The Pathophysiology and Treatment Of Children With Severe Mood Dysregulation

儿童严重情绪失调的病理生理学和治疗

• 批准号: 8158098
• 负责人: Ellen Leibenluft
• 金额: $ 162.89万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8158098
• 关键词: Child; Functional disorder; Moods

Considerable public attention has focused recently on the question of why there has been a rather dramatic upsurge in the rate at which the diagnosis of bipolar disorder (BD) is being assigned to children. In large part the upsurge appears to be due to the fact that children with extremely severe irritability, but without distinct manic episodes, are receiving the diagnosis of BD. At the inception of this project, we defined criteria that would allow us to identify reliably children in this controversial diagnostic group. We called the syndrome severe mood and behavioral dysregulation (SMD), and defined it in terms of impairing symptoms that include abnormal baseline mood (i.e. irritability, anger, and/or sadness), hyperarousal (e.g. insomnia, agitation, distractibility), and increased reactivity to negative emotional stimuli. The specific goals of this project are 1) to identify reliably a group of children with severe mood and behavioral dysregulation in order to characterize them clinically and behaviorally, and follow them longitudinally, 2) to compare the brain function of SMD children (assessed with functional MRI and standardized behavioral testing) to that of children with unequivocal BPD; 3) to test appropriate treatments for SMD.; and 4) to identify the pathophysiology of severe irritability in youth, in order to foster the development of novel interventions. The latter two goals are particularly important, since if youth with SMD are found to have a form of BD that would dictate one course of treatment, whereas if they are found to have (for example) a variant of depression, anxiety, and/or attention deficit hyperactivity disorder, this would dictate a rather different plan for treatment. Since the inception of this project, approximately 200 youth with SMD have been recruited into the project. Approximately 20 new patients were recruited this year. It is very important to note that these youth with SMD suffer very severe psychiatric impairment, and indeed are as ill as are youth with BD in terms of number of medications prescribed, number of psychiatric hospitalizations, and standardized measures of function. In past years, we demonstrated that youth with SMD are at risk for major depression, rather than necessarily BD, in early adulthood, and that they are less likely than youth with BD to have a parent with BD. This work in prior years was conducted in epidemiological samples, which have the advantage of representativeness but the disadvantage of relatively few patients with either BD or SMD. This year we published a longitudinal study of our own clinical sample, which had been followed for a median of 28 months. As expected, we found that youth with BD continued to have episodes of mania and hypomania, whereas only a very small percentage of youth with SMD (1/84)developed a hypomanic or manic episode. In previous years, we demonstrated that youth with BD or SMD, but not those with attention deficit hyperactivity disorder (ADHD), anxiety disorders, or unipolar depression, have deficits in face emotion labeling. This year we published data indicating that, while BD and SMD have similar behavioral deficits, the neural mechanisms mediating that dysfunction differ between groups. Specifically, the nature of amygdala dysfunction during face emotion processing differs among youth with BD, SMD, and ADHD. Ongoing work, being prepared for publication, supports the conclusion from this initial study that the neural mechanisms mediating face emotion processing deficits in BD and SMD differ between groups. This new study uses a face processing paradigm where the faces are presented too quickly for conscious processing. The data indicate amygdala dysfunction in youth with SMD even when the faces are presented preconsciously, and suggest that bottom-up attentional mechanisms may be deficient in youth with SMD. An additional study, being prepared for publication, explores response flexibility deficits in SMD and BD youth. Response flexibility deficits could contribute to the frustration experienced by youth with SMD. In this study, we used fMRI in conjunction with a response reversal paradigm and found striatal and ventral prefrontal dysfunction in SMD youth. To further explore the mechanisms mediating frustration in youth with SMD, we built on previous work using a frustrating paradigm (i.e., a rigged game)in the MEG and ERP environments by insituting an fMRI study using a similar paradigm. Finally, from a public health perspective, it is essential to determine whether the distinction between SMD and BD, which is evident in terms of clinical course, family history, and neural circuitry, is also associated with between-group differences in treatment response. In previous work, we found that lithium was not effective in the treatment of SMD. Last year, we began a double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor antidepressant) plus stimulant is more effective than placebo plus stimulant in the treatment of SMD. Recruitment for the study has been extremely robust and youth are tolerating the experimental treatment well.

