Since decades, psychiatrists, researchers, statisticians, and others debate about how to best design, conduct, and report clinical trials on the treatment in schizophrenia (eg, Kraemer et al1
, Bartko et al2
, and Stroup et al3
), and great efforts have been undertaken to set standards for these issues and to harmonize research for medicine in general (eg, The International Conference on Harmonization [ICH] of Technical Requirements for Registration of Pharmaceuticals for Human Use [www.ICH.org
) or for psychiatric topics (eg, Food and Drug Administration [FDA]-National Institute of Mental Health-Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) workshop on clinical trial design for neurocognitive drugs for schizophrenia5
). Likewise, enormous efforts have been invested in clinical trials on the treatment of schizophrenia, yielding new insights into this demanding task.
Evidence taken for granted nowadays, such as, eg, defined dose ranges for the use of antipsychotics was not available during the decades of treatment with the first-generation drugs. Beyond the study of efficacy in the treatment of positive symptoms, increasing value has been placed on negative and depressive symptoms as well as quality of life and the social functioning of the patients, aspects mostly neglected in previous clinical trials. Apart from these advances, there is still need for additional steps to further improve the validity of trial data as well as the quality of the reporting. Study endpoints such as response or relapse indeed lack a commonly accepted definition.6
Statistical approaches vary considerably, leaving room for speculation whether their choice was partly dependent on the desired outcome.7
The influence of the study sponsor is obvious in head-to-head trials of second-generation antipsychotics (SGAs) reporting a prosponsor overall outcome in 90% of the publication abstract.8
The latest landmark study, the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial, though independently sponsored and carefully designed, stimulated once again the discussion of how clinical trials should be conducted, analyzed, and reported.9
In this context, the current review tries to address a selection of critical aspects, including trial design features, population sample bias, study endpoint choice and definition, outcome assessment and reporting, and other sources of potential bias relevant to clinical trials ().
Important Methodological Problems in Current Antipsychotic Drug Trials and Some Suggestions to Resolve Them