The chief goal of this study is to identify the components 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. One of the chief issues addressed in our work is to identify the core clinical and biologic factors underlying the mood disorder spectrum and migraine that run in families. ? ? The phases of implementation of this research include: (1) development of measures of the spectrum of mood and anxiety disorders in adults and children, and structured interviews for the key components of the study phenotypes including mood, sleep and headache; (2) sampling and recruitment of probands from both clinical and community settings and enrollment and evaluation of the relatives; (3) selection and implementation of core features and endophenotypes for mood disorders and migraine; and (4) establishment of a high risk cohort to study the evolution of these disorders and the specificity of vulnerability markers and endophenotypes prior to clinical onset of these conditions. We have now completed the first phase, have made substantial progress on phases 2 and 3 that involve proband recruitment and clinical and laboratory evaluation, and have established a comprehensive series of measures and begun to enroll children in the high risk study, phase 4 of this research. ? ? (1) Measure development:? During the first two years of this study, diagnostic and laboratory studies of the adults were developed and piloted. These measures have been completed in a large number of probands and relatives, as described below. During the past year, we devoted substantial effort to development of measures and domains of assessment for the study of children and adolescents. With consultation from our collaborators with expertise in diagnostic assessment in children, we extensively modified and tested the psychiatric diagnostic interview in children using our Kiddie-Family Study Interview, in order to tap the dimensions underlying the core features of childhood emotional and behavioral disorders. We also have modified the other measures in the adult study to adapt them for use with children and adolescents. For example, we developed a child headache interview in collaboration with a child neurologist at Children National Medical Center to assess for headaches and migraine, adapted the adult neurologic examination for children, and modified the in vivo monitoring of daily activities for children. Finally, in collaboration with a team of collaborators from the University of Pennsylvania and University of Oregon, we have developed a battery of measures of attention, perception, sensory processing and memory for children.? ? (2) Recruitment of probands and families? Sources of Probands: Clinical Settings: The two most fruitful sources for initial recruitment of clinical samples were the Behavioral Health Program at Suburban Hospital, which is immediately adjacent to the NIH campus, and the NIMH Clinical Research Center, that referred patients who had either been evaluated or treated in clinical protocols for mood disorders. To date, we have enrolled approximately 150 probands from these clinical settings. During the past year, we have established an agreement with Children's National Medical Center to ascertain systematic samples of outpatients with headaches.? ? Local Community Survey: In order to recruit an unbiased sample of probands and controls for our family study, we have conducted a survey of the local community. This sampling strategy enables us to reduce the bias inherent in clinic-based recruitment and other convenience methods such as advocacy groups, advertisements, newsletters, etc. The community sample will serve as a resource for selection of cases and controls for our current and future family studies of risk factors and/or disease spectra. The specific procedure that we have developed for recruitment has had overwhelming success in identifying probands and controls for our family study. The sampling frame is based on a large, commercially available list of verified home addresses from published telephone directory listings that fall within a 50 mile radius of the NIH campus in Bethesda We have used a random sampling procedure to select subsets of 500 names at a time. The procedure involves several mailings, a telephone screen for demographics and physical and mental health problems, and a random sampling of 20% of the non-respondents. Dr. Ronald Kessler, a survey sampling expert from Harvard University Department of Health Policy, has provided advice on establishing the methods for our community recruitment. To date, we have enrolled 265 participants into the study from the community. ? ? As of the date of this report, we have enrolled 598 probands and 557 relatives in the family study. ? ? (3) Phase III: Clinical Components and Endophenotypes? The aims of our future research are to further characterize and assess these clinical phenomena and to explore specific pathways that may be involved in their manifestation. The specific domains tested address the two areas of complexity that remain impediments to replicable findings: core features of the phenotype and pathophysiologic trait markers. The clinical measures that we are collecting include: biologic rhythms, white matter hyperintensities on 1.5 t MRIs, and prospective measures of diet, activity, life stress, and health. Potential trait markers include psychophysiologic measures, autonomic reactivity, sensory thresholds, and cardiovascular reactivity. The conceptual and hypothetical background and specific methods of this work are described in the study protocol. ? ? During the last year 86 probands and 26 relatives have completed the battery of clinical and laboratory measures described above. Preliminary findings comparing participants with mood disorders, migraine and controls for many of these domains including cardiovascular reactivity, sympathovagal dysbalance, white matter hyperintensities on MRI, mood regulation and motor activity patterns, and eyeblink response to aversive stimuli were presented at the NIH research festival. Now that there is a sufficient number of probands in each of the diagnostic groups and controls, we plan to conduct data analyses and prepare publications reporting the initial results of this work.? ? (4) Phase IV: High Risk Study of Offspring? Development of the high risk component of our study involved extensive planning and consultation with experts in multiple domains of focus in our study. Children are generally recruited as offspring of our probands in the family study as well as from a headache clinic at Childrens National Medical Center in Washington D.C. We are conducting the same or parallel studies of children in the same domains that are being assessed in the adult probands and relatives including clinical, psychiatric, physical, neurocognitive, perception, and genetic evaluations. During the past several months, we have piloted these measures and have now begun formal enrollment of children and adolescents in our larger family study. Several children have completed the interview and a parent has reported on them as well and we have begun to process 28 children in the study. During the next year we plan to complete enrollment and initial evaluation of children in this component of our study.
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