Pharmacogenetic Decision Support IT System for Psychiatric Hospitalization: RCT

描述(由申请人提供)：我们建议进行一项随机临床试验(RCT)，以比较根据患者的CYP2D6基因状态接受治疗的严重抑郁障碍(MDD)患者和经验性“护理标准”精神药物治疗的患者的结果。我们假设，根据患者先天药物代谢的药物警报，CYP2D6基因和预测的酶功能状态将改进精神药物的选择，并减少精神科住院时间和再入院时间。试验地点是哈特福德医院，该医院提供两个关键的机构资源：生命研究所(IOL)和遗传学研究中心(GRC)。IOL是一家以研究为基础的大型精神病医院，在行为、精神和成瘾障碍领域以卓越、全面的患者护理、研究和教育而闻名全国。IOL已经开发和实施了临床评估和监测系统(CEMS)，这是一种创新的电子信息系统，可以向住院患者的医生传输临床上可行的指导，并将在这里用作向临床医生提供基因信息的一种高效、快速的方式。由PI G.Rua�o博士领导的GRC一直是联邦医疗保险认证和国家许可的药物遗传临床实验室和咨询的孵化器，自2005年以来已有近4,000名患者被转介到该实验室。IOL和GRC已经发表并提交了药物遗传学数据和一项试点临床研究，支持RCT的基本原理。在随机对照试验中，这项为期5年的R01计划将500名患者分配到标准治疗(S组)，对于这些患者，CYP2D6基因信息已确定但未传递给治疗临床医生，且精神药物治疗已得到经验确定；1000名患者接受基因引导治疗(G组)，基因分型结果和治疗建议在入院24小时内通过CEMS提供给临床医生。CYP2D6基因分型将包括对导致酶功能低于正常或超过正常的所有多态进行测试。对于G组中40%的代谢率较低或代谢速度较快的患者，禁止服用主要由CYP2D6酶代谢的药物。主要终点是住院时间，次要终点是30天再次住院的频率。基于S组和G组遗传分层的其他研究将调查具体的精神药物使用情况。该计划以IOL的高住院患者普查和CEMS系统为基础，该系统由该计划的首席临床医生J.W.歌德博士开发。T.R.Holford博士(耶鲁大学)将担任统计顾问，D.Flockhart博士(印第安纳州)将担任医疗顾问。预期的好处是对提供CYP2D6药物遗传学信息对结果和相关成本的影响进行定量了解，并为指导精神药物治疗的CYP2D6基因分型的比较有效性制定客观基准。

DESCRIPTION (provided by applicant): We propose a Randomized Clinical Trial (RCT) to compare outcomes in patients with major depressive disorder (MDD) treated according to the patient's CYP2D6 genotype status versus empiric "standard-of- care" psychotropic therapy. We hypothesize that CYP2D6 genotype and predicted functional status of the CYP2D6 enzyme with medication alerts suited to the patient's innate drug metabolism will refine psychotropic medication selection and decrease both psychiatric hospital length of stay and re-admission. The trial setting is Hartford Hospital, which offers 2 key institutional resources: the Institute o Living (IOL) and the Genetics Research Center (GRC). The IOL is a major research-based psychiatric hospital with a national reputation for excellence, comprehensive patient care, research and education in the fields of behavioral, psychiatric and addiction disorders. The IOL has developed and implemented the Clinical Evaluation and Monitoring System (CEMS), an innovative electronic messaging system that transmits clinically actionable guidance to the physician on hospitalized patients, and which will be utilized here as an efficient, rapid way to advance genotype information to clinicians. The GRC, led by the PI, Dr. G. Rua�o, has served as incubator for a Medicare-certified and State-licensed pharmacogenetic clinical laboratory and consultation, to which nearly 4000 patients have been referred since 2005. IOL and GRC have published and presented pharmacogenetic data and a pilot clinical study supporting the rationale for the RCT. In the RCT, this 5-year R01 Program will assign 500 patients to standard therapy (Group S) for whom CYP2D6 genetic information is determined but not transmitted to the treating clinician and psychotropic therapy is empirically determined, and 1000 to genetically guided therapy (Group G) where genotyping result and treatment recommendations are furnished via CEMS to the clinician within 24 hours of admission. CYP2D6 genotyping will consist of testing for all polymorphisms that result in an enzyme with sub-normal or supra-normal function. For the 40% of patients in Group G who are poor or rapid metabolizers, medications primarily metabolized by the CYP2D6 enzyme are proscribed. The primary endpoint is hospital length of stay and the secondary endpoint, the frequency of 30 day hospital readmission. Additional research based on genetic stratification of both Group S and Group G will investigate specific psychotropic usage. The Program is anchored by the high inpatient census and CEMS system at IOL, developed by this Program's lead clinician, Dr. J.W. Goethe. Dr. T.R. Holford (Yale) will serve as a statistical consultant and Dr. D. Flockhart (Indiana) will serve as a medical consultant. The expected benefits are quantitative understanding of the effect of providing CYP2D6 pharmacogenetic information on outcomes and associated costs and objective benchmarking for the comparative effectiveness of CYP2D6 genotyping for guiding psychotropic therapy.