31P-MRS and resting state functional connectivity analysis of the effects of 5-hydroxytryptophan and creatine for antidepressant augmentation in patients with SSRI/SNRI-resistant major depressive diso

31P-MRS 和静息态功能连接分析 5-羟色氨酸和肌酸对 SSRI/SNRI 耐药重度抑郁症患者的抗抑郁增强作用

• 批准号: 10836765
• 负责人: Brent Michael Kious
• 金额: $ 50.78万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10836765
• 关键词: 5-Hydroxytryptophan; Affect; Altitude; Amygdaloid structure; Animals; Antidepressive Agents; Asthma; Award; Bioenergetics; Biological; Biological Markers; Blood; Brain; Brain Stem; Chronic; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Trials; Combined Modality Therapy; Creatine; Creatine Supplement; Development; Disease; Double-Blind Method; Energy Metabolism; Epidemiology; Exhibits; Functional Magnetic Resonance Imaging; Funding; Hamilton Rating Scale for Depression; Health; Hippocampus; Hypoxia; Image; Intervention; Intervention Studies; Involutional Depression; Link; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Measures; Mediating; Medical; Mental Depression; Metabolism; Mitochondria; Moods; N-acetylaspartate; National Center for Complementary and Integrative Health; Natural Supplement; Nucleotides; Oral; Outcome; Oxygen; Participant; Patients; Persons; Phase; Phosphocreatine; Phosphorus; Physiological; Placebo Control; Prevalence; Production; Productivity; Prosencephalon; Protons; Randomized; Research; Resistance; Rest; Risk; Rodent; Sea; Selective Serotonin Reuptake Inhibitor; Serotonin; Smoking; Suicide; Suicide attempt; Supplementation; Tryptophan; Tryptophan 5-monooxygenase; United States; Utah; Whole Blood; Work; cingulate cortex; clinical care; clinical outcome measures; comparison control; completed suicide; depressed patient; depressive symptoms; dietary supplements; disability; effectiveness evaluation; emotion regulation; frontal lobe; high risk; improved; inorganic phosphate; mortality; neurochemistry; novel; residence; response; sociodemographic factors; suicidal risk; suicide rate; treatment group; treatment response; tripolyphosphate

Project Summary/Abstract This R61/R33 application is responsive to PAR-18-829, issued by the National Center for Complementary and Integrative Health (NCCIH). In the R61 phase, the award will support the development of a three-armed clinical trial to assess the ability of 5-hydroxtryptophan (5-HTP), creatine monohydrate, and their combination to alter three distinct biomarkers of depression in persons already taking antidepressants: 1) frontal cortical bioenergetics as measured by phosphorus magnetic resonance spectroscopy; 2) subgenual cingulate cortex functional connectivity as measured by resting state functional magnetic resonance imaging; and 3) whole- blood serotonin levels. The study is motivated by evidence that relative hypoxia contributes to depression risk. It has been repeatedly demonstrated that persons with hypoxic medical conditions such as asthma and chronic obstructive pulmonary disease are at higher risk of depression and suicide than both health controls and persons with non-hypoxic medical conditions. Similarly, it has been observed that, compared to the rest of the United States, mountain states like Utah have higher rates of major depressive disorder and suicide, which are not fully explained by other sociodemographic factors. Chronic hypoxia due to altitude of residence may mediate this, via alterations in brain bioenergetics or serotonin synthesis. These deficits could be corrected via supplementation with creatine and 5-HTP, respectively. In the R61 phase, we will conduct a randomized, double-blind, three-armed trial to investigate (Aim 1) the effect of supplementation with the combination of 5- HTP and creatine on spectroscopic markers of depression in persons living at high altitude who have not responded sufficiently to standard antidepressants, as well as (Aim 2) alterations in resting-state functional connectivity in subjects with depression. To assess the ability of 5-HTP supplementation to affect serotonin synthesis, we will also (Aim 3) measure subjects' blood serotonin levels before and after 8 weeks of treatment. In the R33 phase, we will assess whether the above neurochemical correlates of depression and target engagement are associated with antidepressant response. We hypothesize that dual augmentation with creatine and 5-HTP will, compared to augmentation with either agent alone, enhance antidepressant response in persons with MDD as measured by clinical outcomes. We further hypothesize that persons who are responsive to combination treatment will exhibit normalization of markers of brain energy metabolism measured by 31P-MRS and normalization of subgenual cingulate resting state functional connectivity. The research plan described here will form the basis for a subsequent placebo-controlled R01-funded study proposal to further assess the effectiveness of the study intervention for the treatment of MDD in persons with depression that has not responded to first-line agents. This proposal and subsequent R01-level proposals will directly inform the clinical care of MDD while helping to elucidate the mechanisms underpinning it.

项目概要/摘要 此 R61/R33 应用程序响应 PAR-18-829，由国家补充和治疗中心发布 综合健康（NCCIH）。在R61阶段，该奖项将支持三臂机器人的开发 评估 5-羟色氨酸 (5-HTP)、一水肌酸及其组合能力的临床试验 改变已经服用抗抑郁药的人的三种不同的抑郁症生物标志物：1）额叶皮质 通过磷磁共振波谱测量的生物能学； 2）膝下扣带皮层 通过静息态功能磁共振成像测量的功能连接性； 3) 整体- 血液血清素水平。这项研究的动机是有证据表明相对缺氧会增加抑郁风险。 已多次证明，患有哮喘和慢性病等缺氧疾病的人 阻塞性肺疾病患者患抑郁症和自杀的风险高于健康对照组和 患有非缺氧疾病的人。同样，我们观察到，与其他国家相比 在美国，犹他州等山区州的重度抑郁症和自杀率较高， 其他社会人口因素无法完全解释。居住海拔高度造成的慢性缺氧可能 通过改变大脑生物能量或血清素合成来调节这一点。这些缺陷可以通过以下方式纠正 分别补充肌酸和5-HTP。在 R61 阶段，我们将进行随机、 双盲、三组试验，研究（目标 1）补充 5- 组合的效果 HTP 和肌酸对居住在高海拔地区且未患有抑郁症的人的抑郁症光谱标志物的影响 对标准抗抑郁药以及（目标 2）静息态功能的改变有充分的反应 抑郁症患者的连通性。评估 5-HTP 补充剂影响血清素的能力 综合而言，我们还将（目标 3）测量受试者在治疗 8 周之前和之后的血液血清素水平。 在R33阶段，我们将评估上述神经化学物质是否与抑郁症和目标相关 参与度与抗抑郁反应相关。我们假设双重增强 与单独使用任一药物相比，肌酸和 5-HTP 会增强抗抑郁作用 通过临床结果衡量重度抑郁症患者的反应。我们进一步假设人们 对联合治疗有反应的人将表现出脑能量代谢标志物的正常化 通过 31P-MRS 测量和膝下扣带回静息状态功能连接的标准化。这 此处描述的研究计划将构成后续安慰剂对照 R01 资助研究的基础 提议进一步评估该研究干预治疗重度抑郁症患者的有效性 对一线药物没有反应的抑郁症。该提案和后续的 R01 级提案将 直接为 MDD 的临床护理提供信息，同时帮助阐明其背后的机制。