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Early-Onset Bipolar Disorder 319Reliable identification of these symptom complexes requires prospective studiesof patients before their development of BD. Studying a high-risk populationappears to be the best approach for this type of study. Currently, the clearest riskfactor for BD is a family history of BD (Faraone & Tsuang, 2003). As twin andfamily studies have reported a 59–87% heritability of BD, it has become clearthat first-degree relatives of probands with BD are at high risk of BD themselves(Smoller & Finn, 2003). Thus, a readily accessible population at high risk for BDdevelopment would be offspring of parents with BD.Bipolar Offspring Are at High-Riskfor Bipolar Disorder DevelopmentChildren of parents with BD (“bipolar offspring”) may be the most relevant cohortto study in order to understand risk factors for BD. A meta-analysis of studiesconducted before 1997 found bipolar offspring to be at 2.7 times higher riskfor development of any psychiatric disorder and 4 times higher risk for developinga mood disorder than children of parents without psychiatric illness (Lapalme,Hodgins, & LaRoche, 1997). Recent studies have found that 50–60% of bipolaroffspring have some type of psychiatric disorder (K. Chang, Steiner, Dienes,Adleman, & Ketter, 2003; K. D. Chang et al., 2000; Wals et al., 2001), especiallymood, anxiety, and disruptive behavior disorders (Carlson & Weintraub, 1993;K. Chang et al., 2003; K. D. Chang et al., 2000; Wals et al., 2001). Rates of BDspectrum disorders in these offspring range from 14–50%, and rates of MDD rangefrom 7–43% (K. D. Chang & Steiner, 2003).Predictors of BD Among High-RiskOffspring—Putative Prodromal BDFrom these studies of high-risk populations, symptom complexes predating firstmanic episode can be identified. Attention deficit/hyperactivity disorder (ADHD)has been proposed to be a common initial presentation of BD, especially earlyonsetBD. In studies conducted since 1988, approximately 27% of bipolar offspringhave met criteria for ADHD or significant behavioral or attentionproblems (K. D. Chang & Steiner, 2003). This finding, in conjunction with thehigh comorbidity of ADHD and BD in childhood (Faraone, Biederman, Wozniaket al., 1997), has led to the suggestion that ADHD in children with strong familyhistories of BD may be the first sign of developing BD. Furthermore, family studiesof probands with ADHD and BD have supported this comorbidity as representinga familial type of early-onset BD (Faraone, Biederman, Mennin et al., 1997;Faraone, Biederman, Wozniak et al., 1997). In one study of bipolar offspring, sevenout of eight offspring with BD had met criteria for ADHD before obtaining a diagnosisof BD (K. D. Chang et al., 2000). Furthermore, parents with BD who hadretrospectively reported a history of ADHD during their own childhood were morelikely to have children diagnosed with BD as compared to bipolar parents without