43.1 Subthreshold Mania, Cortical Activity, and Family Intervention in Youth at Risk for Bipolar Disorder

In this presentation, we examined brain circuitry underlying intrinsic connectivity in youth at risk for bipolar disorder (BD) with and without significant subthreshold mania symptoms. We randomly assigned youth to family-focused therapy or standard psychoeducation. This work proposes a causal framework for neural and clinical mediators that may underlie symptom improvement and long-term relapse prevention in youth at risk for BD. High-risk youth (<18 years old) with MDD or other specified (subthreshold) BD, and a first- or second-degree relative with BD, were randomly assigned to 4 months (12 sessions) of family-focused therapy high-risk (FFT-HR; psychoeducation, communication, and problem-solving skills) or 4 months (6 sessions) of standardized psychoeducation (enhanced care [EC]). Significant mania symptoms were defined by a baseline Young Mania Rating Scale (YMRS) score of ≥10 (“mixed features,” n = 20). These youth were compared to those with YMRS scores <10 at baseline (“no mixed features,” n = 14). Neuroimaging was conducted at pretreatment and posttreatment (4 months later) to measure neural changes during resting state in subgroups of youth with and without significant baseline mania symptoms. Youth with mixed features had a combination of moderate depression severity (mean [SD] Children’s Depression Rating Scale–Revised [CDRS-R] = 52.1 [15.7]) and the presence of subthreshold mania symptoms (YMRS = 16 [5.5]) compared to youth without mixed features (CDRS-R = 44 [12]; YMRS = 4.8 [2.6]). Youth with mixed features who were randomized to FFT-HR vs EC had stronger resting-state connectivity between the ventrolateral prefrontal cortex (VLPFC) and anterior default mode network (aDMN) from baseline to posttreatment than youth without mixed features (t = 2.16; p = .045). Reductions in mania severity from pre- to posttreatment within the mixed features group were marginally correlated with increased VLPFC-aDMN connectivity (r = -0.42; p < .08) during the same interval, but this association was not observed in the no mixed features group (r = -.12; p = .71). Youth with subthreshold mania symptoms show selective improvements in cortical connectivity in networks critical for emotion regulation after FFT-HR. Larger studies could examine whether targeting subthreshold mania symptoms in youth at risk could prevent progression toward BD.