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Early-Onset Bipolar Disorder 331Pharmacologic Early-Intervention StudiesIt is clear that certain medications have neuroprotective qualities and thereforemay be effective in reducing risk for development of BD in vulnerable populations.However, as yet there have been no true BD prevention studies, only earlyinterventionstudies with eventual prevention in mind. In the first such study, Gellerand colleagues (1998) studied children with major depression and a family historyof affective disorder. Forty percent of participants had a parent with BD, 40%had a more distant relative (aunt, uncle, or cousin) with BD, and 20% had a familyhistory of major depression only (without mania). Participants were randomizedin a double-blind fashion to receive 6 weeks of lithium or placebo. No differenceswere found between the two groups in improvement in depressive symptoms. Thefinal Clinical Global Assessment of Severity scores in both groups, although improved,were still below 60, indicating continuing clinical problems. However,there appeared to be a wide distribution of participants who responded well andparticipants who responded poorly, suggesting that some participants may havehad unique factors associated with response. Whether these factors were relatedto increased family history of BD is unknown, as the authors did not report sucha subanalysis of data grouped by family history. Furthermore, no longitudinalfollow-up was done to investigate potential effects on bipolar outcome of thesechildren, so the prophylactic qualities of lithium cannot be commented on.In another early intervention study, we investigated the use of divalproex (aform of valproate) in 24 bipolar offspring with mood and/or disruptive behavioraldisorders (K. D. Chang, Dienes et al., 2003). None of the participants, aged7–17, had bipolar I or II disorder, but all had at least some mild affective symptomsas manifested by a minimum score of 12 on the Young Mania Rating Scale(YMRS) or Hamilton Rating Scale for Depression (HAM-D). Thus, as discussedearlier, they fit the criteria for offspring at the highest risk for BD development.Many participants had had previous trials of antidepressants and/or stimulants.Participants were tapered off of any current medications, and then begun ondivalproex monotherapy, eventually reaching a mean final dose of 821 mg/day(serum level = 79.0 +/– 26.8 mg /mL). After 12 weeks, 78% of participants wereconsidered responders, having general improvement in mood and functioning,with the majority showing improvement by Week 3. Although this study demonstratedthe potential of divalproex in treating acute symptoms of children withputative prodromal BD, another similar, but placebo-controlled, study found thatboth divalproex and placebo led to equal improvement of affective symptomsin adolescents with cyclothymia or bipolar disorder not otherwise specified whowere bipolar offspring. Notably, though, divalproex was superior to placebo ina subset of patients who had very strong family histories of bipolar disorder(R. L. Findling, 2002; R. L. Findling, Gracious, McNamara, & Calabrese, 2000).As these studies addressed acute improvement, longitudinal controlled studies