title: Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial.
abstract: Although predominant negative symptoms of schizophrenia can be severe enough to cause persistent impairment, effective treatment options are lacking. We aimed to assess the new generation antipsychotic cariprazine in adult patients with predominant negative symptoms.
  
  
  
  In this randomised, double-blind, phase 3b trial, we enrolled adults aged 18-65 years with long-term (>2 year), stable schizophrenia and predominant negative symptoms (>6 months) at 66 study centres (mainly hospitals and university clinics, with a small number of private practices) in 11 European countries. Patients were randomly assigned (1:1) by an interactive web response system to 26 weeks of monotherapy with fixed-dose oral cariprazine (3 mg, 4·5 mg [target dose], or 6 mg per day) or risperidone (3 mg, 4 mg [target dose], or 6 mg per day); previous medication was discontinued over 2 weeks. The primary outcome was change from baseline to week 26 or end of treatment on the Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) analysed in a modified intention-to-treat population of patients who had follow-up assessments within 5 days after last receipt of study drugs with a mixed-effects model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, number 2012-005485-36.
  
  
  
  Between May 27, 2013, and Nov 17, 2014, 533 patients were screened and 461 (86%) patients were randomised to treatment (230 for cariprazine and 231 for risperidone); 460 were included in the safety population (one patient discontinued before study drug intake). 227 (99%) of 230 patients in the cariprazine group and 229 (99%) of 230 patients in the risperidone group were included in the modified intention-to-treat population (178 [77%] in each group completed 26 weeks of treatment). Mean daily doses were 4·2 mg (SD 0·6) for cariprazine and 3·8 mg (0·4) for risperidone. Treatment-emergent adverse events (eg, insomnia, akathisia, worsening of schizophrenia, headache, anxiety) were reported in 123 (54%) patients treated with cariprazine and 131 (57%) patients treated with risperidone. Use of cariprazine led to a greater least squares mean change in PANSS-FSNS from baseline to week 26 than did risperidone (-8·90 points for cariprazine vs -7·44 points for risperidone; least squares mean difference -1·46, 95% CI -2·39 to -0·53; p=0·0022; effect size 0·31). One patient in the risperidone group died of a cause regarded as unrelated to treatment.
  
  
  
  Our results support the efficacy of cariprazine in the treatment of predominant negative symptoms of schizophrenia.
  
  
  
  Gedeon Richter Plc.
authors.affiliation: Medical Division, Gedeon Richter Plc, Budapest, Hungary. Electronic address: gy.nemeth@richter.hu.
authors.forename: György
authors.initials: G
authors.lastname: Németh
authors.affiliation: Medical Division, Gedeon Richter Plc, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Laszlovszky
authors.affiliation: Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary.
authors.forename: Pál
authors.initials: P
authors.lastname: Czobor
authors.affiliation: Medical Division, Gedeon Richter Plc, Budapest, Hungary.
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Szalai
authors.affiliation: Medical Division, Gedeon Richter Plc, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Szatmári
authors.affiliation: Medical Division, Gedeon Richter Plc, Budapest, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Harsányi
authors.affiliation: Medical Division, Gedeon Richter Plc, Budapest, Hungary.
authors.forename: Ágota
authors.initials: Á
authors.lastname: Barabássy
authors.affiliation: Medical Division, Gedeon Richter Plc, Budapest, Hungary.
authors.forename: Marc
authors.initials: M
authors.lastname: Debelle
authors.affiliation: Clinical Development, Forest Research Institute, an Allergan affiliate, Jersey City, NJ, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Durgam
authors.affiliation: Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Bitter
authors.affiliation: Section on Psychosis, Semel Institute for Neuroscience at University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Marder
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: W Wolfgang
authors.initials: WW
authors.lastname: Fleischhacker
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001526:Behavioral Symptoms / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D018967:Risperidone / Q000627:therapeutic use*; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; C533287:cariprazine; D018967:Risperidone