The Pathophysiology and Treatment Of Children With Severe Mood Dysregulation

如上所述，为了回应对患有慢性、严重易怒儿童的适当诊断的担忧，我们定义了一组我们描述为患有严重情绪调节障碍(SMD)的儿童。这些儿童具有极其严重的易怒和过度觉醒的症状(后者类似于注意缺陷多动障碍(ADHD))，尽管他们经常被诊断为双相情感障碍(BD)，但他们确实不符合BD的诊断标准。我们的SMD表型为DSM-5中情绪调节障碍伴焦虑症(DMDD)的新儿科诊断奠定了基础。(DMDD与SMD的不同之处在于，DMDD不需要与注意力缺陷多动障碍(ADHD)相关的过度觉醒症状)。自该项目开始以来，约有220名患有SMD/DMDD的青年被招募到该项目中。今年大约招募了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损害，无论是在处方的药物数量、精神科住院次数和标准化的功能指标方面，他们的病情确实与BD青少年一样严重。同样如上所述，在前几年，我们展示了患有SMD的年轻人和患有BD的年轻人在临床病程、家族史和与行为问题相关的大脑机制方面的差异。因此，虽然我们继续将年轻人与BD和那些在调节大脑机制方面严重易怒的人进行比较，但我们对易怒本身的病理生理学越来越感兴趣。事实上，易怒是儿科精神病学诊所最常见的症状之一。 如上所述，易怒的概念特别适合于符合研究领域标准(RDoC)方法的跨诊断、翻译方法。因此，我们今年的大部分工作涉及检测易怒，不仅在严重易怒的DMDD表型中，而且在其他表现出相当易怒的群体中，包括患有焦虑症、ADHD或双相情感障碍(BD)的青少年。在所有人群中，我们将易怒描述为一个连续变量。我们的神经成像工作的一个主要焦点包括使用令人沮丧的任务，因为易怒的一个标志是难以忍受挫折。在去年发表的研究中，我们展示了易怒和不易怒的年轻人在完成一项令人沮丧的注意力任务时的行为和神经差异。我们已经改进了这一范式，现在正在将其应用于患有DMDD、BD、ADHD和/或焦虑症的青年以及健康青年的大样本中。这种方法使我们能够检查易怒的神经相关性，操作维度，同时也比较DSM-5诊断组在令人沮丧的任务中参与的大脑电路。初步数据(跨组N=70)表明，在令人沮丧的反馈过程中，与非沮丧的反馈相比，易怒程度的增加与杏仁核-顶叶功能连接的增加有关。这可能为易怒儿童的注意障碍提供了一种潜在的解释机制。 我们工作的一个主要重点仍然是治疗。我们继续进行我们的双盲试验，旨在确定西酞普兰(一种5-羟色胺再摄取抑制物(SRI)抗抑郁药，在治疗儿童焦虑中有效)加兴奋剂在治疗青少年严重应激性方面是否比安慰剂加兴奋剂更有效。重要的是，兴奋剂和SRI治疗的毒性往往低于被认为是双相情感障碍一线治疗的非典型抗精神病药物治疗，但由于担心可能导致躁狂发作，兴奋剂和SRI治疗在双相情感障碍患者中相对禁忌。因此，这项治疗试验具有相当大的公共卫生重要性。到目前为止，我们已经随机选择了大约45名儿童参加试验，年轻人对实验治疗的耐受性很好。此外，我们正在协助加州大学洛杉矶分校的合作者进行一项类似的试验，该试验是由外部资助的。我们现在还在扩展我们的治疗工作，包括一项基于计算机的培训的辅助试验，旨在将受试者对面孔的感知从愤怒转变为快乐。这项工作是基于我们之前的工作，展示了患有SMD的年轻人的面部情绪标记缺陷，以及我们的合作者(布里斯托尔大学的Marcus Munafo博士和特拉维夫大学的Yair Bar-Him博士)的工作，即这种面部标记培训可以与特质愤怒和易怒的减少相关。这项工作的第一步是证明我们可以使用内隐面孔情绪识别训练来改变青少年对愤怒面孔和快乐面孔的分类。我们已经训练了大约20名健康的青少年，使用积极和虚假的训练，初步数据表明，只有在积极治疗的情况下，这种转变才会发生。我们现在开始在易怒儿童中进行这种训练的公开试点试验，以测试a)训练在这一人群中是否成功，以及b)它是否与易怒程度降低有关。我们还将使用内隐面孔情绪识别任务，在训练前后扫描易怒的年轻人，以获得关于训练是否在处理情绪面孔时改变大脑电路的先导数据。

As noted above, in response to the concern about the appropriate diagnosis for children with chronic, severe irritability, we defined a group of children whom we described as having severe mood dysregulation (SMD). These children have extremely severe irritability and symptoms of hyperarousal (the latter being similar to those seen in attention deficit hyperactivity disorder (ADHD)) and, although they frequently receive the diagnosis of bipolar disorder (BD), they do not indeed meet diagnostic criteria for BD. Our SMD phenotype formed the basis for the new pediatric diagnosis of mood dysregulation disorder with dysphoria (DMDD) in DSM-5. (DMDD differs from SMD primarily in that DMDD does not require the hyperarousal symptoms, related to attention deficit hyperactivity disorder (ADHD)). Since the inception of this project, approximately 220 youth with SMD/DMDD 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. Also as noted above, in previous years we demonstrated differences between youth with SMD and those with BD in terms of clinical course, family history, and the brain mechanisms associated with behavioral problems. Thus, while we continue to compare youth with BD and those with severe irritability in terms of mediating brain mechanisms, we have become increasingly interested in the pathophysiology of irritability in its own right. Indeed, irritability is one of the most common presenting symptoms in pediatric psychiatry clinics. As noted above, the construct of irritability is particularly well-suited for a transdiagnostic, translational approach consistent with the Research Domain Criteria (RDoC) approach. Therefore, much of our work this year involves examining irritability, not only within