2,3 Therefore, children with depression may be experiencing a first episode bipolar depression. Geller et al report 20% to 49% of children with MDD experience a full manic episode by adulthood.45 A positive family history of BD would seem to further elevate the risk of future mania in a depressed

child; however, the exact risk in these children is not known. Given that many if not most of these children will not ever experience mania, careful diagnosis and biological markers for predication would be essential. Unfortunately, at this time there are Inhibitors,research,lifescience,medical no clear biological markers that do predict such likelihood, despite recent advances in neuroimaging and genetics research. In the future, markers such as decreased amygdalar volume, increased limbic activity, and the short allele of the Inhibitors,research,lifescience,medical serotonin transporter gene, may all be combined to calculate relative risk of BD development.46 Until then we are left to rely on careful clinical assessment and family history. Proposed clinical clues of first episode bipolar depression include an acute onset, psychosis, prominent irritability and labile mood, and poor or brief hypomanic reactions to antidepressants.47 Inhibitors,research,lifescience,medical Furthermore, features of atypical depression, including hypersomnia, hyperphagia, and other neurovegetative symptoms, may indicate risk for future manic episodes.48 Despite the uncertainty of actual BD risk, early interventions Inhibitors,research,lifescience,medical in youth with depression

and family histories of BD are beginning to be studied. Geller and colleagues performed the first such study49 in 30 prepubertal children, all with M.DD and family histories of mood disorder. Forty percent had a parent with BD, 40% had a more distant relative with BD, and 20% had a family history of unipolar depression only. Subjects were randomized to lithium or placebo, and after 6 weeks no differences were found between the two groups in improvement in depressive symptoms. The final Clinical Global Assessment of Severity scores in both groups did improve from baseline, but remained below 60, indicating continuing clinical problems. As there

was a significant Inhibitors,research,lifescience,medical distribution of subjects who responded well and subjects who responded poorly, some subjects may have had the unique factors associated with response, but whether family history was a factor is unknown. Nonetheless, lithium may have limited efficacy in youth with depression at high risk for BD. In another early intervention study, Chang and colleagues Sotrastaurin investigated the effectiveness of open divalproex in 24 bipolar offspring with mood and/or disruptive behavioral disorders.50 None of the subjects, aged 7 to 17, had bipolar I or II disorder, but all had at least some mild affective symptoms as manifested by a minimum score of 12 on the Young Mania Rating Scale (YMRS) or Hamilton Rating Scale for Depression (HAM-D). Of these subjects, 21 % (5) were diagnosed with MDD, and 8% (2) with dys thymia.