Dose Reduction of Risperidone and Olanzapine and Estimated Dopamine D<sub>2</sub> Receptor Occupancy in Stable Patients With Schizophrenia: Findings From an Open-Label, Randomized, Controlled Study
Hiroyoshi Takeuchi, MD, PhD; Takefumi Suzuki, MD, PhD; Robert R. Bies, PhD; Gary Remington, MD, PhD; Koichiro Watanabe, MD, PhD; Masaru Mimura, MD, PhD; and Hiroyuki Uchida, MD, PhD
J Clin Psychiatry 2014;75(11):1209–1214
10.4088/JCP.13m08841
© Copyright 2015 Physicians Postgraduate Press, Inc.
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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.
Trial Registration: UMIN Clinical Trials Registry identifier: UMIN000001834