Sarah Doucette

BACKGROUND: Bipolar disorder is highly heritable and therefore longitudinal observation of children of affected parents is important to mapping the early natural history. AIMS: To model the developmental trajectory of bipolar disorder based on the latest findings from an ongoing prospective study of the offspring of parents with well-characterised bipolar disorder. METHOD: A total of 229 offspring from families in which 1 parent had confirmed bipolar disorder and 86 control offspring were prospectively studied for up to 16 years. High-risk offspring were divided into subgroups based on the parental long-term response to lithium. Offspring were clinically assessed and DSM-IV diagnoses determined on masked consensus review using best estimate procedure. Adjusted survival analysis and generalised estimating equations were used to calculate differences in lifetime psychopathology. Multistate models were used to examine the progression through proposed clinical stages. RESULTS: High-risk offspring had an increased lifetime risk of a broad spectrum of disorders including bipolar disorder (hazard ratio (HR) = 20.89; P = 0.04), major depressive disorder (HR = 17.16; P = 0.004), anxiety (HR = 2.20; P = 0.03), sleep (HR = 28.21; P = 0.02) and substance use disorders (HR = 2.60; P = 0.05) compared with controls. However, only offspring from lithium non-responsive parents developed psychotic disorders. Childhood anxiety disorder predicted an increased risk of major mood disorder and evidence supported a progressive transition through clinical stages, from non-specific psychopathology to depressive and then manic or psychotic episodes. CONCLUSIONS: Findings underscore the importance of a developmental approach in conjunction with an appreciation of familial risk to facilitate earlier accurate diagnosis in symptomatic youth.

AIM: High-risk studies provide the opportunity to describe the early natural history of bipolar disorder (BD); however, findings have varied substantially. In this review, we compare different methods of ascertainment and assessment, and their impact on study findings. METHODS: Through a literature search, we identified 11 high-risk studies meeting inclusion criteria for this review. Studies included were those that focused on lifetime psychopathology in the offspring as the main outcome and provided adequate information on the methods of family ascertainment, as well as on parent and offspring assessment. We compared and contrasted psychopathological outcomes in the offspring among the studies using different methods. RESULTS: High-risk studies that identified affected parents through their involvement in neurobiological research and confirmed diagnosis in the parent and offspring through best estimate procedures tended to report lower rates of co-morbidity in the proband parent, lower rates of psychopathology in the non-proband parent, lower rates of attention deficit hyperactivity disorder and externalizing disorders, and older ages of onset of major mood disorders in the offspring compared with studies that identified affected parents through self-referral and confirmed diagnosis in the parent and offspring through structured research interviews. Studies that identified severely ill parents and used semi-structured assessments tended to have an intermediate position in terms of outcomes. CONCLUSIONS: This review indicates that different methods of family ascertainment and of assessment of parent and offspring impact the findings pertaining to lifetime psychopathology and clinical course of BD in high-risk studies. The implications of this finding for mapping the natural history of BD are discussed.