Establishing Moderators/Biosignatures of Antidepressant Response- Clinical Care

描述(由申请人提供)：及时为抑郁症患者选择最佳治疗方案对于提高缓解率的目标至关重要。由于抑郁症的生物异质性和不同的症状表现，单一的临床或生物标志物不太可能指导治疗选择。相反，从一组临床和生物标记的系统探索中开发出的生物签名更有可能成功。要获得更好的结果，需要两种类型的生物签名：1)生物签名，以最大限度地在治疗开始时为个别患者选择最佳治疗(主持人)；2)生物签名，以确定治疗早期最终结果的指标(调解人)。这种方法有很大的潜力来个人化治疗，并最大限度地增加通过给定的治疗可以完全缓解的患者数量。我们提出了一项治疗MDD的三种不同治疗方法(西酞普兰、安非他酮和认知行为疗法)的比较有效性试验，在该试验中，我们将评估一系列精心挑选的临床(即焦虑性抑郁、早期生活创伤和性别)和生物(即遗传、神经成像、血清、表观遗传学和qEEG)调节因素和结果中介。利用创新的统计方法，确定的主持人和调解人将被用来开发不同的抑郁症治疗反应指数(DTRI)。这项拟议的研究是一项随机两阶段试验(Stagel：12wks；Stage2：12wks)设计，将675名MDD患者(除西酞普兰外，有一项SSRI充分试验的病史)分配到三种治疗条件之一(n=225)。这种两阶段方法类似于顺序多分配随机试验(SMART)设计。这一应用程序汇集了在进行大型临床试验方面具有丰富经验的研究人员和抑郁症神经生物学前沿的专家，包括：临床试验(Trivedi，Fava，Schatzberg，Nierenberg，Shelton，Gaynes，Hollon)，遗传学(Smoller，Binder，McMahan，Perils)，神经成像(Phillips，Sheline，Etkin，Pizzagalli，Buckner)，qEEG(losifescu，Ellenbogen)，神经营养素/细胞因子(Duman，Sanacora，Turck，Shelton)，临床预测因子(Shelton，Hollon，Trivedi，Fava，Nierenberg，Goodman，Yehuda)，神经分泌素标记物(Holsboer，Schatzberg，Shelton，Yehuda)，qEEG(Nestler，Yehuda)，以及认知行为治疗(Hollon，Hollon曼伯，阿诺)。该小组还将由国际知名的生物标志物科学家(Holsboer、Schatzberg、Krystore、Charney、Goodman)以及一批高素质的生物统计学家(Kraemer、Wisniewski、Schoenfeld)指导。 公共卫生相关性：这项研究将使用现有的最先进技术以及开创性的创新方法，检查多个精心挑选的临床和生物标记。在三种不同治疗方法的试验中评估这些标记物的有用性将有助于生成抑郁症治疗反应指数(DTRI)。DTRI将帮助临床医生将治疗方案与MDD患者相匹配，从而及时选择最适合个别患者的治疗方案。这项研究的结果可以显著改善MDD患者的治疗。

DESCRIPTION (provided by applicant): The timely selection of the best treatment for patients with depression is critical to the goal of improving remission rates. Due to the biological heterogeneity and variable symptom presentation of depression, it is unlikely that a single clinical or biological marker can guide treatment selection. Rather, a biosignature developed from a systematic exploration of a group of clinical and biological markers is more likely to be successful. Two types of biosignatures are needed to achieve improved outcomes: 1) biosignatures to maximize the selection of optimal treatment for individual patients at the beginning of treatment (moderators) and 2) biosignatures to identify indicators of eventual outcomes early in treatment (mediators). This approach has great potential to personalize treatment and maximize the number of patients who can be treated to full remission with a given treatment. We propose a comparative effectiveness trial of three mechanistically distinct treatments for MDD (citalopram, bupropion, and cognitive behavioral therapy) in which we will assess a comprehensive array of carefully selected clinical (i.e. anxious depression, early life trauma, & gender) and biological (i.e. genetic, neuroimaging, serum, epigenetic & qEEG) moderators and mediators of outcome. Using innovative statistical approaches the identified moderators and mediators will then be used to develop a differential depression treatment response index (DTRI). The proposed study is a randomized two-stage trial (Stagel:12 wks; Stage2: 12 wks) design with 675 MDD patients (with a history of one adequate trial of an SSRI except citalopram) assigned to one of three treatment conditions (n=225 each). This two stage approach is similar to a Sequential Multiple Assignment Randomized Trial (SMART) design. This application brings together researchers with extensive experience in conducting large clinical trials and experts at the forefront ofthe neurobiology of depression, including: clinical trials (Trivedi, Fava, Schatzberg,Nierenberg, Shelton, Gaynes, Hollon), genetics (Smoller, Binder, McMahan, Perils), neuroimaging (Phillips, Sheline, Etkin, Pizzagalli, Buckner), qEEG (losifescu, Ellenbogen), neurotrophins/cytokines (Duman, Sanacora, Turck, Shelton), clinical predictors (Shelton, Hollon, Trivedi, Fava, Nierenberg, Goodman, Yehuda), neuroendocrine markers (Holsboer, Schatzberg, Shelton, Yehuda), epigenetics (Nestler, Yehuda),and cognitive behavior therapy (Hollon, Manber, Arnow). This team will also be guided by internationally known biomarker scientists (Holsboer, Schatzberg, Krystal, Charney, Goodman), as well as a highly qualified group of biostatisticians (Kraemer, Wisniewski, Schoenfeld). PUBLIC HEALTH RELEVANCE : This study will examine multiple carefully selected clinical and biological markers, using both existing state of-the-art technologies as well as pioneering, innovative approaches. Evaluation of the usefulness of these markers in a trial with three different treatments will assist in generating a depression treatment response index (DTRI). The DTRI will help clinicians match treatments to patients with MDD, resulting in timely selection of treatments best suited for individual patients. Results from this study could significantly improve the treatment of patients with MDD.