Jiang Ping, Sun Xiujia, Ren Juanjuan, Liu Hongmei, Lin Zhiguang, Liu Junwen, Fang Xinyu, Zhang Chen
Department of Biochemistry and Psychopharmacology, Shanghai Mental Health Center, Shanghai, China.
Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China.
Gen Psychiatr. 2021 Mar 29;34(2):e100423. doi: 10.1136/gpsych-2020-100423. eCollection 2021.
Aripiprazole (ARI) is often prescribed alone or in combination with other second-generation antipsychotics (SGAs) to treat patients with schizophrenia. However, this may increase the potential clinical significance of drug-drug interactions. Therapeutic drug monitoring (TDM) is an important and fundamental tool both when administering ARI alone and in combination with other SGAs to monitor ARI pharmacokinetics, adjust the dosage and thereby achieve more effective and safer treatment.
This study retrospectively investigated the effects of four SGA comedications (clozapine, risperidone, quetiapine (QTP) and olanzapine) and other potential factors (sex, age and ARI dose) on the serum concentrations of ARI and dehydroaripiprazole (DARI) in Chinese patients with schizophrenia using TDM data.
High-performance liquid chromatography was used to test the serum concentrations of ARI, DARI and ARI+DARI. In addition, steady-state dose-adjusted serum concentrations (ie, concentration-to-dose ratios, C:D ratios) of ARI, DARI and ARI+DARI; sex; age; ARI dose and SGA comedication dose between 299 inpatients with schizophrenia who received ARI or SGA comedication were all collected and analysed. Spearman's correlation and multiple linear regression analysis were used to evaluate bivariate associations between ARI dose and serum ARI and DARI concentrations and describe the effect of independent variables on serum ARI and DARI concentrations, respectively.
There were significant differences in the C:D ratios of ARI (χ=-3.21, p=0.001) and ARI+DARI (χ=-2.50, p=0.01) between the ARI and SGA groups, as well as in the C:D ratios of ARI (χ=-3.59, p<0.001) and ARI+DARI (χ=-3.10, p=0.002) between the female patients in the two groups. Of the four SGAs, only QTP had significant effects on the C:D ratios of ARI (Z=-4.12, p<0.001) and ARI+DARI (Z=-3.62, p<0.001) when compared with the ARI group in the whole sample and on the C:D ratios of ARI, DARI and ARI+DARI (Z=-3.96, p0.001; Z=-2.22, p=0.03; Z=-3.75, p<0.001, respectively) in women when compared with their counterparts in the ARI group.
Comedication with SGAs resulted in lower C:D ratios of ARI and ARI+DARI compared with ARI monotherapy, and comedication with QTP resulted in lower C:D ratios of ARI and ARI+DARI than ARI monotherapy. Despite this statistical significance of our findings, whether the presently observed effect has clinical significance requires exploration by further research. TDM and dosage regulation of ARI should be performed in Chinese inpatients with schizophrenia who are receiving SGA comedication (especially QTP) to maintain a safe and effective dose-adjusted serum concentration of ARI and DARI.
阿立哌唑（ARI）常单独或与其他第二代抗精神病药物（SGA）联合使用，用于治疗精神分裂症患者。然而，这可能会增加药物相互作用的潜在临床意义。治疗药物监测（TDM）是单独使用ARI以及与其他SGA联合使用时监测ARI药代动力学、调整剂量从而实现更有效和更安全治疗的一项重要且基础的工具。
本研究利用TDM数据回顾性调查了四种SGA联合用药（氯氮平、利培酮、喹硫平（QTP）和奥氮平）以及其他潜在因素（性别、年龄和ARI剂量）对中国精神分裂症患者血清中ARI和脱氢阿立哌唑（DARI）浓度的影响。
采用高效液相色谱法检测ARI、DARI和ARI + DARI的血清浓度。此外，收集并分析了299例接受ARI或SGA联合用药的精神分裂症住院患者的ARI、DARI和ARI + DARI的稳态剂量调整血清浓度（即浓度与剂量比，C:D比）、性别、年龄、ARI剂量和SGA联合用药剂量。采用Spearman相关性分析和多元线性回归分析分别评估ARI剂量与血清ARI和DARI浓度之间的双变量关联，并描述自变量对血清ARI和DARI浓度的影响。
ARI组与SGA组之间ARI（χ=-3.21，p = 0.001）和ARI + DARI（χ=-2.50，p = 0.01）的C:D比存在显著差异，两组女性患者之间ARI（χ=-3.59，p < 0.001）和ARI + DARI（χ=-3.10，p = 0.002）的C:D比也存在显著差异。在四种SGA中，与整个样本中的ARI组相比，仅QTP对ARI（Z=-4.12，p < 0.001）和ARI + DARI（Z=-3.62，p < 0.001）的C:D比有显著影响，与ARI组中的女性患者相比，QTP对女性患者的ARI、DARI和ARI + DARI的C:D比也有显著影响（分别为Z=-3.96，p < 0.001；Z=-2.22，p = 0.03；Z=-3.75，p < 0.001）。
与ARI单药治疗相比，SGA联合用药导致ARI和ARI + DARI的C:D比更低，与ARI单药治疗相比，QTP联合用药导致ARI和ARI + DARI的C:D比更低。尽管我们的研究结果具有统计学意义，但目前观察到的效应是否具有临床意义需要进一步研究探索。对于接受SGA联合用药（尤其是QTP）的中国精神分裂症住院患者，应进行ARI的TDM和剂量调整，以维持ARI和DARI安全有效的剂量调整血清浓度。
