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

284 K. Merikangas and K. Yuinterpret the latter finding. However, the elevation in the risk among offspringcould result from comorbidity, recall bias, a cohort effect, or assortative mating inthe parental generation, or genetic anticipation (Tsuang and Faraone, 1990).Most genetic models described above predict a decrement in risk of diseaseaccording to the degree of relationship to the affected proband. Although a largenumber of studies have reported rates of mood disorders among both the firstandsecond-degree relatives, there is only a single controlled study in which therates of mood disorder were compared between the first- and second-degreerelatives with controls (Gershon et al., 1982). The results of this study revealedthat the rates of bipolar disorder among first-degree relatives of bipolar probandswere approximately twice those of second-degree relatives, which in turn weregreater than those of controls. In contrast, there was no elevation in the rates ofeither MDD or bipolar disorder among the second-degree relatives of MDDprobands, nor was there an increased rate of MDD among the second-degreerelatives of bipolar probands.Age of onsetThe effect of age of onset on the familial aggregation of mood disorders was firstdescribed by Stenstedt (1952) and has subsequently been confirmed in severalstudies. However, there are numerous possible confounding factors that have notbeen adequately addressed in these studies, including: recurrence, comorbidity,biased recall, and personality factors. Moreover, the conclusions of the above-citedstudies have been based on a dichotomous classification of the age of onset ofprobands, rather than significant correlations between the age of onset of probandsand relatives.Sex of probandThe effect of the sex of the proband and relative has been systematically investigatedfor both bipolar disorder and MDD. In general, there is little deviation infamily study data from the sex ratio for bipolar and MDD reported in epidemiologicstudies. In general, the rates of bipolar disorder are nearly equal in male andfemale relatives, whereas there is a female preponderance of mood disordersamong the relatives with MDD. However, the transmission of both bipolar disorderand MDD has been shown to be unrelated to the sex of the proband, withequal rates of mood disorders among the relatives of male and female bipolardisorder and MDD probands (Merikangas et al., 1985; Faraone et al., 1987).In summary, the family studies of bipolar disorder and MDD demonstrate astrong degree of familial aggregation of both of these subtypes of mood disorders.However, the evidence is inconclusive regarding the role of shared underlyingfactors in the expression of these subtypes of mood disorders. The transmission of