Feasibility of reducing the duration of placebo-controlled trials in schizophrenia research

Abstract

Use of placebo-controlled trials in medical and psychiatric research has been controversial, although a consensus is emerging about conditions under which placebo-controlled trials are ethical. In schizophrenia research, the paradigm of slow onset of antipsychotic effects has led to a model in which placebo-controlled trials of 6-8 weeks duration have been used to demonstrate efficacy. Recent evidence that the largest symptom reductions are typically seen in the first weeks of treatment suggests that shorter placebo-controlled studies to demonstrate antipsychotic efficacy are possible. In a pilot study of the feasibility of shortening placebo-controlled studies, we reanalyzed data from placebo-controlled registry trials of olanzapine and risperidone and found that trials as short as 4 weeks could have similar power to longer term 6-8 week studies, given the estimated time course of treatment effects. Although fuller evaluation is required, the results suggest future antipsychotic trials could be shortened from 6-8 weeks to 3-4 weeks with a relatively low increase in sample size requirements. Shortening placebo-controlled trials would reduce patient burden and ethical objections to prolonged administration of placebo and reduce potential bias due to high dropout rates in longer clinical trials.

Fig. 1.

Percentage of Patients With BPRS Total Scores by Treatment Assignment and Study Week—Combined North American Risperidone Trails.

Fig. 2.

Percentage of Patients With BPRS Total Data by Treatment Assignment and Study Week—North American Acute Olanzapine Trail.

Fig. 3.

Mean BPRS Total Scores by Treatment Assignment and Study Week—Combined North American Resperidone Trails. Estimates from mixed model for repeated measures analysis of variance.

Fig. 4.

BPRS Total Scores by Treatment Assignment and Study Week—North American Acute Olanzapine Trail. Estimates from mixed model for repeated measures analysis of variance.

Fig. 5.

Kaplan-Meier Estimates of Time to Initial 20% or More Reduction in BPRS Total Score by Treatment Assignment—Combined North American Risperidone Trials.

Fig. 6.

Kaplan-Meier Estimates of Time to Initial 20% or More Reduction in BPRS Total Score—Acute North American Olanzapine Trial.