the severely irritable DMDD phenotype, but also in other groups that exhibit considerable irritability, including youth with anxiety disorders, ADHD, or bipolar disorder (BD). Across all groups, we characterize irritability as a continuous variable. A major focus of our neuroimaging work includes the use of frustrating tasks, since a hallmark of irritability is difficulty tolerating frustration. In work published last year, we demonstrated behavioral and neural differences between irritable and non-irritable youth while completing a frustrating attentional task. We have improved that paradigm and are now applying it in a large sample of youth with DMDD, BD, ADHD, and/or anxiety disorders, as well as healthy youth. This approach allows us to examine the neural correlates of irritability, operationalized dimensionally, while also comparing DSM-5 diagnostic groups in terms of the brain circuitry engaged during a frustrating task. Preliminary data (N=70 across groups) indicate that increased irritability is associated with increased amygdala-parietal functional connectivity during frustrating, vs. non-frustrating, feedback. This may potentially provide an explanatory mechanism for the attentional dysfunction in irritable children during frustration. A major focus of our work continues to be treatment. We have continued our double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor (SRI) antidepressant that is effective in the treatment of pediatric anxiety) plus stimulant is more effective than placebo plus stimulant in the treatment of severe irritability in youth. Importantly, stimulant and SRI treatment tend to be less toxic than the atypical antipsychotic treatment that is considered first-line treatment for bipolar disorder, yet stimulants and SRI's are relatively contraindicated in patients with bipolar disorder because of concern about possibly inducing a manic episode. Therefore, this treatment trial has considerable public health importance. Thus far, we have randomized approximately 45 children into the trial, and youth are tolerating the experimental treatment well. In addition, we are assisting collaborators at UCLA on a similar trial that is funded extramurally. We are also now extending our treatment work to include an adjunctive trial of computer-based training designed to shift subject's perception of faces from angry toward happy. This work is based on our prior work demonstrating face emotion labeling deficits in youth with SMD, and work by our collaborators (Dr. Marcus Munafo at the University of Bristol and Dr. Yair Bar-Haim at Tel Aviv University) that such face labeling training can be associated with decreases in trait anger and irritability. The first step in this work is to demonstrate that we can use implicit face emotion identification training to shift adolescents categorization of angry vs. happy faces. We have trained approximately 20 healthy adolescents, using active vs. sham training, and preliminary data indicate that such shifting does occur with active treatment only. We are now beginning an open pilot trial of such training in irritable children to test a) whether training is successful in this population and b) whether it is associated with decreased irritability. We will also scan the irritable youth pre and post training, using an implicit face emotion identification task, to obtain pilot data as to whether the training alters brain circuitry while processing emotional faces.