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于提高缓解率的目标至关重要。由于抑郁症的生物学异质性和不同的症状表现，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记物的系统探索中开发的生物标记更有可能成功。需要两种类型的生物标记来实现改善的结果：1)生物标记在治疗开始时最大限度地为个体患者选择最佳治疗（调节因子），2)生物标记在治疗早期确定最终结果的指标（介质）。这种方法具有很大的潜力，可以个性化治疗，并最大限度地提高患者的数量，他们可以通过特定的治疗完全缓解。我们建议对三种机制不同的MDD治疗方法（西酞普兰、安非他酮和认知行为疗法）进行比较效果试验，其中我们将评估一系列精心挑选的临床（如焦虑性抑郁、早期生活创伤和性别）和生物学（如遗传、神经影像学、血清、表观遗传和qEEG）调节因子和结果介质。使用创新的统计方法，确定的调节因子和中介因子将用于开发差异抑郁症治疗反应指数（DTRI）。拟议的研究是一项随机两阶段试验（阶段：12周；阶段：12周）设计，675名重度抑郁症患者（除西酞普兰外，有一项充分的SSRI试验史）被分配到三种治疗条件中的一种（n=225）。这种两阶段方法类似于顺序多任务随机试验（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专家，包括：临床试验（Trivedi, Fava, Schatzberg,Nierenberg, Shelton, Gaynes, Hollon），遗传学（Smoller, Binder, McMahan, Perils），神经影像学（Phillips, Sheline, Etkin, Pizzagalli, Buckner）， qEEG (losifescu, Ellenbogen)，神经营养因子/细胞因子（Duman, Sanacora, Turck, Shelton），临床预测因子（Shelton, Hollon, Trivedi, Fava, Nierenberg, Goodman, Yehuda），神经内分泌标志物（Holsboer, Schatzberg, Shelton, Yehuda），表观遗传学（Nestler, Yehuda），认知行为疗法(Hollon，Manber•阿诺)。该小组还将由国际知名的生物标志物科学家（Holsboer, Schatzberg, Krystal, Charney, Goodman）以及一组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).