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Early-Onset Bipolar Disorder 327BIPOLAR OFFSPRING(general genetic predisposition + shared environmental stress)Decreased amygdalargrayProdromal sibBDNF val66metHealthy sibNormal amygdalargray5-HTT s-alleleAmygdalar overactivationNormal amygdalaractivationDecreased prefrontal/hlpp gray5-HTT I-alleleBIPOLAR DISORDERHEALTHYDecreased executive function/episodic memoryFigure 14-3 Schematic of bipolar disorder (BD) development in children of parents withBD. Offspring siblings share both general genetic predisposition to BD and general environmentalstress. Those with increased genetic predisposition for BD are more likely tohave decreased amygdalar gray matter and overactivation to affective stress. Presence ofthe 5–HTT s-allele further increases amygdalar overactivation and may further decreaseamygdalar gray matter volume, which combined with the other risk factors above, leadsto BD. Presence of the BDNF val66met allele, in all offspring, predisposes to decreasedprefrontal and hippocampal (“hipp”) gray matter volume, which leads to relatively decreasedcognitive function (executive function and episodic memory). These deficitsmoderate course and severity of those offspring developing BD, possibly leading to earlierage at onset, more severe episodes, and worse course and outcome.The val66met polymorphism of the BDNF gene may also affect brain structureand function in areas relevant to BD development. It is theorized that this polymorphismresults in abnormal intracellular packaging and secretion of BDNF,particularly in hippocampal neurons, but perhaps in all areas where BDNF is secreted(Egan et al., 2003). Healthy volunteers with the BDNF vall66met allelewere found to have poorer episodic memory and decreased hippocampal activationon fMRI (Egan et al., 2003; Hariri et al., 2003) and reduced hippocampal andprefrontal gray matter, especially bilateral DLPFC (Pezawas et al., 2004), comparedto val/val carriers. This effect on prefrontal gray matter may be relevant tothe course and severity of BD, as discussed above. For example, adults with BDwho were carriers of the val66met allele had decreased performance on the Wisconsincard-sorting task compared to val/val carriers, implying reduced prefrontalcognitive function in BD patients with the val66met allele. Hippocampal effectsof the BDNF polymorphism may also be relevant in BD. Although our group didnot find hippocampal volumetric differences in children with BD (K. Chang,