Thiele Liv S, Ishtiak-Ahmed Kazi, Thirstrup Janne P, Agerbo Esben, Lunenburg Carin A T C, Müller Daniel J, Gasse Christiane
Department of Affective Disorders, Aarhus University Hospital Psychiatry, 8200 Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark.
Pharmaceuticals (Basel). 2022 Jul 14;15(7):870. doi: 10.3390/ph15070870.
Background: The clinical impact of the functional CYP2C19 and CYP2D6 gene variants on antidepressant treatment in people with depression is not well studied. Here, we evaluate the utility of pharmacogenetic (PGx) testing in psychiatry by investigating the association between the phenotype status of the cytochrome P450 (CYP) 2C19/2D6 enzymes and the one-year risks of clinical outcomes in patients with depression with incident new-use of (es)citalopram, sertraline, or fluoxetine. Methods: This study is a population-based cohort study of 17,297 individuals who were born between 1981 and 2005 with a depression diagnosis between 1996 and 2012. Using array-based single-nucleotide-polymorphism genotype data, the individuals were categorized according to their metabolizing status of CYP2C19/CYP2D6 as normal (NM, reference group), ultra-rapid- (UM), rapid- (RM), intermediate- (IM), or poor-metabolizer (PM). The outcomes were treatment switching or discontinuation, psychiatric emergency department contacts, and suicide attempt/self-harm. By using Poisson regression analyses, we have estimated the incidence rate ratios (IRR) with 95% confidence intervals (95% CI) that were adjusted for covariates and potential confounders, by age groups (<18 (children and adolescents), 19−25 (young adults), and 26+ years (adults)), comparing the outcomes in individuals with NM status (reference) versus the mutant metabolizer status. For statistically significant outcomes, we have calculated the number needed to treat (NNT) and the number needed to genotype (NNG) in order to prevent one outcome. Results: The children and adolescents who were using (es)citalopram with CYP2C19 PM status had increased risks of switching (IRR = 1.64 [95% CI: 1.10−2.43]) and suicide attempt/self-harm (IRR = 2.67 [95% CI; 1.57−4.52]). The young adults with CYP2C19 PM status who were using sertraline had an increased risk of switching (IRR = 2.06 [95% CI; 1.03−4.11]). The young adults with CYP2D6 PM status who were using fluoxetine had an increased risk of emergency department contacts (IRR = 3.28 [95% CI; 1.11−9.63]). No significant associations were detected in the adults. The NNG for preventing one suicide attempt/suicide in the children who were using (es)citalopram was 463, and the NNT was 11. Conclusion: The CYP2C19 and CYP2D6 PM phenotype statuses were associated with outcomes in children, adolescents, and young adults with depression with incident new-use of (es)citalopram, sertraline, or fluoxetine, therefore indicating the utility of PGx testing, particularly in younger people, for PGx-guided antidepressant treatment.
细胞色素P450（CYP）2C19和CYP2D6基因功能变异对抑郁症患者抗抑郁治疗的临床影响尚未得到充分研究。在此，我们通过研究CYP2C19/2D6酶的表型状态与首次使用艾司西酞普兰、舍曲林或氟西汀的抑郁症患者临床结局的一年风险之间的关联，评估药物遗传学（PGx）检测在精神病学中的实用性。
本研究是一项基于人群的队列研究，研究对象为1981年至2005年出生、1996年至2012年被诊断为抑郁症的17297名个体。利用基于芯片的单核苷酸多态性基因型数据，根据个体的CYP2C19/CYP2D6代谢状态将其分为正常代谢者（NM，参照组）、超快代谢者（UM）、快代谢者（RM）、中速代谢者（IM）或慢代谢者（PM）。结局指标为治疗转换或停药、精神科急诊科就诊以及自杀未遂/自我伤害。通过泊松回归分析，我们估计了发病率比（IRR）及其95%置信区间（95%CI），并针对年龄组（<18岁（儿童和青少年）、19 - 25岁（青年）和26岁及以上（成人））对协变量和潜在混杂因素进行了校正，比较了NM状态个体（参照）与突变代谢者状态个体的结局。对于具有统计学意义的结局，我们计算了为预防一种结局所需治疗的人数（NNT）和所需进行基因分型的人数（NNG）。
使用艾司西酞普兰且CYP2C19为PM状态的儿童和青少年，治疗转换风险增加（IRR = 1.64 [95%CI：1.10 - 2.43]），自杀未遂/自我伤害风险增加（IRR = 2.67 [95%CI；1.57 - 4.52]）。使用舍曲林且CYP2C19为PM状态的青年，治疗转换风险增加（IRR = 2.06 [95%CI；1.03 - 4.11]）。使用氟西汀且CYP2D6为PM状态的青年，急诊科就诊风险增加（IRR = 3.28 [95%CI；1.11 - 9.63]）。在成人中未检测到显著关联。对于使用艾司西酞普兰的儿童，预防一次自杀未遂/自杀的NNG为463，NNT为11。
CYP2C19和CYP2D6的PM表型状态与首次使用艾司西酞普兰、舍曲林或氟西汀的抑郁症儿童、青少年和青年的结局相关，因此表明PGx检测在PGx指导的抗抑郁治疗中具有实用性，尤其是在年轻人中。
