Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Schizophr Bull. 2013 May;39(3):564-74. doi: 10.1093/schbul/sbr189. Epub 2012 Jan 30.
Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 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.
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. D2 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 D2 occupancy levels, on neurocognitive functions.
D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%.
These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 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.
抗精神病药物通过阻断精神分裂症治疗中的多巴胺 D2 受体发挥抗精神病作用。然而，D2 受体阻断对神经认知功能的影响仍有待阐明。本分析的目的是评估抗精神病药物对精神分裂症患者神经认知功能多个领域的影响，这是通过 Clinical Antipsychotic Trials in Intervention Effectiveness（CATIE）试验中的估计多巴胺 D2 受体占有率来实现的。
本分析使用了 CATIE 试验的数据。从接受利培酮、奥氮平或齐拉西酮治疗、接受神经认知功能（言语记忆、警觉性、处理速度、推理和工作记忆）和精神病理学评估以及提供用于测量血浆抗精神病药物浓度的血浆样本的 410 名受试者中提取数据。使用群体药代动力学分析和我们最近开发的模型，从血浆抗精神病药物浓度估算神经认知评估日的 D2 受体占有率水平。使用多变量一般线性模型检查临床和人口统计学特征（包括估计的 D2 占有率水平）对神经认知功能的影响。
D2 占有率水平与警觉性和综合评分显著相关。警觉性等神经认知功能在 D2 受体占有率水平>77%的受试者中受损尤为明显。
这些发现表明，规定的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。本研究表明，D2 占有率高于约 80%不仅会增加文献中一致报道的锥体外系副作用风险，而且还会增加认知障碍的风险。
