title: Flexible-dose clinical trials: predictors and outcomes of antipsychotic dose adjustments.
abstract: In a new approach to the interpretation of data from flexible-dose studies, we examined the safety and efficacy measurements that preceded and followed dose changes, to identify clinical factors that predict dose change as well as subsequent outcome of clinical status with dose change. This was a post hoc analysis of 3 flexible-dosed olanzapine studies: acutely ill bipolar I patients with an index manic episode (N = 452) who received olanzapine (5-20 mg/d) or haloperidol (3-15 mg/d); acutely ill patients with schizophrenia (N = 339) who received olanzapine (10-20 mg/d) or risperidone (4-12 mg/d) for 28 weeks; and remitted bipolar I patients (N = 361) who received olanzapine (5-20 mg/d) or placebo for 48 weeks. The major findings of this analysis were: an increase in dose was predicted by baseline illness severity in the acute studies, and a decrease in dose was predicted by illness symptom improvement or worsening of adverse events. Dose decrease was followed by significantly decreased efficacy for patients with acute mania treated with olanzapine or haloperidol, and olanzapine dose increases were followed by improved efficacy. Treatment-emergent extrapyramidal symptom adverse events and akathisia typically predicted dose decreases. Techniques used in this analysis may prove to be useful in assessing the relationship between dose change and safety and efficacy measures.
authors: Lilly Research Laboratories, Eli Lilly and Company, Drop Code 4133, Indianapolis, IN 46285, USA. lipkovichia@lilly.com
authors: Ilya
authors: I
authors: Lipkovich
authors: David
authors: D
authors: Baron
authors: John
authors: J
authors: Houston
authors: Jonna
authors: J
authors: Ahl
authors: Matthew
authors: M
authors: Rotelli
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D001569:Benzodiazepines / Q000008:administration & dosage; D001714:Bipolar Disorder / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D011237:Predictive Value of Tests; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D012559:Schizophrenia / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000077152:Olanzapine