Family Study of Affective and Anxiety Spectrum Disorders

本研究的主要目的是使用遗传流行病学、发展精神病理学和临床精神病学/心理学的方法来确定心境障碍谱的内在表型。主要的研究问题集中在心境障碍谱的家族传播的特异性上（即，症状、症状群、亚型）以及与焦虑症和偏头痛综合征共病在定义心境障碍亚型中的作用。 本研究采用家族研究设计，先证者有情绪、焦虑和偏头痛，嵌套病例对照研究的关键研究问题如下所述。我们建议招募500名先证者，包括双相I型、双相II型、重性抑郁症、惊恐/广泛性焦虑障碍、恐怖症、偏头痛和未受影响的对照组，通过精神病和非精神病临床环境和系统性社区样本进行确定，以提高人群的普遍性。大约2500名一级成年亲属和配偶以及750名子女（8-17岁）将组成家庭研究部分。先证者和亲属将使用结构化诊断访谈和标准化诊断标准进行评估，然后进行临床验证访谈和诊断共识程序。评估工具将收集有关DSM-IV标准以及情绪障碍和共病状况的信息。这将提供用于验证当前诊断系统的诊断阈值和边界的信息。参加这一阶段研究的家庭将被邀请参加下一阶段的研究，该阶段的研究旨在确定情感障碍的家族性内在表型，这些表型可能包括潜在遗传因素的中间表达形式。这些家庭将被纵向跟踪，以评估整个生命周期中心境障碍谱、亚型和综合征的发展。将同时编写单独的方案，以发展对特定内表型的研究，并随着家族的鉴定和表征进行纵向评价。 这项研究的主要贡献将包括：（1）确定在家庭中繁殖的真实的临床表型，并对特定亚型的情绪障碍具有特异性;（2）完善诊断命名法的表型;（3）解决共病障碍的作用，特别是焦虑和偏头痛，作为情绪障碍亚型的指标或匡威;和（4）阐明整个生命周期中心境障碍谱的显著成分的年龄和发育特异性表达模式。 在过去一年中，我们在开展家庭研究方面取得了重大进展。我们现在已经开始招募研究对象，并计划在明年采访一半的先证者和亲属。过去一年的成果包括：（1）根据情感障碍和精神分裂症量表（SADS）开发了一个半结构化的诊断访谈，收集了主要精神障碍的阈下谱;（2）与这些领域的专家协商，生成了睡眠综合征、头痛综合征和病史的诊断访谈;（3）发展系统性的家族史访谈，通过线人报告收集精神障碍的谱和病史;（4）选择和试行一套综合功能领域的自我报告评估;（5）制定系统的系谱查点表，以确定一级、二级和三级亲属;（6）建立一个网络接口和基于SQL服务器的计算机化数据库，以监测招募情况，筛选受试者，输入家庭谱系信息，跟踪研究进展，并准备研究入组的汇总统计数据;（7）列举研究受试者的访谈管理和临床监测程序;（8）雇用和培训10名临床访谈员;（9）与当地转诊来源建立联系;（10）初步准备巢式病例对照研究，以确定具有家族特异性的内表型;和（11）制定从研究参与者及其亲属收集生物样本的程序。

The chief goal of this study is to identify the endophenotypes of the spectrum of mood disorders using the methods of genetic epidemiology, developmental psychopathology and clinical psychiatry/psychology. The major research questions focus on the specificity of familial transmission of the mood disorder spectrum (i.e., symptoms, symptom clusters, subtypes) and the role of comorbidity with anxiety disorders and migraine syndromes in defining subtypes of mood disorders. This study employs a family study design of probands with mood, anxiety and migraine disorders with nested case control studies of the key study questions described below. We propose to recruit 500 probands with bipolar I, bipolar II, major depression, panic/GAD, phobias, migraine, and unaffected controls, ascertained through both psychiatric and non-psychiatric clinical settings and systematic community samples, in order to enhance generalizability to the population. Approximately 2500 first-degree adult relatives and spouses and 750 child offspring (ages 8-17) will comprise the family study component. Probands and relatives will be evaluated using structured diagnostic interviews and standardized diagnostic criteria followed by clinical validation interviews and diagnostic consensus procedures. Assessment instruments will collect information on the DSM-IV criteria as well as the spectrum of mood disorders and comorbid conditions. This will provide information that will be used to validate the diagnostic thresholds and boundaries of the current diagnostic systems. Families enrolled in this phase of research will be invited to participate in the next phase of research which is designed to identify familial endophenotypes of affective disorders that may comprise intermediate forms of expression of underlying genetic factors. These families will be followed longitudinally to evaluate the development of the mood disorder spectrum, subtypes, and syndromes across the lifespan. Separate protocols will be written concurrently to develop the research on specific endophenotypes and longitudinal evaluation as the identification and characterization of families proceeds. The major contributions of this research will include: (1) Identification of clinical phenotypes that breed true in families and are specific to particular subtypes of mood disorders; (2) Refinement of phenotypes for the diagnostic nomenclature; (3) Resolution of the role of comorbid disorders, particularly anxiety and migraine, as indicators of subtypes of mood disorders or the converse; and (4) Elucidation of age and development-specific patterns of expression of salient components of the mood disorder spectrum across the lifespan. During the past year, we have made substantial progress in launching the family study. We have now begun to recruit study subjects and plan to interview half of the probands and relatives during the next year. The accomplishments of the past year include: (1) development of a semi-structured diagnostic interview based on the Schedule for Affective Disorders and Schizophrenia (SADS)that collects subthreshold spectra of the major mental disorders; (2) generation of diagnostic interviews for sleep syndromes, headache syndromes, and medical history in consultation with experts in these domains ;(3) development of a systematic family history interview to collect the spectra of mental disorders and medical history through informant reports; (4) selection and piloting of a package of self-reported assessments of comprehensive domains of function; (5) development of a systematic pedigree enumeration form for identification of first, second and third degree relatives; (6) establishment of a web interface and SQL server-based computerized data base to monitor recruitment, screen subjects, enter family pedigree information, track study progress, and prepare summary statistics on study enrollment;(7) enumeration of procedddures for interview administration and clinical monitoring of study subjects;(8) hiring and training of 10 clinical interviewers; (9) development of liaisons with local referral sources; (10) initial preparation of nested case-control studies to identify endophenotypes with familial specificity; and (11) development of procedures for collection of biologic samples from the study participants and their relatives.