Lock Siobhan K, Legge Sophie E, Kappel Djenifer B, Willcocks Isabella R, Helthuis Marinka, Jansen John, Walters James T R, Owen Michael J, O'Donovan Michael C, Pardiñas Antonio F
Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Leyden Delta B.V., Nijmegen, The Netherlands.
Schizophrenia (Heidelb). 2023 Oct 18;9(1):74. doi: 10.1038/s41537-023-00404-6.
Clozapine is effective at reducing symptoms of treatment-resistant schizophrenia, but it can also induce several adverse outcomes including neutropenia and agranulocytosis. We used linear mixed-effect models and structural equation modelling to determine whether pharmacokinetic and genetic variables influence absolute neutrophil count in a longitudinal UK-based sample of clozapine users not currently experiencing neutropenia (N = 811). Increased daily clozapine dose was associated with elevated neutrophil count, amounting to a 133 cells/mm rise per standard deviation increase in clozapine dose. One-third of the total effect of clozapine dose was mediated by plasma clozapine and norclozapine levels, which themselves demonstrated opposing, independent associations with absolute neutrophil count. Finally, CYP1A2 pharmacogenomic activity score was associated with absolute neutrophil count, supporting lower neutrophil levels in CYP1A2 poor metabolisers during clozapine use. This information may facilitate identifying at-risk patients and then introducing preventative interventions or individualised pharmacovigilance procedures to help mitigate these adverse haematological reactions.
氯氮平对减轻难治性精神分裂症的症状有效，但它也会引发包括中性粒细胞减少和粒细胞缺乏症在内的多种不良后果。我们使用线性混合效应模型和结构方程模型，来确定药代动力学和基因变量是否会影响英国一个纵向样本中目前未出现中性粒细胞减少的氯氮平使用者的绝对中性粒细胞计数（N = 811）。氯氮平每日剂量增加与中性粒细胞计数升高相关，氯氮平剂量每增加一个标准差，中性粒细胞计数就会增加133个细胞/mm³。氯氮平剂量总效应的三分之一由血浆氯氮平和去甲氯氮平水平介导，而这两种物质本身与绝对中性粒细胞计数呈现相反的独立关联。最后，CYP1A2药物基因组学活性评分与绝对中性粒细胞计数相关，这表明在使用氯氮平期间，CYP1A2代谢不良者的中性粒细胞水平较低。这些信息可能有助于识别有风险的患者，进而引入预防性干预措施或个性化药物警戒程序，以帮助减轻这些不良血液学反应。
