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这样一个问题上：为什么双相情感障碍（BD）的诊断分配给儿童的比率急剧上升。这种激增在很大程度上似乎是由于患有极其严重的烦躁但没有明显躁狂发作的儿童被诊断为双相情感障碍。 在这个项目开始时，我们定义了标准，使我们能够在这个有争议的诊断组中可靠地识别儿童。我们将这种综合征称为严重情绪和行为失调（SMD），并将其定义为损害症状，包括基线情绪异常（即烦躁、愤怒和/或悲伤）、过度警觉（例如失眠、烦躁、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) 可靠地识别一组患有严重情绪和行为失调的儿童，以便从临床和行为上描述他们的特征，并纵向跟踪他们，2) 将 SMD 儿童的大脑功能（通过功能性 MRI 和标准化行为测试进行评估）与患有明确 BPD 的儿童进行比较； 3) 测试SMD的适当治疗方法； 4）确定青少年严重烦躁的病理生理学，以促进新干预措施的发展。后两个目标尤其重要，因为如果发现患有 SMD 的青少年患有某种形式的 BD，则需要采取一种治疗方案，而如果发现他们患有（例如）抑郁症、焦虑症和/或注意力缺陷多动障碍的一种变体，则需要采取一种截然不同的治疗计划。 自该项目启动以来，已招募了约 200 名患有 SMD 的青少年加入该项目。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，而且在处方药物数量、精神科住院治疗次数和标准化功能测量方面，他们的病情确实与患有双相情感障碍的青少年一样。 在过去的几年中，我们证明，患有 SMD 的青少年在成年早期有患重度抑郁症的风险，而不一定是患有 BD 的风险，并且与患有 BD 的青少年相比，他们的父母患有 BD 的可能性更小。前几年的这项工作是在流行病学样本中进行的，优点是具有代表性，但缺点是BD或SMD患者相对较少。 今年，我们发表了一项针对我们自己的临床样本的纵向研究，该研究的跟踪时间中位数为 28 个月。 正如预期的那样，我们发现患有 BD 的青少年持续出现躁狂和轻躁狂发作，而只有极少数患有 SMD 的青少年 (1/84) 出现轻躁狂或躁狂发作。 前几年，我们证明，患有 BD 或 SMD 的青少年，但患有注意力缺陷多动障碍 (ADHD)、焦虑症或单相抑郁症的青少年，在面部情绪标记方面存在缺陷。 今年我们发布的数据表明，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各组之间有所不同。具体来说，患有 BD、SMD 和 ADHD 的青少年在面部情绪处理过程中杏仁核功能障碍的性质有所不同。正在进行的、准备发表的工作支持了这项初步研究的结论，即 BD 和 SMD 中介导面部情绪处理缺陷的神经机制在群体之间存在差异。这项新研究使用了一种面部处理范例，其中面部呈现的速度太快，无法进行有意识的处理。 数据表明，即使在前意识地呈现面孔的情况下，患有 SMD 的青少年也会出现杏仁核功能障碍，并表明患有 SMD 的青少年自下而上的注意力机制可能存在缺陷。 另一项正在准备发表的研究探讨了 SMD 和 BD 青少年的反应灵活性缺陷。反应灵活性不足可能会导致患有 SMD 的青少年感到沮丧。 在这项研究中，我们将功能磁共振成像与反应逆转范式结合使用，发现 SMD 青少年的纹状体和腹侧前额功能障碍。 为了进一步探索调节青少年 SMD 挫败感的机制，我们在 MEG 和 ERP 环境中使用令人沮丧的范式（即操纵的游戏）建立之前的工作，通过使用类似的范式进行功能磁共振成像研究。 最后，从公共卫生的角度来看，有必要确定 SMD 和 BD 之间的区别（在临床病程、家族史和神经回路方面很明显）是否也与治疗反应的组间差异相关。 在之前的工作中，我们发现锂对于SMD的治疗效果不佳。去年，我们开始了一项双盲试验，旨在确定西酞普兰（一种血清素再摄取抑制剂抗抑郁药）加兴奋剂在治疗 SMD 方面是否比安慰剂加兴奋剂更有效。该研究的招募非常活跃，年轻人对实验治疗的耐受性很好。