Department of Pharmacology, University of Reims Champagne-Ardenne, HERVI EA 3801, Reims University Hospital, Reims, France.
Department of Psychiatry, Marne Public Mental Health Institution, Reims University Hospital, Reims, France.
Clin Pharmacokinet. 2023 Jun;62(6):807-818. doi: 10.1007/s40262-023-01247-1. Epub 2023 May 5.
Although therapeutic drug monitoring of clozapine is recommended, its optimisation is often adjusted only on the basis of dosage. The aim of this study was to assess the link between clozapine plasma concentrations and clinical response by a meta-analysis of published studies and by an individual participant data meta-analysis.
We conducted a computerised search of bibliographic databases (EMBASE, PubMed, Clinical Trials, and Web of Science) to identify studies that assessed the relationship between clozapine serum or plasma concentrations and clinical efficacy. Using pooled data, we investigated the association between improvement of clinical outcome and clozapine or norclozapine plasma concentrations, the sum of clozapine and norclozapine plasma concentrations, and the coefficient of variation of clozapine plasma concentrations. Using available individual data, we assessed the relationship between clozapine plasma concentrations and clinical response (changes in the Brief Psychiatric Rating Scale score) and identified a threshold level for a favourable clinical response.
Fifteen studies satisfied inclusion criteria. Our meta-analysis showed that responders had clozapine plasma concentrations that were, on average, 117 ng/mL higher than non-responders. The patients with plasma clozapine concentrations above the thresholds identified in each study had a higher likelihood of responding (odds ratio = 2.94, p < 0.001). Norclozapine plasma concentrations were not associated with a clinical response. The meta-analysis of individual data supported this result and confirmed the link between clozapine concentrations and a change in the Brief Psychiatric Rating Scale score and/or the probability of clinical response. Finally, with the analysis of the coefficient of variation of clozapine plasma concentrations, we found that a greater inter-individual fluctuation in plasma concentrations was associated with a loss of clinical response.
Our work confirmed that, in contrast to clozapine doses, clozapine plasma concentrations were related to a favourable clinical response, with a mean difference between responders and non-responders of 117 ng/mL. A threshold for a treatment response of 407 ng/mL was determined, with a high discriminatory capacity, and a sensitivity and specificity of 71% and 89.1%, respectively.
尽管推荐对氯氮平进行治疗药物监测，但通常仅根据剂量来调整其优化。本研究的目的是通过对已发表研究的荟萃分析和个体参与者数据荟萃分析，评估氯氮平血浆浓度与临床反应之间的关系。
我们对文献数据库（EMBASE、PubMed、ClinicalTrials 和 Web of Science）进行了计算机检索，以确定评估氯氮平血清或血浆浓度与临床疗效之间关系的研究。我们使用汇总数据，研究了临床结局改善与氯氮平或去甲氯氮平血浆浓度、氯氮平和去甲氯氮平血浆浓度之和以及氯氮平血浆浓度变异系数之间的关系。使用可用的个体数据，我们评估了氯氮平血浆浓度与临床反应（简明精神病评定量表评分的变化）之间的关系，并确定了有利临床反应的阈值水平。
有 15 项研究符合纳入标准。我们的荟萃分析表明，反应者的氯氮平血浆浓度平均比无反应者高 117ng/mL。在每项研究中确定的血浆氯氮平浓度阈值以上的患者，其反应可能性更高（优势比=2.94，p<0.001）。去甲氯氮平血浆浓度与临床反应无关。个体数据的荟萃分析支持这一结果，并证实了氯氮平浓度与简明精神病评定量表评分的变化以及临床反应的可能性之间的关系。最后，通过分析氯氮平血浆浓度的变异系数，我们发现血浆浓度的个体间波动较大与临床反应丧失有关。
我们的工作证实，与氯氮平剂量不同，氯氮平血浆浓度与有利的临床反应相关，反应者和无反应者之间的平均差异为 117ng/mL。确定了一个治疗反应的阈值为 407ng/mL，具有较高的区分能力，敏感性和特异性分别为 71%和 89.1%。
