Rapid Metabolism Underlying Subtherapeutic Serum Levels of Atypical Antipsychotics Preceding Clozapine Treatment: A Retrospective Analysis of Real-World Data

IF 7.4 2区医学 Q1 CLINICAL NEUROLOGY

CNS drugs Pub Date : 2024-04-18 DOI:10.1007/s40263-024-01079-y

Hasan Çağın Lenk, Robert Løvsletten Smith, Kevin S. O’Connell, Ole A. Andreassen, Espen Molden

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Abstract

Introduction

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.

Methods

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.

Results

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).

Conclusion

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.

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非典型抗精神病药物在氯氮平治疗前血清中低于治疗水平的快速代谢：真实世界数据的回顾性分析

导言：在诊断出耐药性精神分裂症并开始氯氮平治疗之前，需要适当的抗精神病治疗强度。我们的目的是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原因。方法2005年至2023年期间，挪威奥斯陆的一家治疗药物监测服务机构纳入了在开始使用氯氮平前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。患者被分为低 CD (LCD) 和正常 CD (NCD) 亚组。使用包含 147,964 次抗精神病药物测量值的参考样本，LCD 被定义为低于第 25 百分位数的 CD，而 NCD 患者的 CD 值介于各自参考测量值的第 25 百分位数和第 75 百分位数之间。比较了 LCD 组和 NCD 组非氯氮平类抗精神病药物的代谢比率、剂量和治疗水平以下的频率。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）代谢比率较高。奥氮平（p = 0.008）和利培酮（p = 0.016）的代谢比率差异分别与吸烟和 CYP2D6 基因型无关。尽管 LCD 患者的奥氮平剂量（1.25 倍；p = 0.054）和喹硫平剂量（1.6 倍；p = 0.001）高于 NCD 患者，但前者的代谢速度更快，同时奥氮平达不到治疗水平的频率更高（3.结论在开始氯氮平治疗前，LCD 和相关的非氯氮平类抗精神病药物的快速代谢很常见。对于奥氮平和喹硫平，这与治疗浓度不足的风险显著增加有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS drugs 医学-精神病学

CiteScore

12.00

自引率

3.30%

发文量

审稿时长

6-12 weeks

期刊介绍： CNS Drugs promotes rational pharmacotherapy within the disciplines of clinical psychiatry and neurology. The Journal includes: - Overviews of contentious or emerging issues. - Comprehensive narrative reviews that provide an authoritative source of information on pharmacological approaches to managing neurological and psychiatric illnesses. - Systematic reviews that collate empirical evidence to answer a specific research question, using explicit, systematic methods as outlined by the PRISMA statement. - Adis Drug Reviews of the properties and place in therapy of both newer and established drugs in neurology and psychiatry. - Original research articles reporting the results of well-designed studies with a strong link to clinical practice, such as clinical pharmacodynamic and pharmacokinetic studies, clinical trials, meta-analyses, outcomes research, and pharmacoeconomic and pharmacoepidemiological studies. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in CNS Drugs may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand important medical advances.