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 enrolled 106 families in our NIH Family Study of Affective Spectrum Disorders. Interviews are ongoing with more than 500 relatives and spouses of these probands and the data are now being prepared for data entry. The distribution of probands with known diagnoses is: 32 with Bipolar Disorder; 32 with Major Depression; 12 with Migraine; 3 Controls. In addition, DNA collection from probands and their relatives has commenced. Earlier this year we established recruitment collaboration with the MAP Research Unit in the CRC. Subjects enrolled in studies (inpatient or outpatient) are referred to us by MAP investigators. The subject?s medical chart is reviewed to assess eligibility, and then reviewed by a clinician. After clinician?s approval, we discuss our study and consent the subject. All referral information is entered into our tracking database, an interviewer is assigned, and interviews can take place on the inpatient or outpatient units. SDGE staff now meet daily with Dr. Paulo J. Negro, Suburban Hospital?s Behavioral Health Director, to identify inpatients and attendees of SH?s Day Program (outpatients) who are eligible for the Family Study. From the NIMH/ Mood and Anxiety Disorder Program (MAP) Research Unit in the CRC we have received and screened 30 referrals since July, 2005. Of the 27 referred, 26 patients are either in progress or completed. From Suburban Hospital we have received and screened 65 referrals since February, 2005. Fifty-two were eligible, 30 have been consented, and 24 are in progress or completed. From other sources such as the MAP Referrals List, NIH clinical trials website, and Suburban Newsletter we have consented 32 persons and 6 are now in progress. Thirty-eight adult relatives have consented to the study, and clinical interviewers are continuing to contact family members of the probands. Over the past year, SDGE staff members have modified the Schedule for Affective Disorders and Schizophrenia for Children ? Epidemiologic version (K-SADS-E) for use with child offspring (ages 8-11) of probands and controls in the family study to include DSM-IV criteria. The modifications are now complete and we will employ this interview as we are beginning to recruit the children in the families enrolled in our study. This year we completed the development of a diagnostic interview for headaches including migraine, tension-type, cluster, and post-traumatic. This interview was piloted on participants who were identified through the medical history interview as having headaches. We have completed the development of a diagnostic interview for sleep patterns and problems, and it is currently being piloted and validated in the Stanford Sleep Clinic, as well as the Chevy Chase Center for Sleep and Wake Disorders. The study is being done in collaboration with Dr. Helene Emsellem at the Center for Sleep and Wake Disorders in Chevy Chase and Dr. Emmanuel Mignot at Stanford University. The subjects for the study are recruited from the sleep center in Chevy Chase, and the sleep clinic at Stanford University. Subjects are administered the interview by a trained interviewer who is blind to the subject?s sleep diagnosis. The diagnosis that is formed from the interview is then compared with the diagnosis that was established by the doctor in the sleep clinic to assess the accuracy of the sleep interview. Four papers have been drafted following completion of complex genetic epidemiologic data analyses on the Yale Family Study data. They include: (1) Assortative mating for substance use and anxiety disorders, (2) Familial aggregation of anxiety disorders ascertained from the community versus clinics, (3) Migraine and affective disorders: Familial patterns of comorbidity and coaggregation, and (4) The Familial Aggregation of Cannabis Use Disorders. SDGE staff members primarily contributing to these analytic projects and papers have been the fellows, biostatiscian and the Senior Investigator. These papers will be submitted by the end of September 2005. Plans for next year: During the next year, we will continue to recruit probands and families for this study. We anticipate completion of a total of 300 families by the end of the next project period. We are also beginning to establish a cohort of high-risk youth offspring of the probands included in the endophenotypes protocol to investigate the evolution of the components of these conditions in a prospective manner. In collection of a new community sample, we are collaborating with investigators from the National Institute of Neurologic Disease and Stroke (NINDS) and the National Institute of Aging (NIA) in order to screen for neurologic disorders in the local community as well.
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