In September 2005, the National Institute of Mental Health published phase 1 results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, a large-scale, double-blind trial comparing the relative effectiveness of five antipsychotics used to treat patients with schizophrenia: perphenazine, a conventional antipsychotic that has been commercially available since the 1950s, and four atypical agents—olanzapine, quetiapine, risperidone, and ziprasidone—that were introduced in the 1990s. The broad intention of the CATIE study is to determine if the atypical agents used offer any demonstrable clinical and public health advantages over the conventional agents. Concerns over costs and side effects (eg, pronounced weight gain and lipid disturbances) associated with the newer, atypical antipsychotics, as well as doubts about superior efficacy relative to older, conventional agents, served as an impetus to the trial.

The study design chosen for the CATIE study—that of a “large, simple” trial—sought to bypass the limitations of clinical studies that are conducted when pharmaceutical companies seek regulatory approval of a new medication. Studies done in pursuance of drug approval attempt to establish safety and efficacy in controlled clinical settings so as to determine if a drug works at all, and if its use entails specific side effects. Hence, they are typically placebo-controlled and short-term, enroll a small homogeneous population (eg, initially hospitalized patients with no psychiatric or medical comorbidities), forbid or restrict the use of concomitant medications, and take as their endpoints well-defined side effects and measures of core psychopathology. These restrictions heighten the risk that the study findings may not be widely applicable to patients outside the confines of the protocol.