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

280 K. Merikangas and K. Yumethodology including inclusion of control probands and relatives, application ofstandardized diagnostic criteria with structured diagnostic instruments, andblindness with respect to the diagnosis of the probands.Table 13.1 presents a summary of controlled family studies of probands withbipolar disorder and MDD. The weighted average risk ratio (comparing theprevalence of mood disorders among relatives of cases compared to those ofcontrols) for bipolar disorder among relatives of bipolar probands is 10.3, whereasthe average risk ratio of MDD among relatives of bipolar probands compared tothose of controls is 3.2. This indicates a very high magnitude of familial aggregationof bipolar disorder, similar to that found for many of the major diseases forwhich the genetic basis has been identified. In contrast, the average risk ratio forMDD among relatives of probands with MDD compared to those of controls was3.6, indicating only a moderate influence of familial aggregation on non-bipolarmood disorders. Although sex, age, birth cohort, and socioeconomic status aredifferentially associated with MDD (greater risk among females, later birthcohorts, lower socioeconomic status), there is no evidence that they moderatethe familial recurrence risk of mood disorders (Weissman et al., 1986a; Tsuang andFaraone, 1990).Studies of offspring of mood-disorder probands have contributed substantialinformation on developmental influences in the expression of mood disordersamong youth. The high-risk studies on bipolar disorder have revealed an increasedrisk of mood disorders among offspring of parents with bipolar illness (Decinaet al., 1983; Klein et al., 1986; Radke-Yarrow, 1998). There is now a growing bodyof research of the developmental manifestations of bipolar disorder, and severalhigh-risk studies of bipolar disorder are under way.In contrast to bipolar disorder, there are far more high-risk studies of MDD,some of which have now been extended to three generations (Weissman et al.,1997; Warner et al., 1999). Although there is a consistent association betweenmood disorders among parents and offspring (Downey and Coyne, 1990), nearlyall show a lack of familial specificity of mood disorders since the prevalence ofanxiety and behavioral disorders are often equally elevated (Weissman et al.,1984a; Merikangas and Angst, 1995; Harrington et al., 1997; Rende et al., 1999).A review of comorbidity of anxiety and depression by Brady and Kendall (1992)suggests that anxiety and depression may be part of a developmental sequence inwhich anxiety is expressed earlier in life than depression.With respect to subtypes of bipolar disorder, studies of the familial specificity ofthe bipolar I–II distinction have yielded inconclusive results. Whereas somestudies suggest a continuum from bipolar I to bipolar II to major depressionbased on familial overlap (Gershon et al., 1986; McMahon et al., 1995), othersdemonstrate that bipolar II disorder constitutes an independent mood-disorder