Placebo-related effects in clinical trials in schizophrenia: what is driving this phenomenon and what can be done to minimize it?

Abstract

The effect of placebo observed in schizophrenia clinical trials represents a growing problem that interferes with signal detection for treatments, increases costs of development, discourages investment in schizophrenia research and delays the introduction of new treatments. This paper seeks to clarify key issues related to this problem and identify potential solutions to them. Differences between placebo effect and response are characterized. Recent insights into the central nervous system mechanisms of placebo effect are described. This is followed by a description of protocol/study design and study conduct issues that are contributing to a growing placebo effect in clinical trials. Potential solutions to these problems are provided.

Fig. 1

Differences in neural activity in placebo responders and placebo non-responders. These panels depict the relationship between clinical placebo response, as assessed through muscle rigidity at the wrist (a) and electrophysiological placebo responses, as measured by means of a single neuron recording (b), in Parkinson's disease. Note that in placebo responders (left), both muscle rigidity decreases and electrophysiological changes occur, whereas in placebo non-responders neither clinical nor electrophysiological changes take place (Benedetti et al. 2004, 2009).

Fig. 2

Placebo effect in acute schizophrenia trials over time. The mean change from baseline in total Positive and Negative Syndrome Scale (PANSS) scores for subjects receiving placebo across randomized, double-blind, placebo-controlled, clinical trials has increased in the direction of greater improvements that is correlated to the year that the studies were conducted. (Adapted from Kemp et al. .)

Fig. 3

Changes from baseline in total Positive and Negative Syndrome Scale (PANSS) scores in placebo-treated patients (baseline to endpoint) from two phase III antipsychotic development programmes. Analysis of the changes from baseline in total PANSS scores in placebo-treated patients enrolled in two phase III antipsychotic development trials, with earlier trials conducted nearly a decade prior to the later trials, revealed an increased effect of placebo over time.

Fig. 4

Potential drivers of placebo effect in schizophrenia trials. Based upon multiple regression models and selection criteria of p⩽0.2, there were few variables associated with placebo effect in either the week 6 completer population (a) or the last observation carried forward (LOCF) analysis (b). With the exceptions of gender and age in the week 6 completer analysis, no other variables were associated with a placebo effect. There was, however, in more recent conducted trials a nearly 1.6-fold greater risk for placebo effect in both analyses.