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少年常用的处方药物，用于治疗各种儿童期发病的精神疾病。然而，使用抗抑郁药也可能出现严重的精神不良事件，包括烦躁、激动、情绪高涨以及与功能失调的情绪唤醒增加相关的其他不良事件。对于一些青少年来说，这些不良事件会导致终生的精神病理学，例如双相情感障碍。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尚不清楚。此外，临床迫切需要更好地确定哪些青少年服用抗抑郁药会出现不良后果。 极有可能对抗抑郁药物产生不良反应的青少年是那些已经很容易出现情绪唤起功能失调的人。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青少年患主要情绪和其他情绪唤起障碍的比例很高，并且证明对情绪唤起调节至关重要的神经生物学系统的早期破坏，尤其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少年的情绪唤起功能障碍；然而，它们也可能增加并加速其中一些青少年情绪障碍的发生。 研究表明涉及 NIMH 研究领域标准 (RDoC) 唤醒和调节系统的唤醒结构，该系统描述了青少年经历与抗抑郁药物相关的不良精神事件时情绪功能障碍的基本方面。本申请旨在在一项随机试验中使用 RDoC 框架来研究高危青少年中与抗抑郁药物相关的功能失调情绪唤醒相关的病因机制和危险因素。为了实现这些目标，150 名（75 名/中心）高危青少年，即至少有一名患有 I 型双相情感障碍的一级或二级亲属，且有中度至重度抑郁或焦虑症状的青少年，将被随机分配接受心理治疗加艾司西酞普兰或心理治疗加安慰剂的双盲治疗。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，然后将接受长达 16 周的临床评估，以评估觉醒的变化。我们的目的是确定与抗抑郁药物相关的唤醒变化是否是由杏仁核-VLPFC 回路的变化介导的，并确定发生功能障碍性唤醒的神经生物学危险因素。这些知识对于心理健康专业人士来说至关重要，他们对最容易情绪失调的青少年进行治疗的经验证据有限。它还有可能为与情绪唤起功能失调相关的疾病的病理生理学提供信息，并开发治疗这一复杂问题的新靶点。

 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.