Family Study of Affective and Anxiety Spectrum Disorders

情感和焦虑谱系障碍的家庭研究

• 批准号: 8556939
• 负责人: kathleen r merikangas
• 金额: $ 171.77万
• 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/8556939
• 关键词: Address; Adult; Affective; Age; Anxiety; Anxiety Disorders; Attention; Atypical depressive disorder; Auras; Autonomic nervous system; Biological; Biological Factors; Bipolar Disorder; Breeding; Cardiovascular Diseases; Cardiovascular system; Child; Circadian Rhythms; Classic Migraine; Clinical; Cognitive; Communities; Comorbidity; Cues; DSM-IV; Data; Data Analyses; Data Set; Development; Diagnosis; Diagnostic; Diet; Disease; Disease susceptibility; Early treatment; Electronics; Enrollment; Evaluation; Event; Evolution; Family; Family Study; Family history of; Future; Genetic; Genomics; Goals; Headache; Headache Syndrome; Heart Rate; Heritability; Holter Electrocardiography; Hormones; Immunologics; Interview; Laboratories; Lead; Life; Link; Longevity; Magnetic Resonance Imaging; Major Depressive Disorder; Manic; Measures; Medical History; Mental Depression; Mental disorders; Metabolic; Methods; Migraine; Mood Disorders; Moods; National Institute of Mental Health; Neurologic Examination; Nomenclature; Paper; Parents; Participant; Patient Self-Report; Pattern; Pennsylvania; Personality; Persons; Phase; Phenotype; Physical Examination; Preventive Intervention; Psychiatry; Psychology; Psychopathology; Psychophysiology; Public Health; Recording of previous events; Recruitment Activity; Reflex action; Relative (related person); Reporting; Research; Resolution; Risk; Risk Factors; Role; Running; Saliva; Sampling; Series; Sex Characteristics; Sleep; Sleep Disorders; Source; Specificity; Speed; Stress; Structure; Symptoms; System; Testing; Time; United States National Institutes of Health; Universities; Update; Validation; Valsalva Maneuver; Work; Youth; actigraphy; base; blink reflexes; cardiovascular disorder risk; clinical phenotype; cohort; community setting; computerized; design; diaries; disorder subtype; endophenotype; family structure; follow-up; genetic epidemiology; high risk; hypomania; neuropsychological; novel; offspring; proband; sex; social; trait; transmission process

The major aims of this project have been accomplished through establishment of a large community based family study of adult probands who participate in comprehensive clinical and biologic assessments followed by comparable evaluations of their adult and child relatives. Recruitment of probands and evaluation of relatives are now near completion and analyses of the findings are underway. To date, we have enrolled 344 participants into the study from the community, and 238 from clinical sources. Our total enrollment from all sources is 786 probands, of which almost 500 have completed the study, and 1,283 relatives, including 175 children. Over the past year, 11 probands and 49 relatives have been recruited. Probands represent a range of disorders including: 30% with bipolar, 63% with depression, 60% with anxiety, 50% with migraine, and 22% without any of these conditions. During the next 3 months we plan to complete recruitment of probands and evaluation of relatives and will commence data analysis. In order to identify the core features of mood and anxiety disorders and their overlap with cardiovascular diseases and migraine, we have established a set of clinical, psychophysiological and neuropsychological measures. The comprehensive set of measures in the study are divided into three components: (1) clinical information that includes a semi-structured diagnostic interview for mood and anxiety disorders, structured diagnostic interviews for major headache syndromes and for sleep disorders, family history of psychiatric disorders, sleep disorders and headache syndromes, and a series of self-reported measures of symptoms, sleep patterns and personality, medical history, family structure, history and function, and major life and family events; (2) in person evaluation at the NIH Clinical Center that includes physical and neurological examination; autonomic nervous system evaluation using tilt and valsalva maneuver; laboratory measures of metabolic, cardiovascular, and immunologic function; psychophysiologic evaluation including startle reflex and eyeblink reflex; structural magnetic resonance imaging; a computerized cognitive assessment battery; and olfactory function; and (3) two-week assessment of daily activities including an electronic diary that assesses daily rhythms including mood, anxiety, sleep, stress, activity, diet, and social activities; heart rate reactivity