Clinical Pharmacological Unit, Zealand University Hospital, Roskilde, Denmark.
Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospitals, Copenhagen, Denmark.
JAMA Netw Open. 2020 Dec 1;3(12):e2027909. doi: 10.1001/jamanetworkopen.2020.27909.
Genetic polymorphism of genes encoding the drug metabolizing enzymes, cytochrome P450 2D6 and 2C19 (CYP2D6 and CYP2C19), is associated with treatment failure of and adverse reactions to psychotropic drugs. The clinical utility of routine CYP2D6 and CYP2C19 genotyping (CYP testing) is unclear.
To estimate whether routine CYP testing effects the persistence of antipsychotic drug treatment.
DESIGN, SETTING, AND PARTICIPANTS: This single-masked, 3-group randomized clinical trial included patients aged 18 years or older who had been diagnosed within the schizophrenic spectrum (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes, F20-F29) and not previously genotyped. A total of 669 of 1406 potentially eligible patients from 12 psychiatric outpatient clinics in Denmark were approached between July 2008 and December 2009. Overall, 528 patients were genotyped and randomly allocated to 1 of 3 study groups or exclusion in a sequence of 1:1:1:3 using a predictive enrichment design, aiming to double the proportion of poor or ultrarapid metabolizers for CYP2D6 or CYP2C19. Outcome measurements were recorded at baseline and 1-year follow-up. Data analysis was performed in December 2012 and updated March 2019.
The trial included 2 intervention groups, where antipsychotic drug treatment was guided by either CYP test (CYP test-guided [CTG]) or structured clinical monitoring (SCM), in which adverse effects and factors influencing compliance were systematically recorded at least once quarterly, and 1 control group.
Primary outcome was antipsychotic drug persistence, ie, days to first modification of the initial treatment. Secondary outcomes were number of drug and dose changes, adverse effects, and psychotic symptoms, ie, hallucinations and delusions.
A total of 528 participants were genotyped, and 311 (median [interquartile range {IQR} age, 41 [30-50] years; 139 [45%] women; median [IQR] duration of illness, 6 [3-13] years) were randomly allocated to 1 of 3 study groups. Overall, 61 participants (20%) were extreme metabolizers. There was no difference in antipsychotic drug persistence between the CTG group and the control group (hazard ratio [HR], 1.02; 95% CI, 0.71-1.45) or SCM and the control group (HR, 0.88; 95% CI, 0.61-1.26). Subanalyses among extreme metabolizers showed similar results (CTG: HR, 0.99; 95% CI, 0.48-2.03; SCM: HR, 0.93; 95% CI, 0.44-1.96).
The results of this randomized clinical trial do not support routine CYP testing in patients with schizophrenia.
ClinicalTrials.gov Identifier: NCT00707382.
基因编码药物代谢酶细胞色素 P450 2D6 和 2C19（CYP2D6 和 CYP2C19）的遗传多态性与精神药物治疗失败和不良反应有关。常规 CYP2D6 和 CYP2C19 基因分型（CYP 检测）的临床效用尚不清楚。
评估常规 CYP 检测是否会影响抗精神病药物治疗的持续时间。
设计、设置和参与者：这是一项单盲、3 组随机临床试验，纳入了年龄在 18 岁或以上的、被诊断为精神分裂症谱系（国际疾病和相关健康问题统计分类第十版，F20-F29 编码）且之前未进行基因分型的患者。2008 年 7 月至 2009 年 12 月，丹麦 12 家精神病门诊诊所共招募了 1406 名潜在合格患者，其中 669 名患者接受了基因分型，并随机分配到 3 个研究组之一或按 1:1:1:3 的顺序排除在外，采用预测性富集设计，旨在将 CYP2D6 或 CYP2C19 的不良或超快代谢者的比例增加一倍。在基线和 1 年随访时记录了结果测量值。数据分析于 2012 年 12 月进行，并于 2019 年 3 月进行了更新。
该试验包括 2 个干预组，其中抗精神病药物治疗分别由 CYP 检测（CYP 检测指导[CTG]）或结构化临床监测（SCM）指导，在 SCM 中，至少每季度系统地记录一次不良反应和影响依从性的因素，以及 1 个对照组。
主要结果是抗精神病药物的持续时间，即首次调整初始治疗的天数。次要结果是药物和剂量的变化次数、不良反应和精神病症状（幻觉和妄想）。
共有 528 名参与者进行了基因分型，其中 311 名（中位数[IQR 年龄，41 [30-50] 岁；139 [45%] 名女性；中位数[IQR 疾病持续时间，6 [3-13] 年]）被随机分配到 3 个研究组之一。总体而言，61 名参与者（20%）为极端代谢者。CTG 组与对照组（危险比[HR]，1.02；95%置信区间，0.71-1.45）或 SCM 与对照组（HR，0.88；95%置信区间，0.61-1.26）之间的抗精神病药物持续时间无差异。极端代谢者的亚分析结果相似（CTG：HR，0.99；95%CI，0.48-2.03；SCM：HR，0.93；95%CI，0.44-1.96）。
这项随机临床试验的结果不支持对精神分裂症患者进行常规 CYP 检测。
ClinicalTrials.gov 标识符：NCT00707382。
