Placebo response in antipsychotic clinical trials: a meta-analysis

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.