title: Dose reduction of risperidone and olanzapine and estimated dopamine D₂ receptor occupancy in stable patients with schizophrenia: findings from an open-label, randomized, controlled study.
abstract: BACKGROUND
  While acute-phase antipsychotic response has been attributed to 65%-80% dopamine D₂ receptor blockade, the degree of occupancy for relapse prevention in the maintenance treatment of schizophrenia remains unknown.
  
  
  METHODS
  In this secondary study of an open-label, 28-week, randomized, controlled trial conducted between April 2009 and August 2011, clinically stable patients with schizophrenia (DSM-IV) treated with risperidone or olanzapine were randomly assigned to the reduction group (dose reduced by 50%) or maintenance group (dose kept constant). Plasma antipsychotic concentrations at peak and trough before and after dose reduction were estimated with population pharmacokinetic techniques, using 2 collected plasma samples. Corresponding dopamine D₂ occupancy levels were then estimated using the model we developed. Relapse was defined as worsening in 4 Positive and Negative Syndrome Scale-Positive subscale items: delusion, conceptual disorganization, hallucinatory behavior, and suspiciousness.
  
  
  RESULTS
  Plasma antipsychotic concentrations were available for 16 and 15 patients in the reduction and maintenance groups, respectively. Estimated dopamine D₂ occupancy (mean ± SD) decreased following dose reduction from 75.6% ± 4.9% to 66.8% ± 6.4% at peak and 72.3% ± 5.7% to 62.0% ± 6.8% at trough. In the reduction group, 10 patients (62.5%) did not demonstrate continuous D₂ receptor blockade above 65% (ie, < 65% at trough) after dose reduction; furthermore, 7 patients (43.8%) did not achieve a threshold of 65% occupancy even at peak. Nonetheless, only 1 patient met our relapse criteria after dose reduction during the 6 months of the study.
  
  
  CONCLUSIONS
  The results suggest that the therapeutic threshold regarding dopamine D₂ occupancy may be lower for those who are stable in antipsychotic maintenance versus acute-phase treatment. Positron emission tomography studies are warranted to further test our preliminary findings.
  
  
  BACKGROUND
  UMIN Clinical Trials Registry identifier: UMIN000001834.
authors.affiliation: Schizophrenia Division, Complex Mental Illness Program, Centre for Addiction and Mental Health, 250 College St, Toronto, Ontario, M5T 1R8, Canada hirotak@dk9.so-net.ne.jp.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Takefumi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
authors.forename: Gary
authors.initials: G
authors.lastname: Remington
authors.forename: Koichiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Masaru
authors.initials: M
authors.lastname: Mimura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uchida
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D018967:Risperidone / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D055502:Secondary Prevention
chemical_list: D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D001569:Benzodiazepines; D018967:Risperidone; D000077152:Olanzapine