Treatment Research Investigating Depression Effects on Neuroimmune Targets (TRIDENT)

调查抑郁症对神经免疫目标影响的治疗研究 (TRIDENT)

基本信息

批准号：
10369905
负责人：
Adam Wayne Carrico
金额：
$ 121.86万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10369905
关键词：
Acute Aftercare Amino Acids Behavior Therapy Behavioral Brain Catabolism Clinical Research Cognitive Therapy Communication Counseling Depressed mood Development Enrollment Epidemic Evidence based treatment Experimental Models Functional Magnetic Resonance Imaging Gastrointestinal tract structure Gene Expression Generations Genetic Transcription HIV HIV Infections Immune Immune system Immunologic Markers Immunologics Individual Inflammatory Integrase Interoception Leukocytes Link Measures Mediator of activation protein Mental Depression Modernization Negative Valence Neuraxis Neuroimmune Neurosecretory Systems Outcome Participant Pathogenesis Pathway interactions Peripheral Pharmacological Treatment Primary Care Physician Psychoneuroimmunology Psychosocial Assessment and Care Psychosocial Factor Randomized Randomized Controlled Trials Regimen Research Rest Rewards Risk Running Serotonin Signal Pathway Signal Transduction Subgroup System Tryptophan Unipolar Depression Up-Regulation Vagus nerve structure Viral Load result Waiting Lists acute infection antiretroviral therapy base depressive symptoms dysbiosis efficacy evaluation eligible participant evidence base experience follow up assessment gut dysbiosis gut microbiome gut-brain axis improved inhibitor/antagonist innovation microbial microbiome microbiome alteration multidimensional data neural network neurobehavioral neuropsychiatric disorder primary outcome relating to nervous system response stem therapy adherence treatment research

项目摘要

Project Summary Since the early days of the epidemic, psychoneuroimmunology research established that there is a bi- directional relationship between depression and HIV pathogenesis. Among people with HIV (PWH), substantial damage to the gastrointestinal tract occurs during acute HIV infection, which is partially responsible for dysregulation of the gut microbiome (i.e., dysbiosis) and translocation of inflammatory microbial products into the periphery. Even among those receiving effective anti-retroviral therapy (ART), these pathophysiologic alterations in the gut drive persistent immune dysregulation that partially explains amplified risk for depression and other neuropsychiatric disorders in PWH. An important gap is that no prior clinical research in PWH receiving effective ART has examined the functional connections between the microbiome, gastrointestinal tract, immune system, and the brain – the microbiome-gut-brain (MGB) axis. Treatment Research Investigating Depression Effects on Neuroimmune Targets (TRIDENT) is a randomized controlled trial that leverages an evidence-based Cognitive-Behavioral Therapy for Adherence and Depression (CBT-AD) treatment as an experimental probe to advance our understanding of how decreasing depression alters MGB axis pathways in PWH. TRIDENT will enroll 120 depressed PWH taking an integrase strand transfer inhibitor (INSTI)-based ART regimen who have an undetectable viral load. TRIDENT will have a brief run-in period (i.e., waiting period prior to randomization) where potentially eligible participants will be asked to complete a baseline psychosocial assessment, provide biospecimens, and attend a separate baseline fMRI assessment. A total of 120 participants who complete the run-in period will be randomized to receive either: 1) CBT-AD (n = 60); or 2) a wait-list control (WLC) condition (n = 60). Immediately following randomization, CBT-AD participants will receive up to 12 individual sessions over 4 months. WLC participants will have the opportunity to receive the CBT-AD treatment after a 6-month delay. During the intent-to-treat period, follow-up assessments at 2 months and 4 months (i.e., during and immediately following the delivery of CBT-AD) will characterize changes in the microbiome, soluble immune markers relevant to HIV pathogenesis, and leukocyte signaling to measure the conserved transcriptional response to adversity (CTRA). These will be examined as plausible mediators of CBT-AD related improvements in the primary outcome – resting state activation and connectivity of the negative valence system at 6 months (assessed via fMRI). Six months after randomization, WLC participants will crossover and have the opportunity to receive CBT-AD, and all participants (both CBT-AD and WLC) will complete a final follow-up assessment at 10 months. TRIDENT will have an exceptional impact by providing an experimental model to advance our understanding of how decreasing depression changes the MGB axis in PWH. TRIDENT will include multi-level, high dimensional data on the MGB axis to catalyze a new generation of pharmacologic and behavioral treatments for depression and its neurobehavioral substrates in PWH.

项目概要自疫情爆发初期以来，心理神经免疫学研究表明，存在着双重因素：在艾滋病毒感染者（PWH）中，抑郁症与艾滋病毒发病机制之间的直接关系。急性艾滋病毒感染期间会发生胃肠道损伤，这是导致肠道微生物组失调（即菌群失调）以及炎症微生物产物易位至即使在那些接受有效的抗逆转录病毒治疗（ART）的人中，这些病理生理学现象也是如此。肠道的改变会导致持续的免疫失调，这在一定程度上解释了抑郁症风险增加的原因和其他神经精神疾病在 PWH 中的一个重要差距是，之前没有针对 PWH 的临床研究。接受有效的 ART 检查了微生物组、胃肠道之间的功能联系肠道、免疫系统和大脑——微生物组-肠-脑 (MGB) 轴治疗研究调查。抑郁对神经免疫目标的影响 (TRIDENT) 是一项随机对照试验，利用基于证据的依从性和抑郁认知行为疗法（CBT-AD）作为一种治疗方法实验探索以加深我们对减少抑郁如何改变 MGB 轴通路的理解 TRIDENT 将招募 120 名服用基于整合酶链转移抑制剂 (INSTI) 的抑郁症 PWH。 TRIDENT 病毒载量无法检测到的 ART 方案将有一个短暂的磨合期（即等待期）。在随机化之前），潜在合格的参与者将被要求完成基线心理社会评估、提供生物样本并参加单独的基线 fMRI 评估总共 120 项。完成磨合期的参与者将被随机接受： 1) CBT-AD (n = 60)；或 2) 等待名单控制 (WLC) 条件（n = 60）随机化后，CBT-AD 参与者将立即进行。在 4 个月内参加最多 12 场个人会议的 WLC 参与者将有机会获得延迟 6 个月后进行 CBT-AD 治疗在意向治疗期间，2 个月后进行随访评估。 4 个月（即 CBT-AD 交付期间和交付后立即）将体现出以下方面的变化：微生物组、与 HIV 发病机制相关的可溶性免疫标记物以及用于测量 HIV 感染的白细胞信号传导对逆境的保守转录反应（CTRA）将被检查为可能的介质。 CBT-AD 相关的主要结果的改善——静息状态激活和连接性 6 个月时的负价系统（通过随机化后 6 个月评估），WLC 参与者。将交叉并有机会获得CBT-AD，所有参与者（CBT-AD和WLC）将在 10 个月时完成最终的后续评估 TRIDENT 将通过提供一个特殊的影响。实验模型来加深我们对减少抑郁如何改变 MGB 轴的理解 PWH.TRIDENT 将包含 MGB 轴上的多层次、高维度数据，以催化新一代 PWH 中抑郁症及其神经行为基础的药物和行为治疗的研究。