Characterization and Sequential Pharmacotherapy of Severe Mood Dysregulation

描述（由申请人提供）：本R21申请申请资助一项为期两年的探索性/发展性研究，以更好地表征患有严重情绪失调（SMD）的儿童和青少年，并进行一项联合药物治疗的试点研究，作为设计未来干预试验的基础。SMD的特征是严重的、非发作性易怒、亢奋和攻击性。有证据表明，最近儿科双相情感障碍诊断的增加可能是由于对患有SMD的青少年的错误识别，尽管如此，他们在社交和学业失败、认知问题、身体虐待和成人抑郁症方面的风险仍在增加。目前，这些儿童中的许多人接受抗精神病药物治疗，这些药物虽然有镇静作用，但是非特异性的，并与重大的健康风险相关，包括体重过度增加和其他代谢困难。考虑到生活中注意力缺陷/多动障碍（ADHD）、抑郁和焦虑在受抑郁症影响的个体中发病率的增加，有可能针对这些疾病的药物，如兴奋剂和抗抑郁药，以及社会心理治疗，可能更容易被患者和家属接受。该项目将为正在进行的关于SMD的正确诊断方法的讨论提供信息，并为设计明确的干预研究提供基础。拟议的项目将仔细评估患有SMD的儿童和青少年，包括对同时发生的精神和学习障碍的评估，神经心理测试，以及用脑电图（EEG）进行脑成像。这些信息将与一个现有的大型数据库进行比较，该数据库包含有确定的精神疾病的青少年，以及非临床对照对象。参与者将进行两个阶段的药物试验。首先，所有参与者将进行为期4周的开放标签兴奋剂试验，其中包括右旋哌醋甲酯缓释（d-MPH-XR），以确定最佳剂量。一旦剂量确定，参与者将被随机分配到另外8周的双盲氟西汀组，氟西汀是一种选择性血清素再摄取抑制剂，用于治疗抑郁和焦虑，而安慰剂与兴奋剂联合服用。将密切监测参与者的临床反应和潜在的副作用。统计分析将评估SMD和其他疾病之间的潜在差异，并提供这些药物在SMD治疗中的潜在益处的初步信息。将特别强调评估各种结果测量的有用性，以预测未来的研究。该申请与NIMH的优先事项一致，包括开发新的精神障碍分类方法，识别区分疾病的生物标志物，治疗患有合并症的个体，以及探索在儿童和青少年中很少研究的领域的使用，即联合药物治疗。

DESCRIPTION (provided by applicant): This R21 application requests funding for a two-year exploratory/developmental study to better characterize children and adolescents with severe mood dysregulation (SMD), and to conduct a pilot study of combination pharmacotherapy as a basis for designing future intervention trials. SMD is characterized by severe, non-episodic irritability, hyperarousal, and aggression. Evidence suggests that recent increases in the diagnosis of pediatric bipolar disorder might be due to misidentification of youth with SMD, who are nonetheless at increased risk for social and academic failure, cognitive problems, physical abuse, and adult depression. Currently, many of these children are treated with antipsychotic medications that, although sedating, are non-specific and associated with significant health risks, including excessive weight gain and other metabolic difficulties. Given the increased rates of lifetime attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety among SMD-affected individuals, it is possible that medicines that are more specific to these disorders, such as stimulants and antidepressants, as well as psychosocial treatments, might prove more acceptable to patients and families. This project will inform ongoing discussions on the proper diagnostic approach to SMD and provide a foundation for the design of definitive intervention studies. The proposed project will carefully assess children and adolescents with SMD, including evaluations for co-occurring psychiatric and learning disorders, neuropsychological testing, and, brain imaging with electroencephalography (EEG). This information will be compared with a large existing database of youth with established psychiatric conditions, as well as non-clinical control subjects. Participants will proceed to a two- stage medication trial. First, all participants will have a 4-week open-label stimulant trial with dextro- methylphenidate extended release (d-MPH-XR) to determine an optimal dose. Once the dose is established, participants will be randomized to an additional 8 weeks with double-blind fluoxetine, a selective serotonin reuptake inhibitor used for treatment of depression and anxiety, versus placebo taken in combination with the stimulant. Participants will be closely monitored for clinical response and potential side effects. Statistical analyses will assess potential differences between SMD and other disorders, and provide preliminary information on the potential benefits of these medications in SMD treatment. There will be particular emphasis on assessing the usefulness of various outcome measurements in anticipation of future research. The application is consistent with NIMH priorities, including the development of new ways to classify mental disorders, identification of biomarkers that differentiate disorders, treatment of individuals with comorbid conditions, and exploring use of an infrequently researched area, namely combination pharmacotherapy in children and adolescents.