Is the superior efficacy of new generation antipsychotics an artifact of LOCF?

Schizophr Bull. 2007 Jan;33(1):183-91. doi: 10.1093/schbul/sbl025. Epub 2006 Aug 11.


It has been argued that the efficacy superiority found in meta-analyses for some of the atypical antipsychotics is an artifact of higher dropout rates due to side effects in the haloperidol group combined with last-observation-carried-forward (LOCF) analyses. We therefore reanalyzed a number of pivotal studies comparing new generation antipsychotics (NGAs) and conventional antipsychotics (CAs). A total of 5 studies (n = 1271) comparing amisulpride and 3 studies (n = 2454) comparing olanzapine with CAs were reanalyzed using original patient data. We applied 4 different models: LOCF, completer analysis, LOCF but excluding dropouts due to adverse events, and LOCF but excluding all dropouts with the exception of dropouts related to efficacy. Effect sizes expressed as standardized mean differences between NGAs and CAs based on the 4 different analysis models were compared. The overall results were not different irrespective of the model used. Single studies, however, showed higher effect sizes when LOCF instead of other models was used. Overall, it does not seem that higher dropout rates due to side effects in the haloperidol groups together with LOCF analyses consistently biased the results in favor of amisulpride and olanzapine. Because the results of the single studies, however, showed that this may occasionally be the case, future studies should look at the data from different angles applying sensitivity analyses, and they may use alternative statistics such as mixed models, which need to be developed further. Ultimately, strategies to reduce dropout rates are needed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amisulpride
  • Artifacts*
  • Benzodiazepines / adverse effects
  • Benzodiazepines / therapeutic use
  • Bias
  • Flupenthixol / adverse effects
  • Flupenthixol / therapeutic use
  • Haloperidol / adverse effects
  • Haloperidol / therapeutic use
  • Humans
  • Olanzapine
  • Patient Dropouts / statistics & numerical data
  • Psychiatric Status Rating Scales
  • Psychotropic Drugs / adverse effects
  • Psychotropic Drugs / therapeutic use*
  • Randomized Controlled Trials as Topic / statistics & numerical data*
  • Schizophrenia / drug therapy*
  • Schizophrenic Psychology*
  • Sulpiride / adverse effects
  • Sulpiride / analogs & derivatives*
  • Sulpiride / therapeutic use
  • Treatment Outcome


  • Psychotropic Drugs
  • Benzodiazepines
  • Sulpiride
  • Amisulpride
  • Flupenthixol
  • Haloperidol
  • Olanzapine