2/2-Mechanism of Antidepressant-Related Dysfunctional Arousal in High-Risk Youth

 描述（由申请人提供）：抗抑郁药是当今美国青年常用的处方药，用于治疗各种儿童期发作的精神疾病。然而，严重的精神病不良事件也可能出现在抗抑郁药的使用中，包括易怒、激越、情绪升高和其他与功能失调性情绪唤起增加相关的不良事件。对于一些年轻人来说，这些不良事件导致终身精神病理学的发展，如双相情感障碍。重要的是，抗抑郁药增加发生这些不良事件风险的机制在很大程度上是未知的。此外，临床上迫切需要更好地确定哪些服用抗抑郁药的年轻人会产生不良后果。 那些对抗抑郁药产生不良反应的年轻人是那些已经很容易发展出功能失调的情绪唤起的人。来自家庭研究的令人信服的数据表明，有双相情感障碍家族史的年轻人有很高的主要情绪和其他情绪唤醒障碍的发生率，并证明了对情绪唤醒调节至关重要的神经生物学系统的早期破坏，最明显的是杏仁核和腹外侧前额叶皮层（VLPFC）神经回路。抗抑郁药通常用于治疗高危青年的功能失调性情绪唤起;然而，它们也可能增加和加速其中一些青年的情绪障碍发作。 研究涉及NIMH研究领域标准（RDoC）唤醒和调节系统的唤醒结构，该结构描述了年轻人经历不良抗抑郁药相关精神病事件时情绪功能障碍的基本方面。本申请旨在使用RDoC框架进行随机试验，以研究与高危青少年抗抑郁药相关的功能失调性情绪唤起相关的病因机制和风险因素。为了实现这些目标，150名（75名/中心）高危青年，即至少有一名一级或二级亲属患有双相I型障碍，有中度至重度抑郁或焦虑症状，将随机接受双盲治疗，包括心理治疗加艾司西酞普兰或心理治疗加安慰剂。在随机化之前，我们将收集基线磁共振成像（MRI）、行为和生理唤醒指标。随机分组后，青少年将在4周时接受第二次MRI扫描，然后进行长达16周的临床评估，以评估唤醒的变化。我们的目的是确定抗抑郁药相关的觉醒变化是否是由杏仁核-VLPFC电路的变化介导的，并确定神经生物学危险因素发展功能障碍的觉醒。这方面的知识将是至关重要的精神卫生专业人员谁有有限的经验证据，他们的治疗基础上的青年最容易情绪失调。它也有可能告知与功能失调的情绪唤起相关的疾病的病理生理学，以及治疗这一复杂问题的新靶点的开发。

 DESCRIPTION (provided by applicant): Antidepressants are commonly prescribed medications used by American youth today to treat a variety of childhood onset psychiatric disorders. However, serious psychiatric adverse events may also emerge from antidepressant use including irritability, agitation, elevated mood, and other adverse events associated with increased dysfunctional emotional arousal. For some youth, these adverse events lead to the development of lifelong psychopathologies such as bipolar disorder. Importantly, the mechanisms through which antidepressants increase risk for developing these adverse events are largely unknown. Moreover, there is a pressing clinical need to better identify which youth taking antidepressants will develop adverse outcomes. Youth who are highly likely to develop adverse responses to antidepressants are those who are already vulnerable to developing dysfunctional emotional arousal. Compelling data from family studies have shown that youth with a family history of bipolar disorder have high rates of major mood and other disorders of emotional arousal, and demonstrate early disruptions of neurobiological systems critical for the regulation of emotional arousal, most notably in the amygdala and ventrolateral prefrontal cortex (VLPFC) neural circuit. Antidepressants are commonly used to treat dysfunctional emotional arousal in high-risk youth; however, they may also increase and accelerate the onset of mood disorders in some of these youth. Research has implicated involvement of the Arousal construct of the NIMH Research Domain Criteria (RDoC) Arousal and Regulatory Systems, which describes fundamental aspects of emotional dysfunction when youth experience an adverse antidepressant-related psychiatric event. This application aims to use an RDoC framework in a randomized trial to investigate the etiological mechanisms and risk factors associated with antidepressant-related dysfunctional emotional arousal in high-risk youth. To accomplish these aims, 150 (75/site) high-risk youth, i.e. having at least one first- or second-degree relative with bipolar I disorder, who have moderate to severe depression or anxiety symptoms, will be randomized to receive double-blind treatment either with psychotherapy plus escitalopram or psychotherapy plus placebo. Prior to randomization, we will collect baseline magnetic resonance imaging (MRI), behavioral, and physiological measures of arousal. After randomization, youth will undergo a second MRI scan at 4 weeks, and then will be clinically assessed for up to 16 weeks to evaluate for changes in arousal. We aim to determine whether antidepressant-related changes in arousal are mediated by changes in amygdala-VLPFC circuitry, and to identify neurobiological risk factors for developing dysfunctional arousal. This knowledge will be vitally important to mental health professionals who have limited empirical evidence on which to base their treatment of youth most vulnerable for emotion dysregulation. It also has potential to inform the pathophysiology of disorders associated with dysfunctional emotional arousal and the development of novel targets for treating this complex problem.