Dataset Information

Placebo response in antipsychotic clinical trials: a meta-analysis.

ABSTRACT:

Importance

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.

Objectives

To investigate the relationship between antipsychotic medication and placebo response by publication year, and to identify associated study design and implementation variables.

Data sources

MEDLINE, PsycINFO, and PubMed were searched to identify randomized clinical trials of antipsychotic medications published from 1960 to July 2013.

Study selection

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.

Data extraction and synthesis

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.

Main outcomes and measures

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.

Results

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).

Conclusions and relevance

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.

SUBMITTER: Rutherford BR

PROVIDER: S-EPMC4256120 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Placebo response in antipsychotic clinical trials: a meta-analysis.

Rutherford Bret R BR Pott Emily E Tandler Jane M JM Wall Melanie M MM Roose Steven P SP Lieberman Jeffrey A JA

JAMA psychiatry 20141201 12

<h4>Importance</h4>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.<h4>Objectives</h4>To investigate the relationship between antipsychotic medication and placebo response by publication year, and to identify associated study design and implementation variables.<h4>Data sources</h4>MEDLINE, PsycINFO, and PubMed were searched to identify randomized clinical trials of anti ...[more]

PMID: 25321611

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Project description: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).

Project description:ImportanceAntidepressants are commonly used worldwide to treat major depressive disorder. Symptomatic response to antidepressants can vary depending on differences between individuals; however, this variability may reflect nonspecific or random factors.ObjectivesTo investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether this variability is associated with severity of major depressive disorder, antidepressant class, or year of study publication.Data sourcesData used were from a recent network meta-analysis of acute treatment with licensed antidepressants in adults with major depressive disorder. The following databases were searched from inception to January 8, 2016: the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycINFO. Additional sources were international trial registries, drug approval agency websites, and key scientific journals.Study selectionAnalysis was restricted to double-blind, randomized placebo-controlled trials with available data at the study's end point.Data extraction and synthesisBaseline and end point means, SDs, number of participants in each group, antidepressant class, and publication year were extracted. The data were analyzed between August 14 and November 18, 2019.Main outcomes and measuresWith the use of validated methods, coefficients of variation were derived for antidepressants and placebo, and their ratios were calculated to compare outcome variability between antidepressant and placebo. Ratios were entered into a random-effects model, with the expectation that response to antidepressants would be more variable than response to placebo. Analysis was repeated after stratifying by baseline severity of depression, antidepressant class (selective serotonin reuptake inhibitors: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone; serotonin and norepinephrine reuptake inhibitors: desvenlafaxine and venlafaxine; norepinephrine-dopamine reuptake inhibitor: bupropion; noradrenergic agents: amitriptyline and reboxetine; and other antidepressants: agomelatine, mirtazapine, and trazodone), and publication year.ResultsIn the 87 eligible randomized placebo-controlled trials (17 540 unique participants), there was significantly more variability in response to antidepressants than to placebo (coefficients of variation ratio, 1.14; 95% CI, 1.11-1.17; P < .001). Baseline severity of depression did not moderate variability in response to antidepressants. Variability in response to selective serotonin reuptake inhibitors was lower than variability in response to noradrenergic agents (coefficients of variation ratio, 0.88; 95% CI, 0.80-0.97; P = .01), as was the variability in response to other antidepressants compared with noradrenergic agents (coefficients of variation ratio, 0.87; 95% CI, 0.79-0.97; P = .001). Variability also tended to be lower in studies that were published more recently, with coefficients of variation changing by a value of 0.005 (95% CI, 0.002-0.008; P = .003) for every year a study is more recent.Conclusions and relevanceIndividual differences may be systematically associated with responses to antidepressants in major depressive disorder beyond placebo effects or statistical factors. This study provides empirical support for identifying moderators and personalizing antidepressant treatment.

Project description:ImportanceAntidepressants are commonly used to treat major depressive disorder (MDD). Antidepressant outcomes can vary based on individual differences; however, it is unclear whether specific factors determine this variability or whether it is at random.ObjectiveTo investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether variability is associated with MDD severity, antidepressant class, or study publication year.Data sourcesData used were updated from a network meta-analysis of treatment with licensed antidepressants in adults with MDD. The Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycInfo were searched from inception to March 21, 2019. Additional sources were international trial registries and sponsors, drug companies and regulatory agencies' websites, and reference lists of published articles. Data were analyzed between June 8, 2020, and June 13, 2020.Study selectionAnalysis was restricted to double-blind, randomized placebo-controlled trials with depression scores available at the study's end point.Data extraction and synthesisBaseline means, number of participants, end point means and SDs of total depression scores, antidepressant type, and publication year were extracted.Main outcomes and measuresLog SDs (bln σ̂) were derived for treatment groups (ie, antidepressant and placebo). A random-slope mixed-effects model was conducted to estimate the difference in bln σ̂ between treatment groups while controlling for end point mean. Secondary models determined whether differences in variability between groups were associated with baseline MDD severity; antidepressant class (selective serotonin reuptake inhibitors and other related drugs; serotonin and norepinephrine reuptake inhibitors; norepinephrine-dopamine reuptake inhibitors; noradrenergic agents; or other antidepressants); and publication year.ResultsIn the 91 eligible trials (18 965 participants), variability in response did not differ significantly between antidepressants and placebo (bln σ̂, 1.02; 95% CI, 0.99-1.05; P = .19). This finding is consistent with a range of treatment effect SDs (up to 16.10), depending on the association between the antidepressant and placebo effects. Variability was not associated with baseline MDD severity or publication year. Responses to noradrenergic agents were 11% more variable than responses to selective serotonin reuptake inhibitors (bln σ̂, 1.11; 95% CI, 1.01-1.21; P = .02).Conclusions and relevanceAlthough this study cannot rule out the possibility of treatment effect heterogeneity, it does not provide empirical support for personalizing antidepressant treatment based solely on total depression scores. Future studies should explore whether individual symptom scores or biomarkers are associated with variability in response to antidepressants.

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Dataset Information

Placebo response in antipsychotic clinical trials: a meta-analysis.

Importance

Objectives

Data sources

Study selection

Data extraction and synthesis

Main outcomes and measures

Results

Conclusions and relevance

Publications

Placebo response in antipsychotic clinical trials: a meta-analysis.

Similar Datasets

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