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(加州大学洛杉矶分校[D.Miklowitz]和斯坦福[K.Chang])，以回应PAR-09-153，用于精神疾病临床和服务研究的协作R01s。尽管双相情感障碍(BD)给公共卫生造成了相当大的负担，但没有系统地对罹患这种疾病的高危青少年进行心理社会干预。对遗传上易患BD的年轻人的研究发现，临床状态有相当大的风险转化为完全阈值BD I或II障碍。我们提出了一项多点随机对照试验，以测试针对高危青年的多方面、以家庭为重点的治疗(FFT-HR)的有效性。4个月的干预包括心理教育、沟通训练和解决问题，旨在减少情感唤醒，增加压力适应能力，并增加情绪调节能力。在一项治疗发展研究中，我们发现，与短暂的心理教育干预相比，FFT-HR在减少BD高危青少年，特别是高表达情感家庭的青少年中减少情感症状和增强功能方面非常有效。我们将招募150名9-17岁的青年，他们符合BD的可操作性高危标准：(1)诊断为BD或严重抑郁障碍，在过去1-2周内有活跃症状；(2)至少有一名亲生父母有I型或II型BD病史。在诊断和家庭评估之后，我们将随机将受试者分配到：(1)FFT-HR(4个月12次会议)，或(2)强化护理(EC；每周3次家庭教育会议，然后每月4个月的个人支持会议)。需要药物治疗的参与者将由应用最佳实践程序的精神病学家进行治疗。一组60名年轻人将接受治疗前后的fMRI扫描，同时执行两项任务，以激活前额叶-皮质下回路：一项标准的面部内隐情绪感知任务和一项情绪调节任务。我们将比较随机分到两个治疗组的受试者治疗前和治疗后情感症状和功能的变化幅度，以及在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(低)躁狂发作的风险，增强功能。我们假设，高情绪唤醒的指标-父母表达情绪的预处理水平，年轻人的情绪失调，以及年轻人前额叶-皮质下边缘环路(杏仁核、背外侧和腹侧前额叶皮质)的激活-将与对FFT-HR的更大程度的反应有关。最后，我们将检验FFT-HR与EC治疗前后边缘回路激活的变化的影响，以及神经变化与症状改善之间的相关性。与NIMH战略计划一致，这项研究将促进社区环境中一种新的早期干预的转化，并在神经、临床和背景水平确定可用于改进未来治疗的机械性因素。 公共卫生相关性：这项拟议的研究是对高危青少年的早期心理社会干预--以家庭为重点的治疗(FFT-HR)--的第一次最终试验，与简单的心理教育相比，该干预在降低情绪性发病率的严重性、预防或推迟完全综合征躁狂的发病以及增强双相情感障碍高危青少年的功能方面具有决定性意义。我们假设，对家庭干预的反应将受到个人行为因素(情绪失调的程度)、家庭背景变量(表达情绪的水平)和神经因素(涉及情绪调节的前额叶-皮质下边缘回路的激活)的影响。FFT-HR可能被证明是一种成本效益高、易于传播的干预措施，在预防或改善双相情感障碍的自然发展以及减少高危青年中的个人残疾和公共卫生负担方面具有巨大潜力。

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. 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.