Pediatric bipolar disease: current and future perspectives for study of its long-term course and treatment.

A new clinical wisdom has emerged concerning bipolar illness that emphasizes high risk of recurrence through the lifespan, complex genetic liability, economic and social burden, substantial risk of self harm, frequent resistance to pharmacotherapies, and persistence of residual symptoms between major episodes (1,2). These facts underscore the critical importance of early identification and have been impetus for bringing fresh attention to the pediatric age group with several expert panels recently summarizing clinical and methodological priorities for research in the area (3-4). Evidence that pediatric affective disorders continue into adulthood (5-7), that neurocognitive abnormalities may persist after clinical remission (8), and that separate genes may differentially influence age of onset (9) are strong rationale for understanding how early onset bipolar illness impinges on long-term development. In the clinical domain, no validated treatment algorithm currently exists as the literature to date is comprised largely of anecdotal accounts, small case series, and few large scale open label studies employing objective measures of clinical response (10). This void has left both clinicians and parents with the paradox of managing an indisputably handicapping illness uncertain of the risk to children of medications whose long-term effects have been little studied. It is hardly surprising that treatments received by youth with bipolar illness are so variable and that lack of treatment is not uncommon (11). The real world clinical challenge is that absent long-term, large-scale multi-site naturalistic studies of pediatric cohorts, authoritative risk/benefit analyses are not even remotely feasible, leaving treatment decisions hanging on the vagaries of inference, hunch, and conjecture. The purpose of this article is to outline a scientifically informed framework for the long-term observational study of pediatric bipolar illness that extrapolates data from prospective, naturalistic longitudinal research on adult bipolar disease. Because any assumption about the long-term implications of early bipolar illness remains unconfirmed, the adult literature is a necessary starting point for identifying critical benchmarks for prospective studies of illness course, outcome predictors, and treatment effects in children and youth. We therefore review selective aspects of this literature to highlight where the gaps in our knowledge lie, enumerate aims essential to advancing scientific knowledge of psychopathology, nosology, therapeutics and long-term repercussions on social adjustment, and outline necessary methodological prerequisites for such an endeavor. It has been over eight decades since Kraepelin (12) documented the pleomorphic expression of bipolar illness in adults and how its long-term course shifted dynamically over time. Whether or not young people with bipolar illness show similar long-term variations in course, and whether or not long-term outcome can be reliably predicted, is unknown; to date, no prospective study has observed the course of pediatric patients as they transition to adolescence, and then to adulthood. As such, the questions are many: Do the major phenotypes that comprise bipolar illness (e.g., bipolar type I versus type II) remain stable over time in young patients, or does disease expression change as they mature. Does the chronic, irritable, phenotype that is believed to be prototypic of very young bipolars (13) persist across developmental stages, or do these patients eventually express course features seen commonly in adults such as monophasic episodes and lengthy well periods as they age? Is the long-term course more malignant, i.e., are recurrences more frequent, when the illness begins in childhood compared to adolescence, and do teens have greater propensity for lifetime recurrence than adults? Does a propensity for frequent recurrence in youth foreshadow chronicity in adulthood? Is progressive psychosocial deterioration characteristic of prepubertal bipolar illness? Does very early onset of disease predict increased liability for substance abuse and suicidality compared to when the illness onsets in adolescence? Are the variables that predict episode recovery and recurrence in preteens, teens, and adults identical, do course predictors remain stable over time, and are the effects of somatic therapy and psychotherapy in mediating outcome consistent across age groups? These are but a fraction of the substantive questions that require attention in prospective, naturalistic, longitudinal research on early onset bipolar illness if it’s unique and enduring vulnerabilities are to be fully understood.