Skokou Maria, Karavia Eleni A, Drakou Zoi, Konstantinopoulou Vassiliki, Kavakioti Christina-Anna, Gourzis Philippos, Kypreos Kyriakos E, Andreopoulou Ourania
Department of Psychiatry, General University Hospital of Patras, School of Medicine, University of Patras, 26504 Patras, Greece.
Department of Pharmacology, School of Medicine, University of Patras, 26504 Patras, Greece.
Pharmaceuticals (Basel). 2022 Jul 1;15(7):817. doi: 10.3390/ph15070817.
Clozapine is the gold standard for treatment-resistant schizophrenia. Serious and even life-threatening adverse effects, mostly granulocytopenia, myocarditis, and constipation, are of great clinical concern and constitute a barrier to prescribing clozapine, thus depriving many eligible patients of a lifesaving treatment option. Interestingly, clozapine presents variable pharmacokinetics affected by numerous parameters, leading to significant inter- and intra-individual variation. Therefore, therapeutic drug monitoring of plasma clozapine levels confers a significant benefit in everyday clinical practice by increasing the confidence of the prescribing doctor to the drug and the adherence of the patient to the treatment, mainly by ensuring effective treatment and limited dose-related side effects. In the present systematic review, we aimed at identifying how a full range of adverse effects relates to plasma clozapine levels, using the Jadad grading system for assessing the quality of the available clinical evidence. Our findings indicate that EEG slowing, obsessive-compulsive symptoms, heart rate variability, hyperinsulinemia, metabolic syndrome, and constipation correlate to plasma clozapine levels, whereas QTc, myocarditis, sudden death, leucopenia, neutropenia, sialorrhea, are rather unrelated. Rapid dose escalation at the initiation of treatment might contribute to the emergence of myocarditis, or leucopenia. Strategies for managing adverse effects are different in these conditions and are discussed accordingly.
氯氮平是难治性精神分裂症的治疗金标准。严重甚至危及生命的不良反应，主要是粒细胞减少、心肌炎和便秘，引起了极大的临床关注，构成了开具氯氮平处方的障碍，从而使许多符合条件的患者无法获得这种救命的治疗选择。有趣的是，氯氮平呈现出受众多参数影响的可变药代动力学，导致个体间和个体内存在显著差异。因此，血浆氯氮平水平的治疗药物监测在日常临床实践中具有显著益处，主要通过确保有效治疗和限制剂量相关的副作用，提高开处方医生对药物的信心以及患者对治疗的依从性。在本系统评价中，我们旨在使用Jadad评分系统评估现有临床证据的质量，确定一系列不良反应与血浆氯氮平水平之间的关系。我们的研究结果表明，脑电图减慢、强迫症状、心率变异性、高胰岛素血症、代谢综合征和便秘与血浆氯氮平水平相关，而QTc、心肌炎、猝死、白细胞减少、中性粒细胞减少、流涎则与之关系不大。治疗开始时快速增加剂量可能会导致心肌炎或白细胞减少的出现。在这些情况下，管理不良反应的策略各不相同，并将相应进行讨论。
