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.
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