2/2-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。米克洛维茨和斯坦福大学[K]。[张])响应PAR-09-153，精神障碍临床与服务研究协作R01s。尽管双相情感障碍（BD）造成了相当大的公共卫生负担，但尚未有系统地将社会心理干预措施应用于患该疾病的高风险青年。对遗传上易患双相障碍的年轻人的研究已经确定了临床状态有相当大的风险转化为完全阈值双相障碍I或II。我们提出了一项多地点随机对照试验来测试以家庭为中心的多方面治疗对高危青少年（FFT-HR）的疗效。为期4个月的干预包括心理教育、沟通训练和问题解决，旨在降低情感唤醒，增加压力恢复能力，增加情绪调节能力。在一项治疗发展研究中，我们发现FFT-HR与简短的心理教育干预相比，在减少双相障碍高风险青少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绪的家庭。我们将招募150名年龄在9-17岁的青少年，他们符合双相障碍的高危标准：(1)诊断为双相障碍，没有其他明确的诊断或重度抑郁症，在过去1-2周内出现活跃症状；(2)至少有一位亲生父母有I型或II型双相障碍病史。根据诊断和家庭评估，我们将随机分配受试者：(1)FFT-HR（4个月12次），或(2)强化护理（EC，每周3次家庭教育，随后每月4个月的个人支持会议）。需要药物治疗的参与者将由精神科医生应用最佳实践程序进行治疗。60名青少年将接受治疗前和治疗后的功能磁共振成像扫描，同时执行两项任务，显示激活前额叶-皮层下回路：标准的内隐情绪感知面部影响任务和情绪调节任务。我们将比较随机分配到两个治疗组的受试者在治疗前/治疗后情感症状和功能的变化幅度，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在2-4年内保持情绪稳定；(2)降低首次（轻度）躁狂发作的危险并增强功能。我们假设，高情绪唤醒的指标——父母的情绪表达预处理水平、青少年的情绪失调以及青少年前额叶-皮层下边缘回路（杏仁核、背外侧和腹侧前额叶皮层）的激活——将与FFT-HR的更大程度的反应有关。最后，我们将研究FFT-HR与EC对治疗前后边缘回路激活变化的影响，以及4个月后神经变化与症状改善之间的相关性。与NIMH战略计划一致，这项研究将促进在社区环境中翻译一种新的早期干预措施，并在神经、临床和环境水平上确定可用于改进未来治疗的机制因素。

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.