Predictors of Placebo Response in Pharmacological Clinical Trials of Negative Symptoms in Schizophrenia: A Meta-regression Analysis

Abstract

We conducted a meta-regression analysis of all double-blind, randomized, placebo-controlled clinical trials (DBRCTs) reporting effects of drug and placebo on negative symptoms in people with stable schizophrenia and predominant or prominent negative symptoms to assess predictors of placebo response in these individuals. We used Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for systematic reviews and meta-analyses to conduct a systematic literature search to identify DBRCTs assessing treatment efficacy on negative symptoms, as primary outcome, in patients with stable schizophrenia and predominant or prominent negative symptoms. We used Cohen's d, with 95% CIs, as the effect size measure for placebo response, based on negative symptom change scores from baseline to endpoint (range 4 to 24 wk) in the placebo-treated group. We included 18 DBRCTs from 17 publications, assessing the effect of 13 drugs vs placebo on negative symptoms and comprising 998 patients, in the meta-regression analyses. Overall, drugs showed greater efficacy than placebo in reducing negative symptoms, with small effect size (Cohen's d: 0.208, P = .020). Placebo response was significant (P < .001) and clinically relevant (Cohen's d: 2.909), but there was significant heterogeneity and high risk of publication bias. Multivariable meta-regression analyses showed that larger numbers of arms in the trial, larger numbers of study sites and industry sponsorship were significant moderators of placebo response in this population. Our results suggest that some clinical trial design and operational factors affect the level of placebo response in such studies, thus highlighting the need for designs better suited to assess these outcomes.

Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults

“…Studies in other psychiatric populations have also shown a high placebo effect size, such as negative symptoms in schizophrenia (Cohen d = 2.91) and response rate (39.2%) in bipolar depression. 82,83 Although all of these analyses reported a large effect size, the effect size found in RCTs involving patients with TRD is numerically smaller for pill placebo and numerically larger for sham stimulation than the effect sizes reported in these RCTs involving patients without TRD. 14,15,81 In our secondary analysis, we assessed response and remission rates as reported in the individual RCTs.…”

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

“…Placebo response has been documented in other psychiatric disorders such as depression ( Undurraga and Baldessarini, 2012 ), acute schizophrenia ( Leucht et al, 2018 ), stable schizophrenia ( Fraguas et al, 2019 ), bipolar mania ( Yildiz et al, 2011 ; Welten et al, 2015 ), bipolar depression ( Bridge et al, 2009 ; Nierenberg et al, 2015 ), and obsessive compulsive disorder ( Ackerman and Greenland, 2002 ; Kotzalidis et al, 2018 ). Unlike mania, depression, and acute schizophrenia, where severity of symptoms change over a short period of time, ADHD is a relatively stable condition and the reduction of ADHD symptoms during the clinical trial is less likely to be due to the natural course of the disorder.…”

“…An increase of placebo response has been documented before by Khan et al (2017) in a meta-analysis of 17 clinical trials of ADHD medications approved by the US Food and Drug Administration between 2000 and 2009 as well as in other fields of psychiatry such as schizophrenia ( Agid et al, 2013 ; Leucht et al, 2018 ), depression ( Walsh et al, 2002 ; Papakostas and Fava, 2009 ; Undurraga and Baldessarini, 2012 ), obsessive compulsive disorder ( Ackerman and Greenland, 2002 ; Kotzalidis et al, 2018 ), and bipolar disorder ( Sysko and Walsh, 2007 ). Changes over time in baseline severity ( Bridge et al, 2009 ; Nierenberg et al, 2015 ; Cohen et al, 2018 ), number of study centers ( Bridge et al, 2009 ; Yildiz et al, 2011 ; Undurraga and Baldessarini, 2012 ; Agid et al, 2013 ; Leucht et al, 2018 ; Fraguas et al, 2019 ), sex ( Yildiz et al, 2011 ; Welten et al, 2015 ), study quality ( Agid et al, 2013 ), and type of drug ( Agid et al, 2013 ) have frequently been alluded to as an explanation for this time-related increase of placebo response in psychiatry. These covariates do not seem to confound the moderating effect of publication date in our study because none of them were found to be associated with placebo response in any analysis.…”

“…Comprehensive analysis of placebo response and the factors influencing placebo response in RPCCTs has been conducted for schizophrenia, depression, and mania ( Walsh et al, 2002 ; Khan et al, 2003 ; Papakostas and Fava, 2009 ; Yildiz et al, 2011 ; Undurraga and Baldessarini, 2012 ; Nierenberg et al, 2015 ; Welten et al, 2015 ; Leucht et al, 2018 ; Fraguas et al, 2019 ). In contrast, few studies have investigated placebo response in attention deficit hyperactivity disorder (ADHD) ( Newcorn et al, 2009 ; Waschbusch et al, 2009 ; Waxmonsky et al, 2011 ; Buitelaar et al, 2012 ; Khan et al, 2017 ; Cohen et al, 2018 ; Ben-Sheetrit et al, 2020 ).…”

60 years of placebo-controlled antipsychotic drug trials in acute schizophrenia: Meta-regression of predictors of placebo response

“…Other factors may be relevant for placebo response in these populations. (Fraguas et al, 2018) recently reported that more study sites, more study arms and industry sponsorship were significant explanatory variables of placebo response in patients with predominant negative symptoms. Thus, there was partial overlap.…”