Characterization and Sequential Pharmacotherapy of Severe Mood Dysregulation

严重情绪失调的特征和序贯药物治疗

• 批准号: 8241517
• 负责人: JAMES John MCGOUGH
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-06 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241517
• 关键词: Address; Adolescent; Adult; Adverse effects; Affect; Aggressive behavior; Anger; Antidepressive Agents; Antipsychotic Agents; Anxiety; Area; Attention deficit hyperactivity disorder; Behavioral; Biological Markers; Bipolar Disorder; Brain imaging; Child; Chronic; Clinical; Cognitive; Combination Drug Therapy; Combined Modality Therapy; Comorbidity; DSM-IV; Databases; Development; Diagnosis; Diagnostic; Disease; Dose; Double-Blind Method; Early identification; Electroencephalography; Enrollment; Evaluation; Exploratory/Developmental Grant; Factor Analysis; Failure; Family; Fluoxetine; Foundations; Funding; Future; Health; Individual; Intervention Studies; Intervention Trial; Knowledge; Lead; Learning Disorders; Measurement; Measures; Medicine; Mental Depression; Mental disorders; Metabolic; Methylphenidate; Mission; Monitor; Moods; National Institute of Mental Health; Neurocognitive; Neuropsychological Tests; Outcome; Outcome Measure; Participant; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Pilot Projects; Placebo Control; Placebos; Platelet Factor 4; Population; Psychopathology; Rage; Randomized; Request for Applications; Research; Risk; Selective Serotonin Reuptake Inhibitor; Staging; Symptoms; Syndrome; Testing; Titrations; Weight Gain; Youth; base; biosignature; childhood bipolar disorder; design; functional disability; high risk; meetings; open label; physical abuse; preempt; psychosocial; response; social; tool; treatment effect

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. PUBLIC HEALTH RELEVANCE: This study addresses the mission of the NIMH by further characterizing a previously under-recognized group of children and adolescents that are at high risk for lifelong psychopathology and functional impairment. Information derived, in conjunction with use of a large pre-existing database, may lead to more biologically informed approaches to early identification, diagnosis, and personalized treatment of SMD-affected individuals, with a potential to preempt subsequent adult mental illness. This project will establish a basis for ongoing research efforts in SMD.

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/发展研究，以更好地描述患有严重情绪失调(SMD)的儿童和青少年的特征，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、非发作性的易怒、高度觉醒和攻击性。有证据表明，最近儿童双相情感障碍的诊断增加可能是由于对患有SMD的年轻人的错误识别，尽管如此，他们仍面临着更高的社会和学业失败、认知问题、身体虐待和成人抑郁症的风险。目前，这些儿童中的许多人都接受了抗精神病药物的治疗，这些药物虽然是镇静的，但是非特异性的，并与重大的健康风险有关，包括体重过度增加和其他代谢困难。鉴于受SMD影响的个人的终生注意力缺陷/多动障碍(ADHD)、抑郁和焦虑的发生率增加，可能会证明更针对这些障碍的药物，如兴奋剂和抗抑郁药，以及心理社会治疗，可能会被证明更容易被患者和家人接受。该项目将为正在进行的关于SMD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，包括评估共生的精神和学习障碍，神经心理测试，以及脑电成像(EEG)。这些信息将与现有的大型数据库进行比较，这些数据库包括已有精神疾病的年轻人以及非临床对照受试者。参与者将继续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，使用右旋哌醋甲酯缓释剂(d-MPH-XR)以确定最佳剂量。一旦确定了剂量，参与者将被随机分成另外8周，分别服用双盲氟西汀和安慰剂。氟西汀是一种用于治疗抑郁和焦虑的选择性5-羟色胺再摄取抑制剂。参与者将被密切监测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，并就这些药物在SMD治疗中的潜在益处提供初步信息。将特别强调评估各种成果衡量标准的有用性，以期对未来的研究有所帮助。该应用与NIMH的优先事项一致，包括开发对精神障碍进行分类的新方法，识别区分障碍的生物标记物，治疗合并疾病的个人，以及探索使用一个不太常见的研究领域，即儿童和青少年的联合药物治疗。 公共卫生相关性：这项研究通过进一步描述之前未被认识到的儿童和青少年群体的特征，解决了NIMH的使命，这些儿童和青少年具有终身精神病理和功能障碍的高风险。所获得的信息，结合使用一个大型的预先存在的数据库，可能会导致更多的生物知情方法，以早期识别、诊断和个性化治疗受SMD影响的个人，并有可能先发制人，预防随后的成人精神疾病。该项目将为正在进行的SMD研究工作奠定基础。