Evaluation of antipsychotic dose reduction in late-life schizophrenia: A prospective dopamine D<inf>2/3</inf> receptor occupancy study

Ariel Graff-Guerrero, Tarek K. Rajji, Benoit H. Mulsant, Shinichiro Nakajima, Fernando Caravaggio, Takefumi Suzuki, Hiroyuki Uchida, Philip Gerretsen, Wanna Mar, Bruce G. Pollock, David C. Mamo

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Abstract

IMPORTANCE 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 D<inf>2/3</inf> receptor (D<inf>2/3</inf>R) occupancies remain largely unexplored in patients with LLS. OBJECTIVE To evaluate effects of antipsychotic dose reduction on striatal dopamine D<inf>2/3</inf>R occupancies, clinical variables, and blood pharmacokinetic measures in patients with LLS. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS 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. MAIN OUTCOMES AND MEASURES Striatal dopamine D<inf>2/3</inf>R 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 D<inf>2/3</inf>R 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 D<inf>2/3</inf>R occupancy associated with clinical stabilitywas 50%. Extrapyramidal symptoms (EPSs)were more likely to occur with D<inf>2/3</inf>R 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 D<inf>2/3</inf>R occupancies higher than 60%. The baseline D<inf>2/3</inf>R occupancieswere 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 AND RELEVANCE 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 D<inf>2/3</inf>R occupancy in patients with LLS (50%-60%) than previously reported in younger patients (65%-80%).

Original languageEnglish
Pages (from-to)927-934
Number of pages8
JournalJAMA Psychiatry
Volume72
Issue number9
DOIs
Publication statusPublished - 2015 Sep 1

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Dopamine D2 Receptors
Antipsychotic Agents
Schizophrenia
Corpus Striatum
Brief Psychiatric Rating Scale
Pharmacokinetics
olanzapine
Drug-Induced Akathisia
Raclopride
Equipment and Supplies
Risperidone
Ambulatory Care
Dose
Dopamine
Evaluation
Tertiary Care Centers
Prolactin
Positron-Emission Tomography
Outpatients
Carbon

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Psychiatry and Mental health

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Evaluation of antipsychotic dose reduction in late-life schizophrenia : A prospective dopamine D<inf>2/3</inf> receptor occupancy study. / Graff-Guerrero, Ariel; Rajji, Tarek K.; Mulsant, Benoit H.; Nakajima, Shinichiro; Caravaggio, Fernando; Suzuki, Takefumi; Uchida, Hiroyuki; Gerretsen, Philip; Mar, Wanna; Pollock, Bruce G.; Mamo, David C.

In: JAMA Psychiatry, Vol. 72, No. 9, 01.09.2015, p. 927-934.

Research output: Contribution to journalArticle

Graff-Guerrero, A, Rajji, TK, Mulsant, BH, Nakajima, S, Caravaggio, F, Suzuki, T, Uchida, H, Gerretsen, P, Mar, W, Pollock, BG & Mamo, DC 2015, 'Evaluation of antipsychotic dose reduction in late-life schizophrenia: A prospective dopamine D<inf>2/3</inf> receptor occupancy study', JAMA Psychiatry, vol. 72, no. 9, pp. 927-934. https://doi.org/10.1001/jamapsychiatry.2015.0891
Graff-Guerrero, Ariel ; Rajji, Tarek K. ; Mulsant, Benoit H. ; Nakajima, Shinichiro ; Caravaggio, Fernando ; Suzuki, Takefumi ; Uchida, Hiroyuki ; Gerretsen, Philip ; Mar, Wanna ; Pollock, Bruce G. ; Mamo, David C. / Evaluation of antipsychotic dose reduction in late-life schizophrenia : A prospective dopamine D<inf>2/3</inf> receptor occupancy study. In: JAMA Psychiatry. 2015 ; Vol. 72, No. 9. pp. 927-934.
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abstract = "IMPORTANCE 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. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS 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. MAIN OUTCOMES AND MEASURES 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 Unders{\o}gelser 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 stabilitywas 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 occupancieswere 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 Unders{\o}gelser 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 AND RELEVANCE 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{\%}).",
author = "Ariel Graff-Guerrero and Rajji, {Tarek K.} and Mulsant, {Benoit H.} and Shinichiro Nakajima and Fernando Caravaggio and Takefumi Suzuki and Hiroyuki Uchida and Philip Gerretsen and Wanna Mar and Pollock, {Bruce G.} and Mamo, {David C.}",
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TY - JOUR

T1 - Evaluation of antipsychotic dose reduction in late-life schizophrenia

T2 - A prospective dopamine D2/3 receptor occupancy study

AU - Graff-Guerrero, Ariel

AU - Rajji, Tarek K.

AU - Mulsant, Benoit H.

AU - Nakajima, Shinichiro

AU - Caravaggio, Fernando

AU - Suzuki, Takefumi

AU - Uchida, Hiroyuki

AU - Gerretsen, Philip

AU - Mar, Wanna

AU - Pollock, Bruce G.

AU - Mamo, David C.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - IMPORTANCE 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. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS 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. MAIN OUTCOMES AND MEASURES 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 stabilitywas 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 occupancieswere 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 AND RELEVANCE 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%).

AB - IMPORTANCE 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. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS 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. MAIN OUTCOMES AND MEASURES 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 stabilitywas 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 occupancieswere 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 AND RELEVANCE 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%).

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