最近，公众的注意力集中在一个问题上：为什么双相情感障碍（BD）的诊断率在儿童中出现了相当大的激增。在很大程度上，这种激增似乎是由于这样一个事实，即儿童与极其严重的易怒，但没有明显的躁狂发作，正在接受诊断的BD。 在这个项目的开始，我们定义的标准，将使我们能够可靠地识别儿童在这个有争议的诊断组。我们称这种综合征为严重情绪和行为失调（SMD），并根据损害症状对其进行定义，包括异常基线情绪（即易怒，愤怒和/或悲伤），过度觉醒（例如失眠，激动，注意力分散）以及对负面情绪刺激的反应性增加。 该项目的具体目标是：1）可靠地识别一组严重情绪和行为失调的儿童，以便在临床和行为上表征他们，并纵向跟踪他们; 2）将SMD儿童的脑功能（通过功能性MRI和标准化行为测试评估）与明确的BPD儿童的脑功能进行比较; 3）测试SMD的适当治疗。和4）确定青年严重易怒的病理生理学，以促进新的干预措施的发展。后两个目标特别重要，因为如果发现患有SMD的青年患有一种形式的BD，这将决定一个疗程，而如果发现他们患有（例如）抑郁症，焦虑症和/或注意缺陷多动障碍的变体，这将决定一个相当不同的治疗计划。 自该项目开始以来，约有200名患有SMD的青年被招募参加该项目。今年招募了大约20名新患者。值得注意的是，这些患有SMD的青少年患有非常严重的精神障碍，并且在处方药物数量、精神病住院数量和功能标准化措施方面与BD青少年一样患病。 在过去的几年中，我们证明了SMD青年在成年早期有患重度抑郁症的风险，而不一定是BD，并且他们比BD青年更不可能有BD父母。这项工作在前几年进行的流行病学样本，这具有代表性的优势，但相对较少的患者与BD或SMD的缺点。 今年，我们发表了一项对我们自己的临床样本的纵向研究，该研究的平均随访时间为28个月。 正如预期的那样，我们发现患有BD的青少年继续有躁狂和轻躁狂发作，而只有很小比例的患有SMD的青少年（1/84）发展为轻躁狂或躁狂发作。 在过去的几年中，我们证明了BD或SMD的年轻人，而不是那些注意缺陷多动障碍（ADHD），焦虑症或单相抑郁症的年轻人，在面部情绪标签上有缺陷。 今年我们发表的数据表明，虽然BD和SMD具有相似的行为缺陷，但介导功能障碍的神经机制在组间不同。具体而言，在面部情绪处理过程中杏仁核功能障碍的性质在BD，SMD和ADHD青少年中有所不同。正在进行的工作，正在准备出版，支持从这个初步研究的结论，即介导面部情绪处理缺陷的神经机制在BD和SMD组之间不同。这项新研究使用了一种面部处理范式，即面部呈现得太快，无法进行有意识的处理。 这些数据表明，杏仁核功能障碍的青年与SMD，即使是有意识地提出的面孔，并建议自下而上的注意力机制可能是缺乏青年与SMD。 另一项研究，正在准备出版，探讨在SMD和BD青年的反应灵活性赤字。反应灵活性的缺陷可能会导致青年SMD所经历的挫折。 在这项研究中，我们使用功能磁共振成像结合反应逆转范式，发现纹状体和腹侧前额叶功能障碍的SMD青年。 为了进一步探索调解SMD青少年挫折感的机制，我们在以前的工作基础上使用挫折范式（即，一个操纵的游戏）在MEG和ERP环境中，通过使用类似的范例进行fMRI研究。 最后，从公共卫生的角度来看，至关重要的是要确定SMD和BD之间的区别，这是明显的临床过程中，家族史和神经回路，也与治疗反应的组间差异。 在以前的工作中，我们发现锂对SMD的治疗无效。去年，我们开始了一项双盲试验，旨在确定西酞普兰（一种β能再摄取抑制剂抗抑郁药）加兴奋剂是否比安慰剂加兴奋剂更有效地治疗SMD。这项研究的招募工作非常活跃，年轻人对实验性治疗的耐受性很好。