using a holter monitor; activity and sleep using an actiwatch; and saliva hormones collected four times per day. In the past year, we have been running preliminary analyses on several of these clinical components and working with external collaborators to design and implement analyses of all of the measures in the study. This study has yielded substantial methodological developments including the development and validation of a structured diagnostic interview for headache syndromes; systematic assessment of the validity of the NIMH Family Study Diagnostic Interview for Affective Spectrum Disorders that was developed for this study compared to the Structure Clinical Interview for DSM-IV (SCID); and the validity of the NIMH Sleep Diagnostic Interview also developed for this study compared with sleep disorder diagnoses made by sleep experts. We have completed the primary analyses of the familial aggregation of mood disorder subtypes, their patterns of comorbidity, and their co-aggregation in relatives, and have submitted the principal paper that reports these findings. Likewise, we have also completed analyses of the familial aggregation of migraine and comorbid conditions. The major findings confirm the familial aggregation of bipolar disorder and major depression that has been found in earlier family studies of mood disorders but in a community based sample that suspended diagnostic hierarchies of earlier diagnostic systems. The most important finding that emerged from this study is the independent familial transmission of mania and depression suggesting that these two mood states may represent distinct underlying diatheses. The lack of familial aggregation of hypomania suggests that the bipolar spectrum concept may not be a valid entity. We also found strong evidence for familial specificity of atypical depression in probands and interviewed relatives, thereby confirming the validity of this subtype of depression. We also have investigated the familial aggregation of migraine and its links with mood disorders. We found a 2.6-fold increased risk of migraine in the relatives of probands with migraine, primarily attributable to migraine with aura. Sex of the proband was not associated with differential risk of migraine in relatives, thereby indicating that the sex difference in migraine cannot be attributed to genetic factors. Additional analyses that are now being investigated include the familial aggregation of subtypes of sleep disorders, early manifestations of mood and anxiety disorders in offspring of parents with mood spectrum disorders, and heritability analyses of both disorders and underlying traits. During the past several months, we have begun to examine the non-clinical measures as well, with substantial progress in analysis of the eyeblink reflex, actigraphy, olfactory measures and attention using the Attention Network Test. We have also conducted extensive analyses of links between cardiovascular disease and risk factors, migraine and depression in other data sets to develop specific hypotheses for the analyses of the family study data. Some intriguing findings that have emerged include: greater reactivity of the eyeblink reflex among those with migraine with aura compared to those without aura and non-headache controls; greater variability in activity among those with major depression; and increased orienting to cues in those with migraine with aura, and decreased speed of attention among those with depression. Public Health Impact: Integration of the clinical, neuropsychological and psychophysiological measures within families will allow us an in-depth analysis of the biological mechanisms crucial for mood and anxiety disorders and their underlying diatheses. This will not only lead to a better understanding of these conditions, and assist in identifying common genetic mechanisms, but may also lead to the development of novel treatment options and possible strategies for prevention and early intervention in those with elevated risk for these conditions. Future Plans: During the next year, we plan to follow up the probands and relatives to update the diagnostic status, and repeat the measures of circadian rhythms of activity, sleep and cognitive and mood states to test their stability and seasonal changes. We will complete enrollment of children under age 18 and follow up the 150 youth who have already participated in the study. Finally, we will examine common measures to match the NIMH local community to the supplemental study that we are now conducting in the Neurodevelopmental Genomics Study at the University of Pennsylvania.

