A high-risk study of bipolar disorder: Childhood clinical phenotypes as precursors of major mood disorders

John I. Nurnberger, Melvin McInnis, Wendy Reich, Elizabeth Kastelic, Holly C. Wilcox, Anne Glowinski, Philip Mitchell, Carrie Fisher, Mariano Erpe, Elliot S. Gershon, Wade Berrettini, Gina Laite, Robert Schweitzer, Kelly Rhoadarmer, Vegas V. Coleman, Xueya Cai, Faouzi Azzouz, Hai Liu, Masoud Kamali, Christine BruckschPatrick O. Monahan

Research output: Contribution to journalArticlepeer-review

128 Scopus citations


Context: The childhood precursors of adult bipolar disorder (BP) are still a matter of controversy. Objective: To report the lifetime prevalence and early clinical predictors of psychiatric disorders in offspring from families of probands with DSM-IV BP compared with offspring of control subjects. Design: A longitudinal, prospective study of individuals at risk for BP and related disorders. We report initial (cross-sectional and retrospective) diagnostic and clinical characteristics following best-estimate procedures. Setting: Assessment was performed at 4 university medical centers in the United States between June 1, 2006, and September 30, 2009. Participants: Offspring aged 12 to 21 years in families with a proband with BP (n=141, designated as cases) and similarly aged offspring of control parents (n=91). Main Outcome Measure: Lifetime DSM-IV diagnosis of a major affective disorder (BP type I; schizoaffective disorder, bipolar type; BP type II; or major depression). Results: At a mean age of 17 years, cases showed a 23.4% lifetime prevalence of major affective disorders compared with 4.4% in controls (P=.002, adjusting for age, sex, ethnicity, and correlation between siblings). The prevalence of BP in cases was 8.5% vs 0% in controls (adjusted P=.007). No significant difference was seen in the prevalence of other affective, anxiety, disruptive behavior, or substance use disorders. Among case subjects manifesting major affective disorders (n=33), there was an increased risk of anxiety and externalizing disorders compared with cases without mood disorder. In cases but not controls, a childhood diagnosis of an anxiety disorder (relative risk=2.6; 95% CI, 1.1-6.3; P=.04) or an externalizing disorder (3.6; 1.4-9.0; P=.007) was predictive of later onset of major affective disorders. Conclusions: Childhood anxiety and externalizing diagnoses predict major affective illness in adolescent offspring in families with probands with BP.

Original languageEnglish (US)
Pages (from-to)1012-1020
Number of pages9
JournalArchives of general psychiatry
Issue number10
StatePublished - Oct 2011

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Psychiatry and Mental health


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