title: Evaluation of Antipsychotic Dose Reduction in Late-Life Schizophrenia: A Prospective Dopamine D2/3 Receptor Occupancy Study.
abstract: OBJECTIVE
  Patients with late-life schizophrenia (LLS) are highly susceptible to antipsychotic adverse effects. Treatment guidelines endorse lower antipsychotic doses. However, the optimal dose of antipsychotics and associated dopamine D2/3 receptor (D2/3R) occupancies remain largely unexplored in patients with LLS.
  
  
  OBJECTIVE
  To evaluate effects of antipsychotic dose reduction on striatal dopamine D2/3R occupancies, clinical variables, and blood pharmacokinetic measures in patients with LLS.
  
  
  METHODS
  An open-label, single-arm prospective study with a 3- to 6-month follow-up period (January 10, 2007, to October 21, 2013) was conducted at an academic tertiary care center with practice for ambulatory care. Participants included 35 outpatients with clinically stable LLS (patients aged ≥ 50 years receiving olanzapine or risperidone monotherapy at the same dose for 6 to 12 months). Follow-up was completed on October 21, 2013, and analysis was conducted from October 22, 2014, to February 2, 2015.
  
  
  METHODS
  Carbon 11-labeled raclopride positron emission tomography, clinical measures, and blood pharmacokinetic measures performed before and after gradual dose reduction by up to 40% from the baseline dose and at least 3 months after dose reduction.
  
  
  METHODS
  Striatal dopamine D2/3R occupancies with antipsychotics, clinical measures (Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Targeted Inventory on Problems in Schizophrenia, Simpson-Angus Scale, Barnes Rating Scale for Drug-Induced Akathisia, Udvalg for Kliniske Undersøgelser Side Effect Rating Scale), and blood pharmacokinetic measures (prolactin and antipsychotic blood levels).
  
  
  RESULTS
  Dopamine D2/3R occupancy of the entire sample decreased by a mean (SD) of 6.2% (8.2%) following dose reduction (from 70% [12%] to 64% [12%]; P < .001). The lowest D2/3R occupancy associated with clinical stability was 50%. Extrapyramidal symptoms (EPSs) were more likely to occur with D2/3R occupancies higher than 60%: 90.5% (19 of 21) of the participants with baseline EPSs and 76.9% (10 of 13) of the participants with postreduction EPSs had striatal D2/3R occupancies higher than 60%. The baseline D2/3R occupancies were lower in patients with clinical deterioration (n = 5) than in those whose condition remained stable (n = 29) (58% [15%] vs 72% [10%]; P = .03). Following dose reduction, Targeted Inventory on Problems in Schizophrenia score increased (P = .046) and Positive and Negative Syndrome Scale (P = .02), Brief Psychiatric Rating Scale (P = .03), Simpson-Angus Scale (P < .001), Barnes Rating Scale for Drug-Induced Akathisia (P = .03), and Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (P < .001) scores and prolactin (P < .001) and blood antipsychotic (olanzapine, P < .001; risperidone plus the metabolite 9-hydroxyrisperidone, P = .02) levels all decreased.
  
  
  CONCLUSIONS
  Antipsychotic dose reduction is feasible in patients with stable LLS, decreasing adverse effects and improving illness severity measures. The results of the present study suggest a lower therapeutic window of D2/3R occupancy in patients with LLS (50%-60%) than previously reported in younger patients (65%-80%).
authors.affiliation: Multimodal Imaging Group-Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, Faculty of Medicin.
authors.forename: Ariel
authors.initials: A
authors.lastname: Graff-Guerrero
authors.affiliation: Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada4Campbell Family Mental Health Research Institute, Centre for Add.
authors.forename: Tarek K
authors.initials: TK
authors.lastname: Rajji
authors.affiliation: Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada4Campbell Family Mental Health Research Institute, Centre for Add.
authors.forename: Benoit H
authors.initials: BH
authors.lastname: Mulsant
authors.affiliation: Multimodal Imaging Group-Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, Faculty of Medicin.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Multimodal Imaging Group-Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada6Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Fernando
authors.initials: F
authors.lastname: Caravaggio
authors.affiliation: Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada5Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uchida
authors.affiliation: Multimodal Imaging Group-Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, Faculty of Medicin.
authors.forename: Philip
authors.initials: P
authors.lastname: Gerretsen
authors.affiliation: Multimodal Imaging Group-Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Wanna
authors.initials: W
authors.lastname: Mar
authors.affiliation: Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada4Campbell Family Mental Health Research Institute, Centre for Add.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Pollock
authors.affiliation: Department of Psychiatry, Faculties of Medicine and Health Science, University of Malta, Msida.
authors.forename: David C
authors.initials: DC
authors.lastname: Mamo
mesh_terms: D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D001480:Basal Ganglia Diseases / Q000139:chemically induced / Q000378:metabolism; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017072:Neostriatum / Q000378:metabolism*; D000077152:Olanzapine; D049268:Positron-Emission Tomography; D011388:Prolactin / Q000097:blood; D011446:Prospective Studies; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D018967:Risperidone / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D001569:Benzodiazepines; D020891:Raclopride; D011388:Prolactin; D018967:Risperidone; D000077152:Olanzapine