response in repetitive behaviors, yet the results might be driven by three antidepressant trials [ 65 – 67 ].…”

“…The dependent variable was SMC and the independent variable was selected from a list of covariates from the literature [ 9 , 11 , 12 , 49 – 51 ]. First, we conducted univariable and then multivariable meta-regressions similar to our previous analyses in schizophrenia [ 51 ]: we used the factors that were significant in the univariable analysis and then a formal backward stepwise algorithm with a removal criterion of p = 0.15. Meta-regressions were not performed for categorical covariates with less than five data points per level.…”

“…Third, moderators of drug-placebo differences were not investigated and efforts to minimize placebo response could also affect drug response, since they were correlated in social-communication difficulties and overall core symptoms, but not in repetitive behaviors (Additional file 3 : eAppendix-6.5). In addition, some predictors might have a different impact on placebo and drug response [ 51 ]. Nevertheless, a more fine-grained analysis was impeded by the use of diverse experimental interventions with essentially different mechanisms of action (Additional file 3 : eAppendix-5.1), e.g., contrary to schizophrenia [ 49 , 51 , 102 ], for which antipsychotics are the cornerstone of treatment [ 104 ].…”

Blonanserin patch vs. Other Antipsychotics for Acute Schizophrenia: A Systematic Review of Double-blind, Randomized, Placebo-controlled, Phase 3 Trials in Japan

“…Continued trolled trials). A recent meta-regression analysis study reported differences in drug and placebo responses with the publication year, number of participants and sites, mean dose, minimum severity threshold as an inclusion criterion, chronicity, industry sponsorship, type of rating scale, diagnostic criteria, and number of medications [21]. The trials in the present study had some differences in patient characteristics and details of the study design.…”