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15-10-2014 | Mental health | Article

Changing placebo response dilutes antipsychotic trial power


Free abstract

medwireNews: Factors including patients’ expectations may underlie an increased placebo response in antipsychotic randomised controlled trials (RCTs) published since 1960, say researchers.

In their meta-analysis of 105 RCTs published since 1960, Bret Rutherford (Columbia University College of Physicians and Surgeons, New York, USA) and team found that the average symptom change on the Brief Psychiatric Rating Scale (BPRS) improved by 1.1 points per decade of publication.

Patients given placebo in the 1960s worsened by an average of 3.5 points during treatment, whereas those treated in the 2000s had an average improvement of 3.2 points. By contrast, the degree of improvement among patients given active treatment in placebo-controlled trials decreased over time, by 2.0 points per decade.

“The consequence of these divergent trends was a significant decrease in drug-placebo differences from 1960 to the present”, write Rutherford et al in JAMA Psychiatry.

However, patients who were treated in the context of a trial with an active comparator (eg, a head-to-head trial of two antipsychotic drugs) did significantly better than those who received active treatment within a placebo-controlled trial, by an average of 3.8 points on the BPRS.

“One possible explanation for these results is that individuals with schizophrenia become aware of their probability of receiving active medication during the informed consent procedure in an RCT, and this information generates expectations of improvement that influence treatment response”, suggests the team.

The change in response over time was not observed for low-dose or intramuscular treatment. The researchers also found that the benefits of active treatment decreased with increasing study duration and were greater in patients with more severe symptoms at baseline “yet the mean baseline severity in these RCTs appears to be decreasing over time”.

Also, use of single-blind lead-in phases reduced the treatment response in both the active and placebo treatment arms. All these factors together explained 65.8% of the variability in average change in BPRS score.

“Comparing these findings with what is known about placebo response in other disorders such as major depressive disorder, we find that a picture of placebo response emerges in which a substantial portion is caused by general methodological factors rather than the nature of the illness under study”, say the researchers.

They conclude that to improve the power of antipsychotic RCTs, investigators must “recruit more severely ill patients, limit study duration to no longer than 8 to 12 weeks, dispense with single-blind placebo lead-in periods, and maximize the probability of being assigned to placebo as opposed to active medication.”

medwireNews ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2013

By Eleanor McDermid, Senior medwireNews Reporter

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