This proposal is one of two linked applications (UCLA [D. Miklowitz] and Stanford [K. Chang]) in response to PAR-09-153, Collaborative R01s for Clinical and Services Studies of Mental Disorders. Despite the considerable public health burden of bipolar disorder (BD), no psychosocial interventions have been systematically applied to youth at high risk for developing the illness. Research on youth who are genetically predisposed to BD has identified clinical states with considerable risk for conversion to full threshold BD I or II disorder. We propose a multisite RCT to test the efficacy of a multi-faceted family-focused treatment for high- risk youth (FFT-HR). The 4 month intervention consists of psychoeducation, communication training, and problem solving and aims to reduce affective arousal, increase stress resilience, and increase capacities for emotion modulation. In a treatment development study, we found FFT-HR to be highly effective compared to a brief psychoeducational intervention in reducing affective symptoms and enhancing functioning among youth at high risk for BD, particularly those in high expressed emotion families. We will enroll 150 youth ages 9-17 who meet operationalized high-risk criteria for BD: (1) a diagnosis of BD not otherwise specified or major depressive disorder, with active symptoms in the past 1-2 weeks; and (2) at least one biological parent has a history of type I or type II BD. Following a diagnostic and family evaluation, we will randomly assign subjects to: (1) FFT-HR (12 sessions in 4 mos), or (2) enhanced care (EC; 3 weekly family education sessions followed by monthly individual support sessions over 4 mos). Participants who require pharmacotherapy will be treated by psychiatrists applying best-practice procedures. A subset of 60 youths will undergo pre- and post-treatment fMRI scans while performing two tasks shown to activate prefrontal-subcortical circuitry: a standard facial affect task of implicit emotion perception and an emotion regulation task. We will compare the magnitude of pre/post treatment changes in affective symptoms and functioning between subjects randomized to the two treatment arms, and the stability of changes over 2-4 years. We hypothesize that FFT-HR will be more effective than EC in (1) reducing the acute severity of mood symptoms and maintaining mood stability over 2-4 years, and (2) reducing the hazard of a first (hypo)manic episode and enhancing functioning. We hypothesize that indicators of high emotional arousal - pretreatment levels of expressed emotion in parents, emotional dysregulation in youth, and activation in prefrontal-subcortical limbic circuits (amygdala, dorsolateral and ventral prefrontal cortex) in youth - will be associated with a greater magnitude of response to FFT-HR. Finally, we will examine the impact of FFT-HR vs. EC on pre/post treatment changes in activation of limbic circuitry, and correlations between neural changes and symptom improvement over 4 mos. Consistent with the NIMH Strategic Plan, this study will facilitate the translation of a novel early intervention in community settings and identify mechanistic factors at the neural, clinical, and contextual levels that can be used to refine future treatments. PUBLIC HEALTH RELEVANCE: The proposed study is the first definitive trial of an early psychosocial intervention - family-focused treatment for high-risk youth (FFT-HR) - in comparison with brief psychoeducation in reducing the severity of affective morbidity, preventing or delaying the onset of fully syndromal mania, and enhancing functioning in youth at high risk for bipolar disorder. We hypothesize that responses to family intervention will be affected by individual-behavioral factors (degree of emotional dysregulation), family-contextual variables (level of expressed emotion), and neural factors (activation in prefrontal-subcortical limbic circuits that have been implicated in mood regulation). FFT-HR could prove to be a cost-effective and easily disseminable intervention, with great potential to prevent or ameliorate the natural progression of bipolar disorder and reduce individual disability and public health burden among high-risk youth.