Placebo Response in Trials of Negative Symptoms in Schizophrenia: A Critical Reassessment of the Evidence

Abstract

Background Summarizing evidence from clinical trials of patients with schizophrenia with predominant or prominent negative symptoms (NS), a prior meta-analysis reported a large placebo effect in negative symptoms (Cohen’s d = 2.909). Assuming that such an effect was clinically not plausible, we performed a critical re-assessment and an update of the previous results with newly available data from add-on and monotherapy studies. Study Design Random-effect meta/regression analysis of trials that focused on predominant or prominent NS; and adopted a double-blind, randomized, placebo-controlled design. The final pooled meta-analytic database, based on the available add-on and monotherapy studies combined, included 24 publications containing data on a total of 25 studies (21 add-on, 4 monotherapy). Study Results The pooled overall estimate for the placebo effect from the primary analysis for all included studies had a medium effect size, with a Cohen’s d value of 0.6444 (SE = 0.091). The estimates were similar in the add-on and monotherapy studies. Meta-regression indicated that the high placebo response was significantly associated with clinical trial characteristics, including the high ratio of patients assigned to active vs. placebo treatment and short trial duration. Conclusions These results represent a major downward correction for a current effect size estimate of the placebo response in the negative symptoms of schizophrenia. Our findings also pinpoint certain clinical trial characteristics, which may serve as important predictors of the placebo response. The knowledge of these factors can have important implications for drug development and trial design for new drugs for negative symptoms of schizophrenia.

Placebo effects of repetitive transcranial magnetic stimulation on negative symptoms and cognition in patients with schizophrenia spectrum disorders: a systematic review and meta-analysis

“…In addition, placebo effects may increase over the years of the study (93), but this phenomenon was not found in our study and in the study by Czobor et al as well. Regarding the relationship between illness duration and placebo effects, although no significant association was found, a negative association has been reported in previous researches (30,81). Several studies have shown that unbalanced randomization could also increase placebo effects (30,94), and this association was not significant in our study.…”

“…Regarding the relationship between illness duration and placebo effects, although no significant association was found, a negative association has been reported in previous researches (30,81). Several studies have shown that unbalanced randomization could also increase placebo effects (30,94), and this association was not significant in our study. Apart from the above factors, several subjective factors also need to be considered.…”

“…We used a standardized spreadsheet to collect relevant data, including first author, publication year, study design, demographic characteristics, sample size of the sham group, rTMS parameters of the sham group, and outcome measures. We defined placebo effects as the mean difference of outcome measures from baseline to the end of treatment in the sham group ( 30 ). Therefore, results of outcome measures such as mean and standard deviations at baseline and after intervention in the sham group were collected in detail.…”

“…(79) calculated the placebo effect size using the mean change in negative symptoms over the follow-up period in the placebo group. Instead, Czobor et al (30) calculate the placebo effect size by the mean change in negative symptoms between pre-and posttreatment measurements in the sham group. The methodology proposed by Czobor et al is consistent with that employed in our study.…”

“…It is therefore still debated whether factors, such as age, sex, and proportion of females affect placebo effects in psychiatry (92). In a study by Czobor et al (30), they found that placebo effects were significantly related to study duration. Specifically, it decreased over the 8-week study period.…”