title: Early onset of antipsychotic action in schizophrenia: evaluating the possibility of shorter acute efficacy trials.
abstract: Extended placebo-controlled clinical trials in schizophrenia research pose an ethical challenge. This study examines factors that have implications for the design and duration of placebo-controlled acute efficacy trials: Does early response discriminate active drug (AD) from placebo, and are the early differences sustained over time? A post hoc pooled analysis of 2 randomized 6-week double-blind clinical trials was performed comparing patients with schizophrenia treated with placebo or low-dose olanzapine (1 mg/d; placebo/low dose [PBO] group, n = 170) to patients treated with a 10- to 20-mg/d dose of haloperidol or medium- to high-dose olanzapine (7.5 to 17.5 mg/d; AD group, n = 252). Mixed-model repeated-measure analysis tested for group differences. Power analysis was undertaken to compare study designs with shorter durations. At 2 weeks, the mean reduction in the Brief Psychiatric Rating Scale total score was significantly greater for the AD group (-10.1) compared with the PBO group (-4.1; P < 0.001); this difference was sustained until the study ended (6 weeks). A higher proportion of early treatment responders were observed for the AD group (52%) compared with the PBO group (29%; P < 0.001). Early nonresponse to placebo or drug was predictive of subsequent nonresponse (negative predictive value: PBO = 95%, AD = 84%). Power analysis indicates that the placebo-drug differences are robust at 2 weeks. Treatment responders from the AD and the PBO groups followed a similar response path. Early response to antipsychotic treatment discriminated AD from placebo. Reducing placebo-controlled clinical trials from 6 weeks to 2 to 4 weeks was found to be a viable option for efficacy identification in acutely ill patients.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Kinon_Bruce@Lilly.com
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Kinon
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Stauffer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sniadecki
authors.forename: Haya
authors.initials: H
authors.lastname: Ascher-Svanum
authors.forename: Sara
authors.initials: S
authors.lastname: Kollack-Walker
authors.forename: Jayanthi
authors.initials: J
authors.lastname: Jacob
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D010054:Brief Psychiatric Rating Scale; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D018401:Sample Size; D012559:Schizophrenia / Q000188:drug therapy* / Q000453:epidemiology; D012565:Schizophrenic Psychology; D013223:Statistics as Topic / Q000379:methods; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents