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

基本信息

批准号：
8745704
负责人：
Ellen Leibenluft
金额：
$ 141.73万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
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/8745704
关键词：
Address Adult Adverse effects Amygdaloid structure Anger Antidepressive Agents Anxiety Anxiety Disorders Attention Attention deficit hyperactivity disorder Bipolar Disorder Borderline Personality Disorder Brain Bronchopulmonary Dysplasia Characteristics Child Child Psychiatry Childhood Chronic Citalopram Clinical Clinical Protocols Clinical Trials Clinical Trials Design Collaborations Complement Computers Corpus striatum structure Data Depressive disorder Development Diagnosis Diagnostic Diagnostic and Statistical Manual Dimensions Disease Dizygotic Twins Double-Blind Method Drug Formulations Emotional Emotions Exhibits Face Family Feedback Fostering Frustration Functional Magnetic Resonance Imaging Functional disorder Funding Genetic Goals Heritability Hospitalization Hyperactive behavior Impairment Intervention Label Link Manic Measures Mediating Monozygotic Twinning Monozygotic twins Moods Names National Institute of Mental Health Paper Parents Parietal Patients Pharmaceutical Preparations Phenotype Placebos Population Problem behavior Psychiatric therapeutic procedure Psychopathology Public Health Publishing Randomized Recording of previous events Recruitment Activity Reporting Research Research Design Research Personnel Risk Scanning Sum Symptoms Syndrome Testing Therapeutic Training Twin Multiple Birth Unipolar Depression Universities Variant Virginia Work Youth atypical antipsychotic base behavior test comparison group design dysphoria effective therapy face perception genetic epidemiology inhibitor/antagonist instrument interest meetings neural circuit neuroimaging neuromechanism novel prototype response reuptake reward processing standardize measure trait treatment response treatment trial

项目摘要

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 in DSM-5. 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. 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. Since irritable youth have decreased ability to tolerate frustration, this year we continued our work using frustrating tasks inside the fMRI scanner to define the neural circuitry mediating irritability. In a paper in press, we found that, when frustrated, youth with SMD had more difficulty than healthy subjects shifting their attention in order to meet task demands. In addition, when frustrated and receiving negative feedback, compared to healthy subjects, those with SMD exhibited decreased activation in the amygdala, striatum, and parietal regions. On the other hand, when subjects were frustrated and received positive feedback, there was no difference in brain activity between healthy subjects and those with SMD. These findings indicate that in response to negative feedback received in the context of frustration, youth with severe, chronic irritability show abnormally reduced activation in regions implicated in emotion, attention, and reward processing. We will now extend this work by adding comparison groups of youth with BD, anxiety, and attention deficit hyperactivity. In a hypothesis consistent with a Research Domain Criteria (RDoC) formulation, we posit that, across all of these groups, increased irritability will be associated with decreased attentional control and amygdala-parietal-striatal deactivation during frustration. In addition, in a collaboration with extramurally-funded investigators at Virginia Commonwealth University, we will be scanning monozygotic and dizygotic twins while they perform this frustrating task in order to quantify environmental and genetic contributions to the neural mechanisms mediating frustration in healthy youth. In this work, Importantly, our work conceptualizing irritability as a dimensional trait present in healthy youth and across different psychopathologies was greatly facilitated by our development of a brief but valid self- and parent-report instrument that could be used to measure irritability in youth. A variant of this scale was used in the field trials for DSM-5. Our scanning study in twins complements our published and ongoing work on the genetic epidemiology of irritability. In this work, we demonstrated that the heritability of irritability is approximately 0.4 (which is moderate for psychiatric illnesses or traits). Ongoing work is designed to describe the developmental trajectory of genetic influences on irritability i.e., the extent to which different genetic mechanisms mediating irritability come "on-line" as youth develop. Consistent with our finding on the frustration task, we also found attentional dyscontrol in irritable subjects on a task designed to ascertain abnormal attentional bias toward threatening faces. Thus, in both the frustration and the attentional bias tasks, we found attentional dyscontrol in irritable youth in negative emotional contexts. The abnormal attentional bias toward threat that we saw in irritable children is consistent with the bias seen in youth with anxiety, and adds to emerging data about mechanistic and clinical links between anxiety and irritability. This link has considerable public health importance, since anxiety is a frequent but often unrecognized cause of irritability in youth presenting for psychiatric care. Also, the mechanistic link that we discovered between irritability and anxiety is also consistent with our prior data showing that irritable youth are at increased risk to develop anxiety disorders as adults. Potentially, these associations between anxiety and irritability may also be relevant to treatment. Last year, we began a 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 SMD. 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 35 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.

