The Pathophysiology and Treatment of Children with Severe Irritability

儿童严重烦躁的病理生理学和治疗

• 批准号: 9357273
• 负责人: Ellen Leibenluft
• 金额: $ 326.96万
• 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/9357273
• 关键词: Adopted; Adverse effects; Aftercare; Age; Amygdaloid structure; Anger; Antidepressive Agents; Anxiety; Anxiety Disorders; Attention deficit hyperactivity disorder; Behavioral; Bipolar Disorder; Brain; Brain imaging; Child; Child Psychiatry; Childhood; Chronic; Citalopram; Clinical; Cognitive Therapy; Communities; Data; Development; Diagnosis; Diagnostic; Diagnostic and Statistical Manual of Mental Disorders; Dimensions; Disease; Double-blind trial; E-learning; Emotional; Emotions; Exhibits; Face; Family; Fostering; Frustration; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Hospitalization; Impairment; Intervention; Judgment; Label; Left; Life; Longitudinal Studies; Manic; Manuals; Measures; Medial; Mediating; Modeling; Moods; National Institute of Mental Health; Neurosciences; Operant Conditioning; Patients; Perception; Pharmaceutical Preparations; Phenotype; Placebos; Population; Prefrontal Cortex; Process; Protocols documentation; Psychiatry; Public Health; Publishing; Randomized; Recording of previous events; Recruitment Activity; Research; Research Design; Research Domain Criteria; Research Personnel; Risk; Sampling; Stream; Suggestion; Sum; Symptoms; Syndrome; Techniques; Testing; Training; Unipolar Depression; Visual; Work; Youth; atypical antipsychotic; base; brain circuitry; childhood anxiety; common treatment; control trial; design; dysphoria; experience; improved; inhibitor/antagonist; interest; neural circuit; neural correlate; neuroimaging; neuromechanism; novel; prototype; psychosocial; relating to nervous system; response; reuptake; severe mood dysregulation; standardize measure; trait; translational approach; treatment response; trial design

Given concerns about the appropriate diagnosis for children with chronic, severe irritability, we defined the syndrome of severe mood dysregulation(SMD)to capture youth with extremely severe irritability and symptoms of hyperarousal. Our SMD phenotype formed the basis for the new pediatric diagnosis of mood dysregulation disorder with dysphoria(DMDD)in DSM-5. Since the inception of this project, approximately 300 youth with SMD/DMDD have been recruited into the project. Approximately 20 new patients were recruited this year. Youth with DMDD suffer very severe psychiatric impairment, as assessed by medications received, number of psychiatric hospitalizations, and standardized measures of function. As noted above, we demonstrated differences between youth with SMD and those with bipolar disorder (BD) in clinical course, family history, and brain mechanisms associated with symptoms. 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. The construct of irritability is particularly well-suited for the transdiagnostic, translational approach of the Research Domain Criteria (RDoC). Much of our work now involves examining irritability, not only in DMDD, but also in other groups exhibiting irritability, including youth with anxiety disorders, ADHD, or BD. Across groups, we characterize irritability as a continuous variable. A focus of our neuroimaging work includes the use of frustrating tasks, since a hallmark of irritability is difficulty tolerating frustration. Previously, we demonstrated behavioral and neural differences between irritable and non-irritable youth during a frustrating attentional task. We improved that paradigm and obtained fMRI data from approximately 200 youth with DMDD, BD, ADHD, and/or anxiety disorders, as well as healthy youth; these data are currently being analyzed. This approach allows us to examine the neural correlates of irritability, operationalized dimensionally, while also comparing DSM-5 diagnostic groups in the brain circuitry engaged