1/2-Early Intervention for Youth at Risk for Bipolar Disorder

描述（由申请人提供）：本提案是两个相关申请之一（UCLA [D. Miklowitz]和斯坦福大学[K. Chang]）对PAR-09 - 153精神疾病临床和服务研究协作R01的回应。尽管双相情感障碍（BD）的相当大的公共卫生负担，没有心理社会干预已系统地应用于青年在发展的疾病的高风险。对遗传上易患BD的青少年的研究已经确定了临床状态具有相当大的转换为完全阈值BD I或II障碍的风险。我们提出了一个多中心随机对照试验，以测试多方面的家庭为重点的治疗高危青年（FFT-HR）的疗效。为期4个月的干预包括心理教育，沟通训练和解决问题，旨在减少情感唤起，增加压力恢复力，提高情绪调节能力。在一项治疗开发研究中，我们发现FFT-HR与简短的心理教育干预相比，在减少BD高风险青年的情感症状和增强功能方面非常有效，特别是那些高表达情感的家庭。我们将招募150名9 - 17岁的青少年，他们符合BD的操作性高风险标准：（1）诊断为BD（未另行说明）或重度抑郁症，在过去1 - 2周内有活动性症状;（2）至少一名生物学父母有I型或II型BD病史。在诊断和家庭评估后，我们将受试者随机分配至：（1）FFT-HR（4个月内12次）或（2）强化护理（EC;每周3次家庭教育，随后每月4个月进行个人支持）。需要药物治疗的受试者将由精神科医生采用最佳实践程序进行治疗。60名年轻人将接受治疗前和治疗后的fMRI扫描，同时执行两项任务，以激活前额叶皮层下回路：一个标准的面部情感任务的内隐情绪感知和情绪调节任务。我们将比较随机分配至两个治疗组的受试者之间治疗前/后情感症状和功能变化的幅度，以及2 - 4年内变化的稳定性。我们假设FFT-HR在以下方面比EC更有效：（1）降低情绪症状的急性严重程度并维持2 - 4年的情绪稳定性，以及（2）降低首次（轻度）躁狂发作的风险并增强功能。我们假设，高情绪唤起的指标--父母表达情绪的预处理水平，青年的情绪失调，以及前额叶皮层下边缘回路的激活（杏仁核，背外侧和腹侧前额叶皮层）在青年-将与更大幅度的反应FFT-HR。最后，我们将研究FFT-HR与EC对治疗前/后边缘系统激活变化的影响，以及4个月内神经变化与症状改善之间的相关性。与NIMH战略计划一致，本研究将促进社区环境中新型早期干预的翻译，并确定可用于完善未来治疗的神经，临床和背景水平的机制因素。

DESCRIPTION (provided by applicant): 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.