如上所述，为了回应对患有慢性、严重烦躁的儿童进行适当诊断的担忧，我们定义了一组被我们描述为患有严重情绪失调（SMD）的儿童。这些儿童有极其严重的烦躁和过度兴奋的症状（后者类似于注意力缺陷多动障碍（ADHD）），尽管他们经常被诊断为双相情感障碍（BD），但他们确实不符合以下诊断标准： BD。我们的 SMD 表型为 DSM-5 中心境失调障碍伴烦躁不安的新儿科诊断奠定了基础。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。同样如上所述，前几年我们证明了患有 SMD 的青少年和患有 BD 的青少年在临床病程、家族史以及与行为问题相关的大脑机制方面存在差异。由于易怒的年轻人容忍挫折的能力下降，今年我们继续使用功能磁共振成像扫描仪内的令人沮丧的任务来定义介导易怒的神经回路。在一篇即将发表的论文中，我们发现，当受到挫折时，患有 SMD 的青少年比健康受试者更难转移注意力以满足任务要求。此外，与健康受试者相比，当沮丧和收到负面反馈时，患有 SMD 的人杏仁核、纹状体和顶叶区域的激活程度降低。另一方面，当受试者感到沮丧并收到积极反馈时，健康受试者和患有 SMD 的受试者之间的大脑活动没有差异。这些发现表明，为了应对在沮丧的情况下收到的负面反馈，患有严重慢性烦躁的青少年在涉及情绪、注意力和奖励处理的区域表现出异常减少的激活。现在，我们将通过添加患有双相情感障碍、焦虑症和注意力缺陷多动症的青少年作为对照组来扩展这项工作。在与研究领域标准 (RDoC) 一致的假设中，我们假设，在所有这些群体中，烦躁性增加将与挫折期间注意力控制能力下降和杏仁核-顶叶-纹状体失活有关。此外，在与弗吉尼亚联邦大学外部资助的研究人员合作中，我们将在同卵双胞胎和异卵双胞胎执行这项令人沮丧的任务时对其进行扫描，以量化环境和遗传对介导健康青少年沮丧的神经机制的贡献。在这项工作中，重要的是，我们开发了一种简短但有效的自我报告和家长报告工具，可用于衡量青少年的烦躁情绪，极大地促进了我们将烦躁概念化为健康青少年和不同精神病理学中存在的一种维度特征的工作。 DSM-5 的现场试验中使用了该量表的一个变体。我们对双胞胎的扫描研究补充了我们已发表和正在进行的易怒遗传流行病学研究。在这项工作中，我们证明了烦躁的遗传力约为 0.4（对于精神疾病或特征来说是中等的）。正在进行的工作旨在描述遗传对烦躁性影响的发展轨迹，即随着青少年的发展，介导烦躁性的不同遗传机制“上线”的程度。与我们在挫折任务中的发现一致，我们还在一项旨在确定对威胁面孔的异常注意力偏向的任务中发现易怒受试者的注意力失调。因此，在挫折和注意力偏差任务中，我们发现在消极情绪背景下易怒的年轻人注意力失调。我们在易激惹的儿童中看到的对威胁的异常注意偏差与在患有焦虑症的青少年中看到的偏差是一致的，并且增加了有关焦虑和易激惹之间的机制和临床联系的新数据。这种联系具有相当大的公共卫生重要性，因为焦虑是导致寻求精神科护理的青少年烦躁的常见但往往未被认识到的原因。此外，我们发现的烦躁和焦虑之间的机制联系也与我们之前的数据一致，即烦躁的青少年成年后患焦虑症的风险增加。潜在地，焦虑和烦躁之间的这些关联也可能与治疗相关。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（SRI）抗抑郁药，可有效治疗儿童焦虑症）加兴奋剂在治疗 SMD 方面是否比安慰剂加兴奋剂更有效。重要的是，兴奋剂和 SRI 治疗往往比非典型抗精神病药物治疗的毒性要小，非典型抗精神病药物被认为是双相情感障碍的一线治疗方法，但兴奋剂和 SRI 治疗在双相情感障碍患者中相对禁忌，因为担心可能诱发躁狂发作。因此，该治疗试验具有相当大的公共卫生重要性。到目前为止，我们已经随机招募了大约 35 名儿童参加试验，青少年对实验治疗的耐受性良好。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由校外资助的类似试验。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训练的辅助试验，旨在将受试者对面孔的感知从愤怒转变为快乐。这项工作基于我们之前的工作，展示了患有 SMD 的青少年的面部情绪标签缺陷，以及我们的合作者（布里斯托大学的 Marcus Munafo 博士和特拉维夫大学的 Yair Bar-Haim 博士）的工作，这种面部标签训练可能与特质愤怒和烦躁的减少有关。