during a frustrating task. We also demonstrated in a community-based sample (N=109) that the same frustrating task has good test-retest reliability in inducing frustration (therefore, it might be used pre- and post-treatment as a measure of treatment response). Also, the child's ratings of his/her frustration during the task correlated with his/her ratings of irritability in daily life, supporting the suggestion that the task assesses processes relevant to the child's symptoms. We have also piloted an additional frustration task both inside and outside the scanner, to try to improve even further our ability to detect neural mechanisms mediating frustration. We continue our work comparing the neural circuitry mediating face emotion processing among youth with DMDD, BD, and healthy youth. As with the frustration work, we now incorporate a dimensional approach, examining neural associations with continuous measures of irritability. In work published this year, we compared the impact of irritability on brain activation across youth with BD, DMDD, and healthy subjects. Brain activity was measured while youth performed a labeling task with happy, fearful, and angry faces of varying emotional intensity. We found differences between BD and DMDD in associations between irritability and brain activity. Specifically, irritability correlated with amygdala activity across all intensities for all emotions in the DMDD group; such correlation was present in the BD group only for fearful faces. In the ventral visual stream, associations between neural activity and irritability were found more consistently in the DMDD group than in the BD group, especially in response to ambiguous angry faces. These data suggest that the circuitry mediating a dimension, such as irritability, might vary across diagnoses. RDoC does not explicitly incorporate a longitudinal perspective; arguably, such a perspective is more central to the diagnosis of BD than to other diagnoses, such as DMDD, anxiety disorders, and ADHD. Therefore, compared to the latter three diagnoses, cross-sectional dimensions alone may not be less able to explain the circuitry of a trait when that trait appears within the context of BD. Second, these data suggest that treatment approaches, such as one described below designed to modify irritable children's responses to angry faces, might be less effective in irritable youth with BD than in those with DMDD. This work emphasizes the importance of integrating both categorical (i.e., diagnostic group) and dimensional (e.g., irritability) research approaches. Another unexplored aspect of the RDoC framework is whether traits interact neurally. We are interested in possible interactions between anxiety and irritability, given cross-sectional and longitudinal associations between these traits and possible shared circuitry mediating them. In healthy youth and those with DMDD, ADHD, anxiety disorders (N=115), we found that irritability and anxiety jointly influenced left amygdala to left medial prefrontal cortex (mPFC) connectivity during viewing of intensely angry faces. Specifically, decreased connectivity was associated with high levels of both anxiety and irritability, whereas increased connectivity was associated with high levels of anxiety but low levels of irritability. This study yields the important conclusion that the circuitry mediating dimensional traits should not be considered in isolation from each other. A major focus of our work is treatment. We continue 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. Stimulant and SRI treatment tend to have fewer side-effects than atypical antipsychotic treatment, which that is considered first-line treatment for BD, yet stimulants and SRI's are relatively contraindicated in patients with BD because of concern about possibly inducing a manic episode. Therefore, this work has considerable public