Imaging Genetic Predictors of Psychotherapy Outcomes in Unipolar Depression

描述（由申请人提供）：尽管有许多有效的重度抑郁症（MDD）干预措施，但治疗反应存在显著异质性。提高治疗反应率的一个障碍是缺乏生物标志物来预测谁会对给定的治疗产生反应。此外，对抑郁症状和治疗反应的遗传介质缺乏了解。在试图从基因到抑郁表型建立联系的过程中，大脑活动是基因和行为之间的关键中介。在MDD中，多巴胺（DA）系统特别令人感兴趣，因为它们是奖励反应性（或缺乏快感）的基础。该建议将研究MDD中对奖励的神经反应、调节DA系统功能输出的候选基因的等位基因变异以及对心理治疗的反应之间的关系。成像遗传学在基础和临床认知神经科学中已经是一种富有成效的方法，但尚未应用于了解MDD心理治疗反应的异质性。参与者将在奖励预期和反馈任务（货币激励延迟）期间接受功能性神经成像，并在开始抑郁症短期行为激活治疗（BASD）心理治疗之前进行候选多巴胺基因（COMT，DAT 1等）的基因分型。候选DA多态性将作为额纹状体奖励网络激活以及心理治疗反应的预测因子进行检查。将进一步检查额-纹状体奖励网络激活作为DA多态性对治疗反应影响的介体。这种方法是研究计划的重要一步，其最终目标是生成和验证成像遗传模型，这些模型最终可能预测MDD对药理学和心理治疗性抗抑郁药治疗的反应。

DESCRIPTION (provided by applicant): Though there are many effective interventions for Major Depressive Disorder (MDD) available, there is significant heterogeneity in treatment response. One obstacle to improved treatment response rates is the lack of biomarkers to predict who will respond to a given treatment. Further, there is a lack of understanding of genetic mediators of both depressive symptoms and treatment response. In the attempt to form links from genes to depressive phenotype, brain activity is a key intermediate between genes and behavior. In MDD, dopamine (DA) systems are of particular interest, as they underlie reward responsivity (or its lack, anhedonia). This proposal will examine relations between neural response to rewards in MDD, allelic variations of candidate genes regulating functional output of DA systems, and response to psychotherapy. Imaging-genetics has been a fruitful approach in basic and clinical cognitive neuroscience but has not yet been applied to understand heterogeneity of psychotherapy response in MDD. Participants will undergo functional neuroimaging during a reward anticipation and feedback task (Monetary Incentive Delay) and will be genotyped for candidate dopamine genes (COMT, DAT1, and others) before initiating a course of Brief Behavioral Activation Treatment for Depression (BATD) psychotherapy. Candidate DA polymorphisms will be examined as predictors of both fronto-striatal reward network activation as well as psychotherapy treatment response. Fronto-striatal reward network activation will be examined further as a mediator of DA polymorphism effects on treatment response. This approach is an important step in a program of research with the ultimate goal of generating and validating imaging genetic models that may ultimately predict response to both pharmacological and psychotherapeutic antidepressant treatments in MDD.