Dose reduction of risperidone and olanzapine and estimated dopamine D<inf>2</inf> receptor occupancy in stable patients with schizophrenia: Findings from an open-label, randomized, controlled study

Hiroyoshi Takeuchi, Takefumi Suzuki, Robert Bies, Gary Remington, Koichiro Watanabe, Masaru Mimura, Hiroyuki Uchida

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: While acute-phase antipsychotic response has been attributed to 65%-80% dopamine D<inf>2</inf> receptor blockade, the degree of occupancy for relapse prevention in the maintenance treatment of schizophrenia remains unknown. Method: 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 D<inf>2</inf> 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 D<inf>2</inf> 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 D<inf>2</inf> 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 D<inf>2</inf> 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.

Original languageEnglish
Pages (from-to)1209-1214
Number of pages6
JournalJournal of Clinical Psychiatry
Volume75
Issue number11
DOIs
StatePublished - Nov 1 2014

Fingerprint

olanzapine
Risperidone
Dopamine D2 Receptors
Antipsychotic Agents
Schizophrenia
Maintenance
Dopamine
Acute-Phase Reaction
Delusions
Secondary Prevention
Diagnostic and Statistical Manual of Mental Disorders
Positron-Emission Tomography
Randomized Controlled Trials
Pharmacokinetics
Recurrence
Dose
Controlled
Therapeutics
Population

ASJC Scopus subject areas

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

Cite this

Dose reduction of risperidone and olanzapine and estimated dopamine D<inf>2</inf> receptor occupancy in stable patients with schizophrenia : Findings from an open-label, randomized, controlled study. / Takeuchi, Hiroyoshi; Suzuki, Takefumi; Bies, Robert; Remington, Gary; Watanabe, Koichiro; Mimura, Masaru; Uchida, Hiroyuki.

In: Journal of Clinical Psychiatry, Vol. 75, No. 11, 01.11.2014, p. 1209-1214.

Research output: Contribution to journalArticle

Takeuchi, Hiroyoshi ; Suzuki, Takefumi ; Bies, Robert ; Remington, Gary ; Watanabe, Koichiro ; Mimura, Masaru ; Uchida, Hiroyuki. / Dose reduction of risperidone and olanzapine and estimated dopamine D<inf>2</inf> receptor occupancy in stable patients with schizophrenia : Findings from an open-label, randomized, controlled study. In: Journal of Clinical Psychiatry. 2014 ; Vol. 75, No. 11. pp. 1209-1214.
@article{8edf5188ec694ac0a0aa259729f91b7d,
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. Method: 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.",
author = "Hiroyoshi Takeuchi and Takefumi Suzuki and Robert Bies and Gary Remington and Koichiro Watanabe and Masaru Mimura and Hiroyuki Uchida",
year = "2014",
month = "11",
day = "1",
doi = "10.4088/JCP.13m08841",
language = "English",
volume = "75",
pages = "1209--1214",
journal = "Journal of Clinical Psychiatry",
issn = "0160-6689",
publisher = "Physicians Postgraduate Press Inc.",
number = "11",

}

TY - JOUR

T1 - Dose reduction of risperidone and olanzapine and estimated dopamine D2 receptor occupancy in stable patients with schizophrenia

T2 - Findings from an open-label, randomized, controlled study

AU - Takeuchi, Hiroyoshi

AU - Suzuki, Takefumi

AU - Bies, Robert

AU - Remington, Gary

AU - Watanabe, Koichiro

AU - Mimura, Masaru

AU - Uchida, Hiroyuki

PY - 2014/11/1

Y1 - 2014/11/1

N2 - 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. Method: 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.

AB - 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. Method: 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.

UR - http://www.scopus.com/inward/record.url?scp=84927566215&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84927566215&partnerID=8YFLogxK

U2 - 10.4088/JCP.13m08841

DO - 10.4088/JCP.13m08841

M3 - Article

C2 - 25099201

AN - SCOPUS:84927566215

VL - 75

SP - 1209

EP - 1214

JO - Journal of Clinical Psychiatry

JF - Journal of Clinical Psychiatry

SN - 0160-6689

IS - 11

ER -