health importance. We have randomized approximately 50 children into the trial, and youth are tolerating the treatment well. We are now developing and testing two novel psychosocial approaches to treating irritability. The first involves computer-based training designed to shift a subject's perception of ambiguous faces from angry toward happy. In work published this year, we found that youth with DMDD tend to judge ambiguous faces as angry rather than happy; that we can change this judgment with computer-based training; and that this is associated with decreased irritability. This was an open trial, without a control condition. We have begun a controlled trial of this new Interpretation Bias Treatment, along with brain imaging before and after training. Recruitment has been robust. We are also now piloting a manual-based cognitive behavioral treatment targeting irritability. This has a strong emphasis on behavioral techniques i.e., exposing the child to tolerable, but frustrating situations, to improve the child's ability to tolerate such situations. The treatment is based on our neuroscience-based model of irritability, including irritable children's hypothesized deficits in the process and content of instrumental learning. We are now piloting a neuroimaging paradigm designed to assess such deficits in irritable youth. Such a paradigm could that can be used pre- and post- treatment to document changes in the circuitry mediating these processes during successful treatment.

考虑到对患有慢性、严重烦躁的儿童进行适当诊断的担忧，我们定义了严重情绪失调综合征（SMD），以捕捉具有极度严重烦躁和过度警觉症状的青少年。我们的 SMD 表型为 DSM-5 中心境失调伴烦躁症 (DMDD) 的新儿科诊断奠定了基础。自该项目启动以来，已招募了约 300 名患有 SMD/DMDD 的青少年加入该项目。今年招募了大约20名新患者。 根据接受的药物治疗、精神病住院次数和标准化功能测量来评估，患有 DMDD 的青少年患有非常严重的精神障碍。如上所述，我们证明了患有 SMD 的青少年和患有双相情感障碍 (BD) 的青少年在临床病程、家族史和与症状相关的大脑机制方面的差异。虽然我们继续在调节大脑机制方面比较患有双相情感障碍的青少年和患有严重烦躁的青少年，但我们对烦躁本身的病理生理学越来越感兴趣。事实上，烦躁是儿科精神病学中最常见的症状之一。 烦躁的概念特别适合研究领域标准 (RDoC) 的跨诊断、转化方法。现在，我们的大部分工作涉及检查烦躁情绪，不仅是 DMDD，还包括其他表现出烦躁情绪的群体，包括患有焦虑症、ADHD 或 BD 的青少年。在各个群体中，我们将烦躁性描述为一个连续变量。我们神经影像学工作的一个重点包括使用令人沮丧的任务，因为烦躁的标志是难以忍受沮丧。之前，我们证明了易怒和不易烦躁的年轻人在一项令人沮丧的注意力任务中的行为和神经差异。我们改进了这一范式，并从大约 200 名患有 DMDD、BD、ADHD 和/或焦虑症的青少年以及健康青少年中获得了 fMRI 数据；目前正在分析这些数据。这种方法使我们能够在维度上检查烦躁性的神经相关性，同时还比较在令人沮丧的任务期间参与的大脑回路中的 DSM-5 诊断组。我们还在基于社区的样本（N = 109）中证明，相同的令人沮丧的任务在引起沮丧方面具有良好的重测可靠性（因此，它可以在治疗前和治疗后用作治疗反应的衡量标准）。此外，孩子在任务期间对他/她的挫败感的评价与他/她对日常生活中烦躁的评价相关，支持任务评估与孩子的症状相关的过程的建议。我们还在扫描仪内部和外部试验了一项额外的挫败感任务，以尝试进一步提高我们检测介导挫败感的神经机制的能力。 我们继续研究比较患有 DMDD、BD 和健康青年的青少年面部情绪处理的神经回路。与挫折工作一样，我们现在采用了一种维度方法，通过连续测量烦躁性来检查神经关联。 在今年发表的研究中，我们比较了烦躁对患有 BD、DMDD 和健康受试者的青少年大脑激活的影响。当青少年执行标记任务时，他们会测量大脑活动，并用不同情绪强度的快乐、恐惧和愤怒的面孔进行标记。我们发现 BD 和 DMDD 在烦躁和大脑活动之间的关联上存在差异。具体来说，在 DMDD 组中，所有情绪强度下的烦躁都与杏仁核活动相关。这种相关性仅在 BD 组中存在于恐惧的面孔上。在腹侧视觉流中，DMDD 组的神经活动与烦躁之间的关联比 BD 组更一致，尤其是在对模糊的愤怒面孔做出反应时。这些数据表明，介导某个维度（例如烦躁）的电路可能因诊断而异。 RDoC 没有明确纳入纵向视角；可以说，与 DMDD、焦虑症和 ADHD 等其他诊断相比，这种观点对于 BD 的诊断更为重要。 因此，与后三种诊断相比，当某个特征出现在双相情感障碍的背景下时，仅凭横截面维度可能无法更无法解释该特征的电路。其次，这些数据表明，治疗方法（例如下面描述的旨在改变易怒儿童对愤怒面孔的反应的治疗方法）对于患有 BD 的易怒青少年可能不如患有 DMDD 的青少年有效。这项工作强调了整合分类（即诊断组）和维度（例如烦躁）研究方法的重要性。 RDoC 框架的另一个尚未探索的方面是特征是否在神经上相互作用。考虑到这些特征之间的横向和纵向关联以及调节它们的可能的共享电路，我们对焦虑和烦躁之间可能的相互作用感兴趣。在健康青少年和患有 DMDD、ADHD、焦虑症的青少年 (N=115) 中，我们发现在观看极度愤怒的面孔时，烦躁和焦虑共同影响左杏仁核到左内侧前额叶皮层 (mPFC) 的连接。具体来说，连通性下降与高水平的焦虑和烦躁有关，而连通性的增加则与高水平的焦虑和低水平的烦躁有关。这项研究得出了重要的结论，即介导尺寸特征的电路不应彼此孤立地考虑。 我们工作的一个主要重点是治疗。我们继续进行双盲试验，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）加兴奋剂在治疗严重烦躁方面是否比安慰剂加兴奋剂更有效。兴奋剂和 SRI 治疗往往比非典型抗精神病药物治疗的副作用更少，非典型抗精神病药物被认为是 BD 的一线治疗方法，但兴奋剂和 SRI 治疗 BD 患者相对禁忌，因为担心可能诱发躁狂发作。因此，这项工作具有相当大的公共卫生重要性。我们随机招募了大约 50 名儿童参加试验，青少年对治疗的耐受性良好。 我们现在正在开发和测试两种治疗烦躁的新型心理社会方法。第一个涉及基于计算机的训练，旨在将受试者对模糊面孔的感知从愤怒转变为快乐。在今年发表的研究中，我们发现患有 DMDD 的年轻人倾向于将模糊的面孔视为愤怒而不是快乐；我们可以通过基于计算机的培训来改变这种判断；这与烦躁情绪的减少有关。这是一项公开试验，没有控制条件。我们已经开始对这种新的解释偏差治疗进行对照试验，并在训练前后进行脑成像。招聘一直很强劲。我们现在还在试点一种针对烦躁的基于手动的认知行为治疗。这非常强调行为技巧，即将孩子暴露在可以忍受但令人沮丧的情况下，以提高孩子容忍这种情况的能力。该治疗基于我们基于神经科学的烦躁模型，包括假设烦躁儿童在工具学习的过程和内容中存在缺陷。我们现在正在试验一种神经影像学范式，旨在评估易怒青少年的此类缺陷。这样的范例可以在治疗前和治疗后使用，以记录在成功治疗期间介导这些过程的电路的变化。