Center for Psychopharmacology, Diakonhjemmet Hospital, Vinderen, PO Box 85, 0319, Oslo, Norway.
Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway.
CNS Drugs. 2024 Jun;38(6):473-480. doi: 10.1007/s40263-024-01079-y. Epub 2024 Apr 18.
Adequate antipsychotic treatment intensity is required before diagnosing resistant schizophrenia and initiating clozapine treatment. We aimed to investigate potential rapid drug metabolism underlying low dose-adjusted serum concentration (CD) of non-clozapine atypical antipsychotics preceding clozapine treatment.
Patients using non-clozapine, atypical antipsychotics (aripiprazole, risperidone, olanzapine, or quetiapine) within 1 year before starting clozapine were included in this study from a therapeutic drug monitoring service in Oslo, Norway, between 2005 and 2023. Patients were assigned into low CD (LCD) and normal CD (NCD) subgroups. Using a reference sample with 147,964 antipsychotic measurements, LCD was defined as CDs below the 25th percentile, while patients with NCD exhibited CDs between the 25th and 75th percentile of the respective reference measurements. Metabolic ratios, doses, and frequency of subtherapeutic levels of non-clozapine antipsychotics were compared between LCD and NCD groups.
Preceding clozapine treatment, 110 out of 272 included patients (40.4%) were identified with LCD. Compared with the NCD group, LCD patients exhibited higher metabolic ratios of olanzapine (1.5-fold; p < 0.001), quetiapine (3.0-fold; p < 0.001), and risperidone (6.0-fold; p < 0.001). Metabolic ratio differences were independent of smoking and CYP2D6 genotype for olanzapine (p = 0.008) and risperidone (p = 0.016), respectively. Despite higher doses of olanzapine (1.25-fold; p = 0.054) and quetiapine (1.6-fold; p = 0.001) in LCD versus NCD patients, faster metabolism among the former was accompanied by higher frequencies of subtherapeutic levels of olanzapine (3.3-fold; p = 0.044) and quetiapine (1.8-fold; p = 0.005).
LCD and associated rapid metabolism of non-clozapine antipsychotics is frequent before starting clozapine treatment. For olanzapine and quetiapine, this is associated with significantly increased risk of having subtherapeutic concentrations.
在诊断抗精神病药物难治性精神分裂症和开始氯氮平治疗之前，需要进行足够的抗精神病药物治疗强度。我们旨在研究氯氮平治疗前非氯氮平非典型抗精神病药物低剂量调整血清浓度（CD）的潜在快速药物代谢。
本研究纳入了 2005 年至 2023 年期间，挪威奥斯陆治疗药物监测服务中使用氯氮平前 1 年内使用非氯氮平非典型抗精神病药物（阿立哌唑、利培酮、奥氮平或喹硫平）的患者。患者分为低 CD（LCD）和正常 CD（NCD）亚组。使用包含 147964 种抗精神病药物测量值的参考样本，LCD 定义为低于第 25 百分位数的 CD，而 NCD 患者的 CD 则介于各自参考测量值的第 25 至 75 百分位数之间。比较了 LCD 和 NCD 组之间非氯氮平抗精神病药物的代谢比率、剂量和亚治疗水平的频率。
在开始氯氮平治疗之前，272 名纳入患者中有 110 名（40.4%）被确定为 LCD。与 NCD 组相比，LCD 患者的奥氮平（1.5 倍；p < 0.001）、喹硫平（3.0 倍；p < 0.001）和利培酮（6.0 倍；p < 0.001）的代谢比率更高。奥氮平和利培酮的代谢比率差异分别独立于吸烟和 CYP2D6 基因型（奥氮平：p = 0.008；利培酮：p = 0.016）。尽管与 NCD 患者相比，LCD 患者的奥氮平和喹硫平剂量更高（奥氮平：1.25 倍；p = 0.054；喹硫平：1.6 倍；p = 0.001），但前者的代谢更快，奥氮平和喹硫平的亚治疗水平频率更高（奥氮平：3.3 倍；p = 0.044；喹硫平：1.8 倍；p = 0.005）。
在开始氯氮平治疗之前，非氯氮平非典型抗精神病药物的 LCD 及其相关的快速代谢很常见。对于奥氮平和喹硫平，这与亚治疗浓度的风险显著增加有关。
