The overall hypothesis of this prospective natural history study is that a prepubertal and early adolescent bipolar I disorder phenotype (PEA-BP) exists and that it is on a continuum with adult onset BP. As the pioneering study in a contentious field, a conservative phenotype was selected for credibility. Specifically, to address the problems of differentiating mania from ADHD and of the ubiquitous manifestation of irritability across child psychiatry diagnoses, PEA-BP was defined by DSM-IV BP-I manic or mixed phase with elation or grandiosity as one criterion. This criterion avoided diagnosing mania by symptoms that overlapped with those of ADHD and ensured that subjects had at least one of the cardinal symptoms of mania, analogous to DSM-IV MOD requiring sad mood or anhedonia. Support for the hypothesized existence of PEA-BP came from validation by unique symptoms that did not overlap with those of ADHD, longitudinal stability of the diagnosis (did not become ADHD or other disorders on follow-up), and significantly higher familial aggregation in the PEA-BP vs. ADHD or healthy control groups. Postulated continuity across the age span was supported by the occurrence of PEA-BP and adult BP within the same families, by family based linkage disequilibrium of the BDNF Val66 allele in both age groups, and by the similarity of predictors of outcome (maternal warmth, psychosis) across ages. But, PEA-BP presented with chronicity, long episode duration, ultradian rapid cycling (multiple daily cycles, every day or almost every day for years), and high levels of psychosis and mixed mania. Thus, phenomenological characteristics of PEA-BP resembled those seen in the most severely ill adults (about 20% of adult BP has this severe course). Given these data, the next research question is whether children with PEA-BP (aged 10.8 q 2.7 at baseline) will develop the more """"""""typical"""""""" adult course with relatively discrete episodes of shorter duration and less ultradian cycling, as they reach late adolescence and early adulthood. To address this intriguing question, follow-up is proposed through the 10-year assessment point (mean age 20.8 q 2.7), in this well characterized, comprehensively assessed sample that has 96.6% retention (259/268 subjects). This prospective, longitudinal study would provide prognostic data to families and physicians;inform genetic, neuroimaging, and long-term treatment studies;and enlighten controversies about the existence of childhood mania.
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