A Multi-Dimensional and Integrative Approach to Examining the High-Risk and Ultra-High-Risk Stages of Bipolar Disorder

• Pathophysiological alterations were identified in the high-risk and ultra-high-risk stages of bipolar disorder (BP).
• Deficits in processing speed and visual-spatial memory were observed in the ultra-high-risk stage of BP.
• Abnormalities associated with the ultra-high-risk stage are suggestive of risk for the full development of BP.
• Our data support that the underlying abnormalities of BP may become apparent long before the official onset.
• Identifying the early development of BP opens the avenue for early intervention.

BackgroundValidating the high-risk (HR) and ultra-high-risk (UHR) stages of bipolar disorder (BP) may help enable early intervention strategies.MethodsWe followed up with 44 offspring of parents with BP, subdividing into the HR and UHR categories. The offspring were aged 8–28 years and were free of any current DSM-IV diagnoses. Our multilevel, integrative approach encompassed gray matter (GM) volumes, brain network connectivity, neuropsychological performance, and clinical outcomes.FindingsCompared with the healthy controls (HCs) (n = 33), the HR offspring (n = 26) showed GM volume reductions in the right orbitofrontal cortex. Compared with the HR offspring, the UHR offspring (n = 18) exhibited increased GM volumes in four regions. Both the HR and UHR offspring displayed abnormalities in the inferior occipital cortex regarding the measures of degree and centrality, reflecting the connections and roles of the region, respectively. In the UHR versus the HR offspring, the UHR offspring exhibited upwards-shifted small world topologies that reflect high clustering and efficiency in the brain networks. Compared with the HCs, the UHR offspring had significantly lower assortativity, which was suggestive of vulnerability. Finally, processing speed, visual–spatial, and general function were impaired in the UHR offspring but not in the HR offspring.InterpretationThe abnormalities observed in the HR offspring appear to be inherited, whereas those associated with the UHR offspring represent stage-specific changes predisposing them to developing the disorder.