title: Joint modeling of dropout and outcome in three pivotal clinical trials of schizophrenia.
abstract: BACKGROUND
  Dropout is a serious challenge to clinical trials in psychiatry, yet standard outcome analyses with mixed models do not account for dropout, while joint modeling uses dropout from a survival model to adjust the outcome from a mixed model, but is untested in clinical trials of schizophrenia.
  
  
  OBJECTIVE
  To compare mixed and joint modeling in three acute phase pivotal placebo controlled trials of schizophrenia.
  
  
  METHODS
  Data were reanalyzed on 611 in-patients with acute schizophrenia who participated in three pivotal randomized controlled trials that compared placebo with olanzapine or risperidone (dropout rates placebo: 62.6% and medication: 37.4%). The outcome measures were BPRS or PANSS total change scores. Mixed-effects models for repeated measures and joint models were computed and compared to examine the time-treatment interaction. Effect size comparisons were made.
  
  
  RESULTS
  Antipsychotic treatment was superior to placebo across analyses. Time treatment interactions were significant (p<.05) for the mixed (beta=2.33) and joint models (beta=2.62). Compared with mixed modeling, joint modeling reduced the estimated change score for treatment (21.24 vs 19.74) and placebo (1.64 vs -1.11). The effect size differences between placebo and treatment groups were greater for joint (ES=.89) than mixed modeling (ES=0.83). Sensitivity analysis replicated this trend of results in each of the three trials.
  
  
  CONCLUSIONS
  Compared to mixed modeling, joint modeling results in a greater separation between treatment and placebo groups. This offers preliminary evidence that joint modeling may be useful in the analysis of antipsychotic placebo controlled RCTs.
authors: University of Haifa, Israel. Electronic address: stezlev@gmail.com.
authors: Stephen Z
authors: SZ
authors: Levine
authors: University of Haifa, Israel.
authors: Yair
authors: Y
authors: Goldberg
authors: Department of Psychiatry and Psychotherapy, Technische Universität München, Germany.
authors: Myrto
authors: M
authors: Samara
authors: Psychiatric Institute, University of Illinois at Chicago, USA.
authors: John M
authors: JM
authors: Davis
authors: Department of Psychiatry and Psychotherapy, Technische Universität München, Germany.
authors: Stefan
authors: S
authors: Leucht
mesh_terms: D014150:Antipsychotic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008962:Models, Theoretical; D010352:Patient Dropouts / Q000706:statistics & numerical data*; D011569:Psychiatric Status Rating Scales; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D018967:Risperidone / Q000627:therapeutic use*; D012559:Schizophrenia / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D018967:Risperidone
keywords: Clinical trial; Dropout; Outcome; Placebo