title: Dopamine D2 receptor occupancy and cognition in schizophrenia: analysis of the CATIE data.
abstract: BACKGROUND
  Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial.
  
  
  METHODS
  The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on neurocognitive functions.
  
  
  RESULTS
  D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%.
  
  
  CONCLUSIONS
  These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.
authors.affiliation: Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakurai
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
authors.forename: Scott T
authors.initials: ST
authors.lastname: Stroup
authors.forename: Richard S E
authors.initials: RS
authors.lastname: Keefe
authors.forename: Tarek K
authors.initials: TK
authors.lastname: Rajji
authors.forename: Takefumi
authors.initials: T
authors.lastname: Suzuki
authors.forename: David C
authors.initials: DC
authors.lastname: Mamo
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Pollock
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: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000378:metabolism / Q000627:therapeutic use; D003072:Cognition Disorders / Q000378:metabolism* / Q000523:psychology; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D010879:Piperazines / Q000378:metabolism / Q000627:therapeutic use; D017448:Receptors, Dopamine D2; D018967:Risperidone / Q000378:metabolism / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D013844:Thiazoles / Q000378:metabolism / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; C581293:DRD2 protein, human; D065127:Dopamine D2 Receptor Antagonists; D010879:Piperazines; D017448:Receptors, Dopamine D2; D013844:Thiazoles; D001569:Benzodiazepines; C092292:ziprasidone; D018967:Risperidone; D000077152:Olanzapine