Bipolar Offspring: A Window into Bipolar Disorder Evolution Kiki Chang, Hans Steiner, Kimberly Dienes, Nancy Adleman, and Terence Ketter Children of parents with bipolar disorder (bipolar off- spring) represent a rich cohort for study with potential for illumination of prodromal forms of bipolar disorder. Due to their high-risk nature, bipolar offspring may present phenomenological, temperamental, and biological clues to early presentations of bipolar disorder. This article re- views the evidence for establishing bipolar offspring as a high-risk cohort, the studies which point to possible prodromal states in bipolar offspring, biological findings in bipolar offspring which may be indicators of even higher risk for bipolar disorder, initial attempts at early intervention in prodromal pediatric bipolar disorder, and implications for future research. Biol Psychiatry 2003; 53:945–951 © 2003 Society of Biological Psychiatry Key Words: Bipolar disorder, offspring, prodromal, child, adolescent Introduction C hildren of parents with bipolar disorder (BD) (here- tofore referred to as “bipolar offspring”) represent a rich cohort for study with potential for illumination of prodromal forms of BD. It has been well established that bipolar offspring are at high risk for development of BD (DelBello and Geller 2001). Due to their high-risk nature, bipolar offspring may present phenomenological, temper- amental, and biological clues to early presentations of BD. Bipolar offspring are also genetically less diverse than bipolar samples that are mixed for presence or absence of family history. Bipolar offspring who have not yet devel- oped BD or other serious psychiatric illness also may be a relatively “pure” population to study. They often have not had exposure to psychotropic medications or years of substance abuse, both of which can confound determina- tion of cause or effect in both phenomenological and biological presentation. Granted, bipolar offspring often have had exposure to significant environmental stressors, such as having a parent with bipolar disorder who may be prone to mood episodes, substance abuse, and hospitalizations (Chang et al 2001). As quantifying the contribution of environ- mental factors to development of psychopathology is difficult, assessment of bipolar offspring at as young an age as possible is important. Yet, not all bipolar offspring will develop BD (indeed, the majority will not). In the absence of firm indications of the central pathogenic processes involved in BD, it would be difficult to predict from an early age which particular offspring will develop BD. Thus, it may be more efficient to concentrate on those offspring with early psychiatric difficulties; however, the natural evolution of early syndromes in at-risk offspring has not been established. Some may not progress at all to BD or may progress to an entirely different disorder. Disruptive behavioral disorders have been postulated to be early precursors to bipolar disorder in certain children (Carlson and Weintraub 1993). While disruptive behavior disorders are themselves not uncommon in children, their presence in bipolar offspring may raise the risk of BD development above those of nonbipolar offspring; how- ever, it is unlikely that the presence of these disorders alone in offspring would be good indicators of impending BD. More likely, as will be discussed, a combination of mood difficulties and disruptive behavior disorders is a more specific marker of prodromal BD. If such children were indeed prodromal for fully developed BD, then study of these children would be crucial for identification of prodromal states, leading to the possibility of early inter- vention and prevention of worsening symptoms and poorer outcome. This article will review the evidence for establishing bipolar offspring as a high-risk cohort, the studies which point to possible prodromal states in bipolar offspring, biological findings in bipolar offspring which may be indicators of even higher risk for BD, initial attempts at early intervention in prodromal pediatric BD, and implications for future research. From the Division of Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California. Address reprint requests to Kiki Chang, M.D., Stanford University School of Medicine, Division of Child and Adolescent Psychiatry, 401 Quarry Road, Stanford CA 94305-5540. Received October 22, 2002; revised December 20, 2002; accepted December 31, 2002. © 2003 Society of Biological Psychiatry 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00061-1