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：
7969348
负责人：
Ellen Leibenluft
金额：
$ 137.64万
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/7969348
关键词：
Address Adverse effects Age Agitation Amygdaloid structure Anger Antidepressive Agents Anxiety Anxiety Disorders Attention Attention deficit hyperactivity disorder Behavioral Bipolar Disorder Borderline Personality Disorder Brain Bronchopulmonary Dysplasia Characteristics Child Childhood Chronic Citalopram Clinical Clinical Trials Clinical Trials Design Data Data Collection Depressed mood Depressive disorder Development Diagnosis Diagnostic Emotions Exhibits Face Family history of Functional Magnetic Resonance Imaging Functional disorder Goals Hospitalization Impairment Label Lithium Major Depressive Disorder Manic Mediating Moods Names Nature Parents Patients Pharmaceutical Preparations Phenotype Placebos Process Psychopathology Public Health Publications Publishing Recruitment Activity Reporting Risk Sampling Sleeplessness Specific qualifier value Symptoms Syndrome Testing Therapeutic Time Unipolar Depression Variant Work Youth atypical antipsychotic depression design emerging adult emotional stimulus inhibitor/antagonist meetings neural circuit neuroimaging relating to nervous system reuptake standardize measure treatment planning treatment response

项目摘要

Considerable public attention has focused recently on the question of why there has been a rather dramatic upsurge recently 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 behvioral testing) to that of children with unequivocal BPD; 3) to test appropriate treatments for SMD. The latter is 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 150 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. A limitation of those data were that subjects were only followed untl the age of 18, which is not through the age of risk for BD. In work published this year, we examined associations between chronic irritability, as one would see in SMD, and psychopathology in an epidemiologic sample followed from age 13 to age 33. Importantly, the latter is through the major age of risk for BD. Once again, we found an association between chronic irritability and risk for unipolar depressive disorders and anxiety disorders, but not BD. This further bolsters the argument that, at least from a categorical perspective, SMD should not be considered to be a developmental phenotype of BD. In previous years, we had 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 emotionl labeling. This year we are preparing for publication data which indicate that, while BD and SMD have similar behavioral deficits, the neural dysfunction mediating that dysfunction differs between groups. Specifically, the nature of amygdala dysfunction during face emotion processing differs among youth with BD, SMD, and ADHD. Ongoing work is designed to further specify the precise nature of the amygdala dysfunction in these groups, and to ascertain whether explicit labeling is needed in order to elicit between-group differences in amygdala activity (preliminary data suggest that it is not). 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. This year, we began a doubel-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor antidepressant) plus stimulant is more effective than placebo puls stimulant in the treatment of SMD. The choice of citalopram and stimulant was motivated by three considerations: 1) youth with SMD meet criteria for ADHD; 2) youth with SMD frequently meet current criteria for anxiety disorders, and data indicated that serotonergic reuptake inhibitor antidepressants are effective in the treatment of pediatric anxiety disorders; and 3) youth with SMD are at increased risk to develop unipolar depressive disorders and anxiety disorders as they mature, and both these conditions can be treated by serotonergic reuptake inhibitor antidepressants. Data collection is currently onoging.

最近，相当多的公众注意力集中在这样一个问题上：为什么最近将双相情感障碍 (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、注意力不集中）和注意力增加。对负面情绪刺激的反应。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) 比较 SMD 儿童的脑功能（用功能性脑功能障碍评估）对患有明确 BPD 的儿童进行 MRI 和标准化行为测试； 3）测试SMD的适当治疗方法。后者尤其重要，因为如果发现患有 SMD 的青少年患有某种形式的 BD，则需要接受一个疗程，而如果发现他们患有（例如）抑郁、焦虑和/或注意力缺陷的变体多动症，这将决定一个相当不同的治疗计划。自该项目启动以来，已招募了约 150 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。这些数据的一个局限性是，受试者只被跟踪到 18 岁，这并没有达到 BD 的风险年龄。在今年发表的研究中，我们在 13 岁至 33 岁的流行病学样本中研究了慢性烦躁（如 SMD 中所见）与精神病理学之间的关联。重要的是，后者是 BD 的主要危险年龄。我们再次发现慢性烦躁与单相抑郁症和焦虑症风险之间存在关联，但与双相情感障碍无关。这进一步支持了这样的论点：至少从绝对角度来看，SMD 不应被视为 BD 的一种发育表型。前几年，我们已经证明，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，在面部情绪标签方面存在缺陷。今年，我们正在准备发表数据，这些数据表明，虽然 BD 和 SMD 具有相似的行为缺陷，但介导功能障碍的神经功能障碍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。正在进行的工作旨在进一步明确这些群体中杏仁核功能障碍的确切性质，并确定是否需要明确的标记才能引起杏仁核活动的组间差异（初步数据表明不需要）。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。今年，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。选择西酞普兰和兴奋剂是出于三个考虑：1）患有 SMD 的青少年符合 ADHD 的标准； 2）患有SMD的青少年经常符合当前的焦虑症标准，并且数据表明5-羟色胺再摄取抑制剂抗抑郁药可有效治疗小儿焦虑症； 3) 患有 SMD 的青少年随着年龄的增长，患单相抑郁症和焦虑症的风险会增加，而这两种疾病都可以通过血清素再摄取抑制剂抗抑郁药来治疗。目前正在进行数据收集。