Signal Detection and Placebo Response in Schizophrenia: Parallels with Depression

Placebo response and the rate of failed clinical trials are increasing in schizophrenia, resembling previous experience with antidepressant clinical trials. In depression, the percent of patients randomized to placebo was shown to be strongly associated with drug-placebo differences (signal detection).We hypothesized that this factor would also be important in recent schizophrenia clinical trials. To test this hypothesis a database of acute schizophrenia placebo-controlled studies conducted between 1997 and 2008 was constructed. The database contained 27 studies, with 79 active treatment arms. As percentage of patients randomized to placebo increased, mean placebo improvement decreased (p = 0.047) and mean drug-placebo differences tended to increase (p = 0.166). The frequency of significant contrasts from studies with ≥ 25% randomized to placebo was 83.3%, compared with 58.3% in studies with <25% randomized to placebo. Caveats to these findings include limited data and confounding of potentially influential factors. These limitations prevent definitive conclusions. However, results are consistent with previous findings in depression where having a higher percent of patients randomized to placebo increased drug-placebo differences.