Bipolar Disorders: Mixed States, Rapid-Cycling, and Atypical Forms

298 K. Merikangas and K. YuAlthough there have been numerous controlled family studies of psychiatricdisorders, there are very few that were designed to investigate the specificity ofcore components of the phenotypes. Those that have examined subtypes ofpsychiatric disorders have not provided sufficient evidence for familial specificity.The experienced investigators in this field tended to abandon this research becauseof the advent of opportunities to identify genes in the early 1990s. This wasunfortunate because this was also the time when there had been numerousadvances in methods and analyses for family studies (Weissman et al., 1986b),including population-based ascertainment of common disorders and appropriateselection of controls (Kendler, 1990; Klein, 1993; Hill and Neiswanger, 1997) andrandom-effects regression models that incorporate familial clustering.The recent shift in psychiatric genetics to identify endophenotypes, or underlyingbiologic factors, that explain familial recurrence is an important step in movingfrom broad phenotypes to specific components of disorders. Recent advances inneuroscience and the behavioral sciences, not available to the pioneers in familystudy research in psychiatry, will be important tools in enhancing this process.Substantial effort should be devoted to the application of genetic epidemiologicstudies that are designed to define more homogeneous components of mooddisorders and associated biologic markers that may yield higher familial relativerisk than the heterogeneous category of major depression. Ironically, however,genetic mapping strategies may also assist in defining subtypes (Reus and Freimer,1997). Nevertheless, lessons from other disorders have demonstrated that, even afterthe identification of the gene for single-gene disorders, the classification still requiresadditional testing to identify sources of heterogeneity in phenotypic expression.For example, despite the identification of the actual gene for Marfan’s syndrome, thechecklist criteria appear to be remarkably similar to those within the realm ofDSM-IV. Likewise, recent studies of neurofibromatosis have examined familialspecificity of diverse clinical manifestations of the same genetic mutations.Two directions of research that are particularly promising for informing phenotypicvalidity include: (1) genetic epidemiologic strategies and prospective longitudinalstudies for phenotype refinement; and (2) studies designed to identifyendophenotypes of mood disorders, informed by advances in neuroscience.Future directionsThe tremendous progress in molecular biology, neuroscience, and related fields islikely to lead to new approaches to the genetics of psychiatric disorders of humandiseases. Identification of all of the genes in the human genome and their functionalvariation will provide opportunities for studying the impact of thosevariants on phenotypic outcomes of interest. Studies of gene regulation,