Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, Chiba, Japan.
J Clin Psychiatry. 2020 Jul 28;81(5):19r13113. doi: 10.4088/JCP.19r13113.
The objective of this study was to examine the extent of possible dissociation in pharmacokinetic decay between central dopamine D₂ receptor occupancy with antipsychotics and their peripheral blood concentrations.
MEDLINE and Embase were searched using the following keywords: (positron emission tomography OR PET OR single-photon emission computed tomography OR SPECT) AND (dopamine OR D2) AND (receptor* OR occupanc*) AND antipsychotic*, with a limitation of English language (last search: December 14, 2019).
The search identified 18 studies that met the following criteria: (1) including patients with schizophrenia spectrum disorders and/or healthy subjects, (2) using positron emission tomography or single-photon emission computed tomography, and (3) examining the time courses of D₂ occupancy with antipsychotics and their blood concentrations.
The ratios of D₂ occupancy reduction rate (%) from peak to blood concentration reduction rate (%) from peak (relative attenuation ratio) were calculated.
Among the studies, oral risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perospirone, haloperidol, sulpiride, and clozapine and long-acting injectable risperidone and haloperidol were included. Relative attenuation ratios were less than 1, indicating a slower central versus peripheral attenuation, across the time points for all antipsychotic types and doses with only a few exceptions. The ratio decreased in a dose-dependent as well as a peak D₂ occupancy-dependent fashion. It contrarily increased in a time-dependent manner.
The findings indicate pharmacokinetic attenuation of antipsychotics was generally slower at the central versus the peripheral level and pose a critical challenge to the current dosing strategy that primarily relies on peripheral pharmacokinetics of antipsychotics.
本研究旨在考察抗精神病药物的中枢多巴胺 D₂ 受体占有率与外周血浓度之间的药代动力学衰减是否存在分离。
使用以下关键词在 MEDLINE 和 Embase 上进行搜索：（正电子发射断层扫描 OR PET OR 单光子发射计算机断层扫描 OR SPECT）和（多巴胺 OR D2）和（受体* OR 占有率*）和抗精神病药*，限制为英语（最后一次搜索：2019 年 12 月 14 日）。
该搜索确定了 18 项符合以下标准的研究：（1）包括精神分裂症谱系障碍患者和/或健康受试者，（2）使用正电子发射断层扫描或单光子发射计算机断层扫描，（3）检查抗精神病药物的 D₂ 占有率和其血药浓度的时间过程。
计算 D₂ 占有率从峰值下降的百分比与血药浓度从峰值下降的百分比之间的比值（相对衰减比）。
研究中包括口服利培酮、奥氮平、喹硫平、阿立哌唑、齐拉西酮、哌罗匹隆、氟哌啶醇、舒必利和氯氮平，以及长效注射用利培酮和氟哌啶醇。除了少数例外，所有抗精神病药类型和剂量的相对衰减比均小于 1，表明在所有时间点，中枢衰减速度均慢于外周。该比值呈剂量依赖性和峰值 D₂ 占有率依赖性下降，而呈时间依赖性增加。
这些发现表明，抗精神病药物的药代动力学衰减在中枢与外周水平通常较慢，这对当前主要依赖抗精神病药物外周药代动力学的给药策略提出了严峻挑战。
