Control group bias in randomized atypical antipsychotic medication trials for schizophrenia

Context: It has been suggested that the need for concurrent placebo control groups in new schizophrenia studies might be minimized by making comparisons with external placebo. This strategy requires an assumption of constancy, that the novel medication will perform the same way in a study with only active controls as it would have in a placebo-controlled trial. Objective: To test this constancy assumption in active- and low dose-controlled trials vs placebo-controlled trials of atypical antipsychotic medications. Data Sources: A comprehensive search of bibliographic databases, conference proceedings, and Food and Drug Administration databases through November 24, 2003. Study Selection: English-language, randomized, double-blind clinical trials of newer atypical antipsychotic medications in otherwise unselected acutely ill adults with schizophrenia or schizoaffective disorder that reported baseline and intent-to-treat end point change values for the Brief Psychiatric Rating Scale. Data Extraction: Study number, sample size, reported dosage for each arm, trial duration, percentage of men, average age, trial arm treatment completion rate, baseline and within-arm end point change in the Brief Psychiatric Rating Scale, method of scoring the Brief Psychiatric Rating Scale, and date of publication were extracted from each study independently by 2 of us (S.W.W. and C.B.B.) each. Data Synthesis: There were 32 studies comprising 66 risperidone, olanzapine, quetiapine, and ziprasidone arms including 7264 patients. Random-effects analysis revealed that in atypical antipsychotic medication arms, the degree of improvement was nearly double in active-controlled-trials than that seen with the same drugs and dosages in placebo-controlled studies. An effect of design was also observed in low dose-controlled studies vs placebo-controlled studies in ineffective and intermediate antipsychotic medication dose ranges. Conclusions: The observed control group bias indicates that the constancy assumption does not hold in recent antipsychotic medication trials. These results suggest that caution is indicated when considering active- or low close-controlled studies requiring comparisons with external placebo as alternatives to placebo-controlled trials for establishing efficacy of new medications for schizophrenia.