Yoshida Kazunari, Bies Robert R, Suzuki Takefumi, Remington Gary, Pollock Bruce G, Mizuno Yuya, Mimura Masaru, Uchida Hiroyuki
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
Geriatric Mental Health Program, Centre for Addiction and Mental Health, Toronto, ON, Canada; Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA; Indiana Clinical and Translational Sciences Institute, Indianapolis, IN, USA.
Schizophr Res. 2014 Mar;153(1-3):184-8. doi: 10.1016/j.schres.2014.01.017. Epub 2014 Feb 1.
The objective of this study was to evaluate the relationship between antipsychotic-induced tardive dyskinesia (TD) and estimated dopamine D2 receptor occupancy levels in patients with schizophrenia, using the dataset from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE).
The dataset from 218 subjects (risperidone, N=78; olanzapine, N=100; ziprasidone, N=40) who presented with a score of zero on the Abnormal Involuntary Movement Scale (AIMS) at baseline in Phase 1 of the CATIE study, and remained for ≥6months, was used. Peak and trough dopamine D2 receptor occupancy levels on the day of the AIMS assessment at the endpoint were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our D2 prediction model. The estimated dopamine D2 receptor occupancy levels were compared between patients who presented an AIMS score of ≥2 at endpoint and those with a score of zero, using the Mann-Whitney U test.
Estimated dopamine D2 receptor occupancy levels at trough were significantly higher in subjects who developed involuntary movements (N=23) than those who did not (N=195) (71.7±14.4% vs. 64.3±19.3%, p<0.05) while no significant difference was found in the estimated peak D2 receptor occupancy between them (75.4±8.7% vs. 72.1±9.9%, p=0.07). When the analyses were separately conducted for the three drugs, there were no significant differences in estimated peak or trough D2 occupancy although the values were consistently numerically higher among those developing involuntary movements.
Greater dopamine D2 receptor blockade with antipsychotics at trough might increase the risk of tardive involuntary movements although this finding needs to be replicated in larger trials.
本研究旨在利用临床抗精神病药物干预有效性试验（CATIE）的数据，评估精神分裂症患者中抗精神病药物所致迟发性运动障碍（TD）与估计的多巴胺D2受体占有率水平之间的关系。
使用CATIE研究第1阶段基线时异常不自主运动量表（AIMS）评分为零且持续≥6个月的218名受试者（利培酮，N = 78；奥氮平，N = 100；齐拉西酮，N = 40）的数据。使用群体药代动力学分析和我们的D2预测模型，根据血浆抗精神病药物浓度估算终点时AIMS评估当天的多巴胺D2受体占有率峰值和谷值水平。使用Mann-Whitney U检验比较终点时AIMS评分≥2的患者与评分为零的患者之间估计的多巴胺D2受体占有率水平。
出现不自主运动的受试者（N = 23）的谷值时估计多巴胺D2受体占有率水平显著高于未出现不自主运动的受试者（N = 195）（71.7±14.4%对64.3±19.3%，p<0.05），而两者之间的估计峰值D2受体占有率无显著差异（75.4±8.7%对72.1±9.9%，p = 0.07）。对三种药物分别进行分析时，估计的峰值或谷值D2占有率无显著差异，尽管在出现不自主运动的患者中这些值在数值上始终较高。
抗精神病药物在谷值时对多巴胺D2受体的更大阻断可能会增加迟发性不自主运动的风险，尽管这一发现需要在更大规模的试验中得到重复验证。
