title: Treatment of early non-response in patients with schizophrenia: assessing the efficacy of antipsychotic dose escalation.
abstract: BACKGROUND
  Early non-response to antipsychotic treatment in patients with schizophrenia has been shown in multiple studies to predict poor response at short-term trial endpoint. Therefore, strategies to address the challenge of non-improvement early in the course of treatment are needed. A novel trial design was developed to assess the potential utility of antipsychotic dose escalation in patients with an inadequate initial treatment response. This design was embedded in a study intended to assess the efficacy of low dose lurasidone in patients with schizophrenia. The purpose of this report is to describe the background, rationale and design of this study that included a novel method for the assessment of the potential for dose-response in early non-responding patients with schizophrenia.
  
  
  METHODS
  In this 6-week, international, multicenter, double-blind trial, eligible adults with acute schizophrenia were randomized to receive fixed doses of lurasidone 20 mg/day, 80 mg/day (active control), or placebo in a 1:2:1 ratio. Patients initially randomized to lurasidone 80 mg/day who did not have a Positive and Negative Syndrome Scale total score improvement ≥ 20% at Week 2 were re-randomized on a 1:1 basis to receive either lurasidone 80 mg/day or lurasidone 160 mg/day for the remainder of the trial. All other groups remained on their initially assigned treatment. The formal primary objective of the study was to evaluate the efficacy of low-dose lurasidone (20 mg/day) compared to placebo; secondary objectives included evaluating the efficacy of lurasidone 80 mg/day versus 160 mg/day in early non-responders, and evaluating the efficacy of lurasidone in all subjects initially randomized to 80 mg/day versus placebo.
  
  
  CONCLUSIONS
  Since a lack of early improvement predicts poor response to short-term antipsychotic treatment in patients with schizophrenia, several treatment strategies have been proposed to enhance treatment outcome in early non-responders. A novel clinical trial design involving a placebo arm and re-randomization of early non-responders to increased or maintained antipsychotic dose was developed. The study design described in this report provides a robust method to assess the value of antipsychotic dose escalation in patients with schizophrenia who demonstrate poor initial treatment response.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01821378; initial registration March 22, 2013.
authors.affiliation: Sunovion Pharmaceuticals Inc., Fort Lee, NJ, USA. antony.loebel@sunovion.com.
authors.forename: Antony
authors.initials: A
authors.lastname: Loebel
authors.affiliation: New York Medical College, Valhalla, NY, USA. citrome@cnsconsultant.com.|ᅟ, 11 Medical Park Drive, Suite 106, Pomona, NY, 10970, USA. citrome@cnsconsultant.com.
authors.forename: Leslie
authors.initials: L
authors.lastname: Citrome
authors.affiliation: The Zucker Hillside Hospital, Glen Oaks, and the Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA. CCorrell@nshs.edu.
authors.forename: Christoph U
authors.initials: CU
authors.lastname: Correll
authors.affiliation: Sunovion Pharmaceuticals Inc., Fort Lee, NJ, USA. jane.xu@sunovion.com.
authors.forename: Jane
authors.initials: J
authors.lastname: Xu
authors.affiliation: Sunovion Pharmaceuticals Inc., Fort Lee, NJ, USA. josephine.cucchiaro@sunovion.com.
authors.forename: Josephine
authors.initials: J
authors.lastname: Cucchiaro
authors.affiliation: The Zucker Hillside Hospital, Glen Oaks, and the Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA. jkane2@nshs.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Kane
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D054833:Isoindoles / Q000009:adverse effects; D000069056:Lurasidone Hydrochloride / Q000008:administration & dosage*; D008875:Middle Aged; D012559:Schizophrenia / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D054833:Isoindoles; D000069056:Lurasidone Hydrochloride