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332 REVERSIBLE DISORDERS OF BRAIN DEVELOPMENTare still needed to determine the efficacy of valproate in actual prevention ofBD development.Physiological Effects of Candidate Pharmacologic AgentsWhen considering pharmacologic intervention, risks versus benefits of treatmentalso need to be considered. For example, potential adverse effects of valproatetherapy include sedation, weight gain, and potential neuroendocrine effects leadingto polycystic ovarian syndrome or osteoporosis (K. Chang & Simeonova,2004). Although these conditions are relatively manageable and reversible, theseare fairly acute adverse effects, mostly occurring over weeks to a few years. Asvalproate has been used extensively since the 1980s in patients with epilepsy orBD, including children, researchers should have long-term adverse effects data.Yet currently there is little published in this regard (Rana et al., 2005). Therefore,it is not only difficult to quantify the risks of not receiving treatment for childrenat putative risk for BD, but also difficult to discern the long-term risks of receivingsuch treatment.Furthermore, although behavioral effects of these medications may be largelypositive, what are the direct effects on the brain? Six bipolar offspring with putativeprodromal BD who participated in the previously discussed divalproex study(K. D. Chang, Dienes et al., 2003), were scanned pre- and postdivalproex treatmentusing functional magnetic resonance imaging (fMRI), performing a taskinvolving watching affectively valenced pictures. participants had significantlygreater prefrontal (DLPFC) activation after divalproex treatment compared tohealthy controls also scanned at 12-week intervals. figure 14-4).Thus, it appears that functional changes in the brain may be detected aftermedication treatment. These findings are consistent with the hypothesis that assymptoms and functioning improve in children at high risk for BD development,prefrontal- areas increase in activation in order to maintain relative euthymia(K. D. Chang, Chang, Garrett, Adleman, & Reiss, 2003).Additional studies with control groups and larger cohorts need to be studied inthis regard. Analysis of gray matter volumes pre- and posttreatment could alsoshed light on neurogenic effects of these medications, similar to such studies withlithium (Moore, Bebchuk, Wilds, Chen, Manji, et al., 2000). For example, in ourgroup of bipolar offspring with BD with decreased amygdalar volume, those withprior exposure to lithium or valproate tended to have greater amygdalar gray mattervolume than those who did not (K. Chang, Karchemskiy, Barnea-Goraly, Garrett,et al., 2005). However, we do not know whether administration of these medicationsled to new amygdalar neurons or instead protected existing neurons fromdeath due to toxicity or apoptosis.It is not clear whether these brain changes after medication treatment are safeand/or desirable, but when coupled with behavioral and symptomatic improvement,it would seem that these are positive effects on brain structure and func-