Establishing Moderators/Biosignatures of Antidepressant Response- Clinical Care

描述（由申请人提供）：及时选择抑郁症患者的最佳治疗方法对提高缓解率至关重要。由于抑郁症的生物学异质性和多变的症状表现，单一的临床或生物学标志物不太可能指导治疗选择。相反，从一组临床和生物标志物的系统探索中开发的生物特征更有可能成功。需要两种类型的生物特征来实现改善的结果：1）生物特征，以在治疗开始时最大限度地为个体患者选择最佳治疗（调节剂），以及2）生物特征，以在治疗早期识别最终结果的指标（介导剂）。这种方法具有很大的潜力，个性化治疗和最大限度地提高患者的数量谁可以治疗到完全缓解与给定的治疗。我们提出了一个比较有效性试验的三个机制不同的治疗抑郁症（西酞普兰，安非他酮和认知行为疗法），我们将评估一个全面的阵列精心挑选的临床（即焦虑抑郁症，早期生活创伤，性别）和生物（即遗传，神经影像学，血清，表观遗传和qEEG）的调节剂和介导的结果。使用创新的统计方法，确定的主持人和调解人，然后将用于开发一个差异抑郁症治疗反应指数（DTRI）。拟定的研究是一项随机两阶段试验（阶段1：12周;阶段2：12周）设计，675例MDD患者（有一项SSRI充分试验的病史，西酞普兰除外）被分配至三种治疗条件之一（每种n=225）。这两个阶段的方法类似于顺序多分配随机试验（SMART）设计。该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，谢尔顿，Gaynes，Hollon），遗传学（Smoller，Binder，McMahan，Perils），神经影像学（菲利普斯、Sheline、Etkin、Pizzagalli、Buckner）、qEEG（losifescu，Ellenbogen），神经营养因子/细胞因子（Duman，Sanacora，Turck，谢尔顿），临床预测因子（谢尔顿、霍伦、特里维迪、法瓦、尼伦伯格、古德曼、耶胡达）、神经内分泌标志物（Holsboer，Schatzberg，谢尔顿，Yehuda），表观遗传学（Nestler，Yehuda）和认知行为疗法（Hollon，Manber，Arnow）。该团队还将由国际知名的生物标志物科学家（Holsboer，Schatzberg，Krystal，Charney，Goodman）以及高素质的生物统计学家（Kraemer，Wisniewski，Schoenfeld）指导。

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).