Effect Size Deflation With Increasing Sample Size in Adjunctive Trials for Negative Symptoms in Schizophrenia: A Meta-Analysis and Meta-Regression Across Mechanisms of Action

This differential placebo-active scaling with increased sample size is unlikely to be of physiological origin and may indicate that site management issues contribute to negative clinical results in large-scale trials for the negative symptoms of schizophrenia. Current power analytic approaches do not adequately consider the consequences of sample size-dependent effect size deflation, leading to excessive risk of type II error with increasing sample size or site numbers and decreasing recruitment density.