Further Evidence for Robust Familiality of Pediatric Bipolar I Disorder: Results From a Very Large Controlled Family Study of Pediatric Bipolar I Disorder and a Meta-Analysis

Objective: To determine the risk for bipolar I disorder in first-degree relatives of children with DSM-IV bipolar I disorder via meta-analysis and expanded controlled study.

Data Sources and Extraction: Meta-Analysis. We searched the PubMed database for scientific articles published in the world literature in the English language through 2011. The keywords searched were bipolar disorder, first-degree relatives, family study, control. All online abstracts were reviewed and relevant full manuscripts were collected and reviewed. Citations were also examined for other potential relevant articles. We included only controlled family studies that examined rates of bipolar I disorder in all first-degree relatives (parents and siblings) of pediatric bipolar I probands and included only studies that had age- and sex-matched controls. Family history studies were excluded. Also excluded were studies that were not in English, did not report the rates of all first-degree relatives, and reported only bipolar spectrum rates. We also excluded family studies that included only adult probands. We conducted a meta-analysis of the 5 controlled family studies of pediatric bipolar I probands that met our search criteria using the random effects model of DerSimonian and Laird.

Method: Family Study. We greatly expanded our previous sample of DSM-IV bipolar I probands using structured diagnostic interviews. Our new study included 239 children satisfying full DSM-IV diagnostic criteria for bipolar I disorder (n = 687 first-degree relatives), 162 ADHD (without bipolar I disorder) probands (n = 511 first-degree relatives), and 136 healthy control (without ADHD or bipolar I disorder) probands (n = 411 first-degree relatives). We used the Kaplan-Meier cumulative failure function to calculate survival curves and cumulative, lifetime risk in relatives. Cox proportional hazard models were used to calculate the risk of bipolar I disorder in relatives.

Results: The pooled odds ratio for bipolar I disorder in relatives was estimated to be 6.96 (95% confidence interval [CI], 4.8 to 10.1). We also found first-degree relatives of bipolar I probands to be significantly more likely than first-degree relatives of both ADHD (hazards ratio [HR] = 2.73; 95% CI, 1.66 to 4.50; P < .001) and control probands (HR = 2.71; 1.57 to 4.66; P < .001) to have bipolar I disorder.

Conclusions: Our results document an increased familial risk for bipolar I disorder in relatives of pediatric probands with DSM-IV bipolar I disorder.’ ‹