Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics

Am J Psychiatry. 2006 Feb;163(2):185-94. doi: 10.1176/appi.ajp.163.2.185.


Objective: In many parts of the world, second-generation antipsychotics have largely replaced typical antipsychotics as the treatment of choice for schizophrenia. Consequently, trials comparing two drugs of this class--so-called head-to-head studies--are gaining in relevance. The authors reviewed results of head-to-head studies of second-generation antipsychotics funded by pharmaceutical companies to determine if a relationship existed between the sponsor of the trial and the drug favored in the study's overall outcome.

Method: The authors identified head-to-head comparison studies of second-generation antipsychotics through a MEDLINE search for the period from 1966 to September 2003 and identified additional head-to-head studies from selected conference proceedings for the period from 1999 to February 2004. The abstracts of all studies fully or partly funded by pharmaceutical companies were modified to mask the names and doses of the drugs used in the trial, and two physicians blinded to the study sponsor reviewed the abstracts and independently rated which drug was favored by the overall outcome measures. Two authors who were not blinded to the study sponsor reviewed the entire report of each study for sources of bias that could have affected the results in favor of the sponsor's drug.

Results: Of the 42 reports identified by the authors, 33 were sponsored by a pharmaceutical company. In 90.0% of the studies, the reported overall outcome was in favor of the sponsor's drug. This pattern resulted in contradictory conclusions across studies when the findings of studies of the same drugs but with different sponsors were compared. Potential sources of bias occurred in the areas of doses and dose escalation, study entry criteria and study populations, statistics and methods, and reporting of results and wording of findings.

Conclusions: Some sources of bias may limit the validity of head-to-head comparison studies of second-generation antipsychotics. Because most of the sources of bias identified in this review were subtle rather than compelling, the clinical usefulness of future trials may benefit from minor modifications to help avoid bias. The authors make a number of concrete suggestions for ways in which potential sources of bias can be addressed by study initiators, peer reviewers of studies under consideration for publication, and readers of published studies.

Publication types

  • Comparative Study
  • Review

MeSH terms

  • Antipsychotic Agents / therapeutic use*
  • Benzodiazepines / therapeutic use
  • Bias
  • Dibenzothiazepines / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Industry / economics
  • Drug Industry / statistics & numerical data*
  • Humans
  • Olanzapine
  • Patient Selection
  • Publication Bias / statistics & numerical data*
  • Quetiapine Fumarate
  • Randomized Controlled Trials as Topic / statistics & numerical data
  • Reproducibility of Results
  • Research Design / standards
  • Research Design / statistics & numerical data
  • Research Support as Topic / economics
  • Research Support as Topic / statistics & numerical data*
  • Risperidone / therapeutic use
  • Schizophrenia / drug therapy*
  • Treatment Outcome


  • Antipsychotic Agents
  • Dibenzothiazepines
  • Benzodiazepines
  • Quetiapine Fumarate
  • Risperidone
  • Olanzapine