Dopamine D2 Receptor Occupancy and Cognition in Schizophrenia: Analysis of the CATIE Data
Dopamine D2 Receptor Occupancy and Cognition in Schizophrenia: Analysis of the CATIE Data
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DOI：
10.1093/schbul/sbr189
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发表时间：
2013-05-01
影响因子：
6.6
通讯作者：
Uchida, Hiroyuki
中科院分区：
文献类型：
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作者：
Sakurai, Hitoshi;Bies, Robert R.;Uchida, Hiroyuki
前言：抗精神病药物通过阻断多巴胺D-2受体发挥抗精神病作用，治疗精神分裂症。然而，D-2受体阻滞剂对神经认知功能的影响仍有待阐明。本分析的目的是评估在临床抗精神病药物干预有效性试验（CATIE）中，抗精神病药物估计的多巴胺D-2受体结合率对精神分裂症患者神经认知功能几个领域的影响。方法：本分析使用CATIE试验的数据集。从410例接受利培酮、奥氮平或齐拉西酮治疗的受试者中提取数据，接受神经认知功能（言语记忆、警惕性、处理速度、推理和工作记忆）和精神病理学评估，并提供血浆样本用于测量血浆抗精神病药物浓度。使用群体药代动力学分析和我们最近开发的模型，从血浆抗精神病药浓度估计神经认知评估当天的D-2受体占用水平。采用多变量一般线性模型研究临床和人口统计学特征（包括估计的D-2占用水平）对神经认知功能的影响。结果：D-2占用水平与警觉性和概括性得分显着相关。神经认知功能，包括警觉性，在显示D-2受体占用水平> 77%的受试者中尤其受损。讨论：这些结果表明，处方抗精神病药物剂量与整体神经认知功能和警觉性之间存在非线性关系。这项研究表明，1）2占用率超过约80%不仅会增加锥体外系副作用的风险，正如文献中一致报道的那样，还会增加认知障碍的风险。
Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D-2 receptors in the treatment of schizophrenia. However, effects of D-2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D-2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D-2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D-2 occupancy levels, on neurocognitive functions. Results: D-2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D-2 receptor occupancy level of >77%. Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that 1)2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.