该项目的主要目标是通过建立一个以社区为基础的大型成年先证者家庭研究来实现的，先证者参与全面的临床和生物学评估，然后对其成年和儿童亲属进行可比较的评估。 先证者的招募和亲属的评估现已接近完成，并对结果进行分析正在进行中。 迄今为止，我们已招募了 344 名来自社区的参与者和 238 名来自临床的参与者参加这项研究。我们从所有来源招募的总人数为 786 名先证者，其中近 500 名已完成研究，以及 1,283 名亲属，其中包括 175 名儿童。去年，11名先证者和49名亲属被招募。先证者代表一系列疾病，包括：30% 患有双相情感障碍，63% 患有抑郁症，60% 患有焦虑症，50% 患有偏头痛，22% 没有任何这些疾病。 在接下来的3个月内，我们计划完成先证者的招募和亲属的评估，并将开始数据分析。 为了确定情绪和焦虑障碍的核心特征及其与心血管疾病和偏头痛的重叠，我们建立了一套临床、心理生理学和神经心理学测量方法。研究中的综合措施分为三个部分：（1）临床信息，包括针对情绪和焦虑障碍的半结构化诊断访谈、针对严重头痛综合征和睡眠障碍的结构化诊断访谈、精神疾病家族史、睡眠障碍和头痛综合症，以及一系列自我报告的症状、睡眠模式和性格、病史、家庭结构、历史和功能以及重大生活和家庭事件的测量； (2) 在 NIH 临床中心进行亲自评估，包括身体和神经系统检查；使用倾斜和瓦氏动作评估自主神经系统； 代谢、心血管和免疫功能的实验室测量；心理生理评估，包括惊吓反射和眨眼反射；结构磁共振成像； 计算机化认知评估电池；和嗅觉功能； (3) 两周的日常活动评估，包括评估日常节律的电子日记，包括情绪、焦虑、睡眠、压力、活动、饮食和社交活动；使用动态心电图监测心率反应性；使用 actiwatch 进行活动和睡眠；每天收集四次唾液激素。在过去的一年中，我们一直在对其中几个临床成分进行初步分析，并与外部合作者合作设计和实施研究中所有措施的分析。 这项研究取得了重大的方法学进展，包括开发和验证头痛综合征的结构化诊断访谈；系统评估为本研究开发的 NIMH 家庭研究情感谱系障碍诊断访谈与 DSM-IV (SCID) 结构临床访谈的有效性；与睡眠专家做出的睡眠障碍诊断相比，NIMH 睡眠诊断访谈的有效性也得到了提高。 我们已经完成了对情绪障碍亚型的家庭聚集、其合并症模式以及其在亲属中的共同聚集的初步分析，并提交了报告这些发现的主要论文。同样，我们还完成了偏头痛和合并症的家族聚集性分析。主要发现证实了双相情感障碍和重度抑郁症的家族聚集性，这一点在早期情绪障碍家庭研究中发现，但在基于社区的样本中发现，该样本中止了早期诊断系统的诊断等级。这项研究最重要的发现是躁狂症和抑郁症的独立家族传播，表明这两种情绪状态可能代表不同的潜在素质。轻躁狂缺乏家族聚集性表明双相情感谱概念可能不是一个有效的实体。我们还在先证者和受访亲属中发现了非典型抑郁症家族特异性的有力证据，从而证实了这种抑郁症亚型的有效性。我们还调查了偏头痛的家族聚集性及其与情绪障碍的联系。我们发现患有偏头痛的先证者亲属患偏头痛的风险增加了 2.6 倍，这主要归因于有先兆的偏头痛。先证者的性别与亲属中偏头痛的风险差异无关，因此表明偏头痛的性别差异不能归因于遗传因素。目前正在研究的其他分析包括睡眠障碍亚型的家族聚集、患有情绪谱系障碍的父母后代的情绪和焦虑障碍的早期表现，以及这两种疾病和潜在特征的遗传性分析。 在过去的几个月里，我们也开始研究非临床测量，在使用注意力网络测试分析眨眼反射、体动记录、嗅觉测量和注意力方面取得了实质性进展。我们还对其他数据集中的心血管疾病与危险因素、偏头痛和抑郁症之间的联系进行了广泛的分析，为家庭研究数据的分析提出了具体的假设。一些有趣的发现包括：与无先兆偏头痛和非头痛对照者相比，有先兆偏头痛患者的眨眼反射反应性更强；重度抑郁症患者的活动差异较大；有先兆偏头痛的人对线索的定向能力增强，抑郁症患者的注意力速度下降。 公共卫生影响： 家庭内临床、神经心理学和心理生理学措施的整合将使我们能够深入分析对情绪和焦虑症及其潜在素质至关重要的生物学机制。这不仅将有助于更好地了解这些疾病，并有助于识别常见的遗传机制，而且还可能导致开发新的治疗方案以及可能的策略，以预防和早期干预这些疾病风险较高的人。 未来计划： 明年，我们计划对先证者和亲属进行随访，更新诊断状态，并重复测量活动、睡眠、认知和情绪状态的昼夜节律，以测试其稳定性和季节变化。我们将完成 18 岁以下儿童的入组工作，并对已经参与该研究的 150 名青少年进行追踪。最后，我们将研究常用措施，将 NIMH 当地社区与我们目前在宾夕法尼亚大学神经发育基因组学研究中进行的补充研究相匹配。