Rothschild Anthony J, Parikh Sagar V, Hain Daniel, Law Rebecca, Thase Michael E, Dunlop Boadie W, DeBattista Charles, Conway Charles R, Forester Brent P, Shelton Richard C, Macaluso Matthew, Brown Krystal, Lewis David, Gutin Alexander, Jablonski Michael R, Greden John F
University of Massachusetts Medical School and UMass Memorial Healthcare, Worcester, MA 01655, United States.
University of Michigan Comprehensive Depression Center and Department of Psychiatry, and National Network of Depression Centers, Ann Arbor, MI 48109, United States.
Psychiatry Res. 2021 Feb;296:113649. doi: 10.1016/j.psychres.2020.113649. Epub 2020 Dec 15.
We evaluated the clinical validity of a combinatorial pharmacogenomic test and single-gene Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines against patient outcomes and medication blood levels to assess their ability to inform prescribing in major depressive disorder (MDD). This is a secondary analysis of the Genomics Used to Improve DEpression Decisions (GUIDED) randomized-controlled trial, which included patients with a diagnosis of MDD, and ≥1 prior medication failure. The ability to predict increased/decreased medication metabolism was validated against blood levels at screening (adjusted for age, sex, smoking status). The ability of predicted gene-drug interactions (pharmacogenomic test) or therapeutic recommendations (single-gene guidelines) to predict patient outcomes was validated against week 8 outcomes (17-item Hamilton Depression Rating Scale; symptom improvement, response, remission). Analyses were performed for patients taking any eligible medication (outcomes N=1,022, blood levels N=1,034) and the subset taking medications with single-gene guidelines (outcomes N=584, blood levels N=372). The combinatorial pharmacogenomic test was the only significant predictor of patient outcomes. Both the combinatorial pharmacogenomic test and single-gene guidelines were significant predictors of blood levels for all medications when evaluated separately; however, only the combinatorial pharmacogenomic test remained significant when both were included in the multivariate model. There were no substantial differences when all medications were evaluated or for the subset with single-gene guidelines. Overall, this evaluation of clinical validity demonstrates that the combinatorial pharmacogenomic test was a superior predictor of patient outcomes and medication blood levels when compared with guidelines based on individual genes.
我们评估了一种组合式药物基因组学检测和单基因临床药物基因组学实施联盟（CPIC）指南针对患者预后和药物血药浓度的临床有效性，以评估它们为重度抑郁症（MDD）开具处方提供信息的能力。这是对用于改善抑郁症决策的基因组学（GUIDED）随机对照试验的二次分析，该试验纳入了诊断为MDD且既往有≥1次用药失败的患者。根据筛查时的血药浓度（根据年龄、性别、吸烟状况进行调整）验证预测药物代谢增加/减少的能力。根据第8周的预后（17项汉密尔顿抑郁量表；症状改善、反应、缓解）验证预测的基因-药物相互作用（药物基因组学检测）或治疗建议（单基因指南）预测患者预后的能力。对服用任何符合条件药物的患者进行了分析（预后N = 1022，血药浓度N = 1034）以及服用有单基因指南药物的亚组（预后N = 584，血药浓度N = 372）。组合式药物基因组学检测是患者预后的唯一显著预测指标。当分别评估时，组合式药物基因组学检测和单基因指南都是所有药物血药浓度的显著预测指标；然而，当两者都纳入多变量模型时，只有组合式药物基因组学检测仍然显著。对所有药物进行评估时或对有单基因指南的亚组进行评估时，均无实质性差异。总体而言，这项临床有效性评估表明，与基于单个基因的指南相比，组合式药物基因组学检测是患者预后和药物血药浓度的更优预测指标。
