Mapping the developmental trajectory of bipolar disorder: Importance of prerequisite groundwork

Australian & New Zealand Journal of Psychiatry, 51(8) Investigating the pathways to bipolar disorder at both clinical and biobehavioral levels is extremely important to advance research and clinical practice. This work has its origins in longitudinal studies of children of depressed parents (Weissman et al., 1987) and in studies of youth at clinical risk of developing psychosis (Yung et al., 2004). Longitudinal prospective studies of well-defined high-risk groups over the peak risk period are essential for understanding the complex interplay of risk processes in determining illness onset and in identifying opportunities for early intervention. Given heritability estimates around 80%, children of parents with confirmed bipolar disorder are an informative and identifiable high-risk group. Methodologically, there are challenges, including phenotypic and etiological heterogeneity, to contend with. That is, the nature of the bipolar trait (as indicated by a spectrum of bipolar-related disorders segregating in relatives of bipolar patients) and differences in the range of early clinical antecedents of emerging bipolar disorder points to considerable phenotypic heterogeneity. Furthermore, there is evidence of bipolar subtypes with potentially different etiology, pathophysiology, clinical course and treatment response underscoring the importance of etiologic heterogeneity. Several international offspring studies have described the emerging clinical trajectory and early course of bipolar disorder and are investigating the associated changes in multi-level biopsychosocial risk factors—in some cases based on prospective observations approaching up to 20 years (Duffy et al., 2014). However, most have not considered the influence of heterogeneity on outcomes. Despite differences in recruitment and assessment methods among independent bipolar offspring studies, their findings have been remarkably convergent. Specifically, that (1) mania (using adult criteria) is rare prior to puberty, even in individuals from multigenerational families with highly penetrant illness; (2) bipolar disorder usually debuts as depressive episodes that are indistinguishable from unipolar depression in mid-adolescence; and (3) bipolar-related mood episodes are not uncommonly presaged by childhood clinical antecedents, including sleep, anxiety, and sub-affective disorders which likely have a different meaning in these high-risk children than in children without a family history of bipolar disorder. But individual offspring studies have varied in reported rates of comorbid disorders, quality of remission, and range of antecedent conditions. Presumably, these differences reflect variation in parent bipolar subtype, health of the other parent, comorbidity of the bipolar parent, early risk and trauma exposures of the offspring, and the social context of rearing—all of which are subject to cultural factors. Outcome differences can be expected to be increasingly more challenging to reconcile across different risk populations and study approaches. In fact, the early course of bipolar disorder charted from prospective studies of high-risk offspring is strikingly different from that derived from studies of clinical samples of children diagnosed with pediatric bipolar disorder. Pediatric or very-earlyonset bipolar disorder is characterized by pre-pubertal mania, high rates of comorbid neurodevelopmental disorders (such as attention-deficit/ hyperactivity disorder [ADHD] and pervasive developmental disorder), an ultra rapid cycling course with poor quality of remission, and substantially reduced global functioning. These features are far less prominent in familial high-risk populations. In part, this discrepancy reflects that few psychiatric symptoms have phenotypic specificity and often span diagnostic boundaries. Therefore, sometimes mania-like symptoms may not be related to a bipolar diathesis or reflect any Mapping the developmental trajectory of bipolar disorder: Importance of prerequisite groundwork