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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 placebo-response 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).

SUBMITTER: Leucht S

PROVIDER: S-EPMC6785090 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Leucht Stefan S Chaimani Anna A Mavridis Dimitris D Leucht Claudia C Huhn Maximilian M Helfer Bartosz B Samara Myrto M Cipriani Andrea A Geddes John R JR Davis John M JM

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20190618 11

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 ...[more]

PMID: 31212302

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Project description:Because increasing placebo response rates decrease drug-placebo differences and increase the number of failed trials, it is imperative to determine what is causing this trend.To investigate the relationship between antipsychotic medication and placebo response by publication year, and to identify associated study design and implementation variables.MEDLINE, PsycINFO, and PubMed were searched to identify randomized clinical trials of antipsychotic medications published from 1960 to July 2013.Included were randomized clinical trials lasting 4 to 24 weeks, contrasting antipsychotic medication with placebo or an active comparator, and enrolling patients 18 years of age or older with schizophrenia or schizoaffective disorder.Standardized mean change scores were calculated for each treatment arm, plotted against publication year, and tested with Spearman rank correlation coefficients. Hierarchical linear modeling identified factors associated with the standardized mean change across medication and placebo treatment arms.We hypothesized that the mean change in placebo-treated patients would significantly increase from 1960 to the present, that a greater change would be observed in active comparator vs placebo-controlled trials, and that more protocol visits would increase the symptom change observed.In the 105 trials examined, the mean change observed in placebo arms increased significantly with year of publication (n=39, r=0.52, P=.001), while the mean change in effective dose medication arms decreased significantly (n=208, r=-0.26, P<.001). Significant interactions were found between assignment to effective dose medication and publication year (t260=-5.55, P<.001), baseline severity (t260=5.08, P<.001), and study duration (t260=-3.76, P<.001), indicating that the average drug-placebo difference significantly decreased over time, with decreasing baseline severity and with increasing study duration. Medication treatment in comparator studies was associated with significantly more improvement than medication treatment in placebo-controlled trials (t93=2.73, P=.008).The average treatment change associated with placebo treatment in antipsychotic trials increased since 1960, while the change associated with medication treatment decreased. Changes in randomized clinical trials leading to inflation of baseline scores, enrollment of less severely ill participants, and higher expectations of patients may all be responsible.

Project description:ImportancePatients' previous experience with performance-based cognitive tests in clinical trials for cognitive impairment associated with schizophrenia can create practice-related improvements. Placebo-controlled trials for cognitive impairment associated with schizophrenia are at risk for these practice effects, which can be difficult to distinguish from placebo effects.ObjectivesTo conduct a systematic evaluation of the magnitude of practice effects on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) in cognitive impairment associated with schizophrenia and to examine which demographic, clinical, and cognitive characteristics were associated with improvement in placebo conditions.Design, setting, and participantsA blinded review was conducted of data from 813 patients with schizophrenia who were treated with placebo in 12 randomized placebo-controlled clinical trials conducted mostly in outpatient clinics in North America, Europe, Asia, and Latin America from February 22, 2007, to March 1, 2014. A total of 779 patients provided data for the primary outcome measure at baseline and at least 1 follow-up. Seven trials had prebaseline assessments wherein the patients knew that they were not receiving treatment, allowing a comparison of practice and placebo effects in the same patients.InterventionsPlacebo compared with various experimental drug treatments.Main outcomes and measuresComposite score on the MCCB.ResultsOf the 813 patients in the study (260 women and 553 men; mean [SD] age, 41.2 [11.5] years), the mean MCCB composite score at baseline was 22.8 points below the normative mean, and the mean (SEM) total change in the MCCB during receipt of placebo was 1.8 (0.2) T-score points (95% CI, 1.40-2.18), equivalent to a change of 0.18 SD. Practice effects in the 7 studies in which there was a prebaseline assessment were essentially identical to the postbaseline placebo changes. Baseline factors associated with greater improvements in the MCCB during receipt of placebo included more depression/anxiety (F1,438?=?5.41; P?=?.02), more motivation (F1,272?=?4.63; P?=?.03), and less improvement from screening to baseline (F1,421?=?59.32; P?<?.001).Conclusions and relevancePlacebo effects were minimal and associated with the number of postbaseline assessments and several patient characteristics. Given that the patients performed 2.28 SDs below normative standards on average at baseline, a mean placebo-associated improvement of less than 0.2 SD provides evidence that ceiling effects do not occur in these trials. These minimal changes in the MCCB could not be responsible for effective active treatments failing to separate from placebo.

Project description:BackgroundAntipsychotics improve the positive symptoms of schizophrenia. However, little is known about the extent of antidepressive effects of antipsychotics and their correlation with effects on other symptom domains in schizophrenia. The aim was to investigate whether antidepressive effects of antipsychotics have a significant correlation with the effects on specific symptom domains of schizophrenia.MethodsElectronic databases were searched to identify eligible studies that reported antidepressive effects of antipsychotics for the treatment of adult patients with schizophrenia in double-blind, randomized placebo-controlled trials (RCTs). Mean change from baseline in depressive symptoms was meta-analyzed, and the correlation with the effects on other symptom domains was examined through meta-regression analysis.ResultsThirty-five RCTs (13 890 patients) were included in this meta-analysis. Overall, antipsychotics showed greater efficacy than placebo in reducing depressive symptoms, with small to medium effect sizes (standardized mean difference = -0.27, 95% confidence interval -0.32 to -0.22, P < .001). All the antipsychotics, except for chlorpromazine, haloperidol, and ziprasidone, were associated with significantly greater decreases in depressive symptoms compared with placebo (standardized mean difference = -0.19 to -0.40). A higher antidepressive effect was significantly correlated with a higher improvement in Positive and Negative Syndrome Scale/Brief Psychiatric Rating Scale total, positive, and negative, and Positive and Negative Syndrome Scale-general psychopathology symptoms (β = .618, P < .001; β = .476, P < .001; β = .689, P < .001; β = .603, P < .001, respectively).ConclusionsSecond-generation antipsychotics (except for ziprasidone) were associated with small to medium effects sizes on improvement in depressive symptoms among adult patients with schizophrenia. The antidepressive effect of antipsychotics was significantly correlated with improvement in other symptom domains, with the highest correlation observed for improvement in negative symptoms.Prospero registration numberCRD42019133015.

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

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

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