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.

项目摘要/摘要 该R61/R33申请响应于国家互补中心和 综合健康（NCCIH）。在R61阶段，该奖项将支持开发三臂 临床试验评估5-Hydroxtryptophan（5-HTP），肌酸一水合物及其组合的能力 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 通过磷磁共振光谱法测量的生物能学； 2）亚果状皮层 通过静止状态功能磁共振成像来衡量的功能连通性； 3） 血清素水平。这项研究是由证据表明相对缺氧导致抑郁症风险的动机。 反复证明，患有哮喘和慢性疾病的患者 阻塞性肺疾病比健康控制和自杀的风险更高 患有非催产疾病的人。同样，已经观察到，与其他的 美国，犹他州等山地州的重度抑郁症和自杀率较高，这是 没有通过其他社会人口统计学因素来完全解释。由于居住海拔高度而引起的慢性缺氧可能 通过改变脑生物能或5-羟色胺合成的改变来调解这一点。这些赤字可以通过 分别补充肌酸和5-HTP。在R61阶段，我们将进行随机的， 双盲，三臂试验，以调查（AIM 1）补充5-- HTP和肌酸在抑郁症的光谱标志物上居住在高海拔的人 对标准抗抑郁药的反应充分，以及（AIM 2）静止状态功能的变化 抑郁症受试者的连通性。评估5-HTP补充影响5-羟色胺的能力 合成，我们还将（目标3）在治疗8周之前和之后测量受试者的血清素血清素水平。 在R33阶段，我们将评估上述抑郁症和靶标的神经化学相关 参与与抗抑郁反应有关。我们假设与 肌酸和5-HTP将与单独使用任何一种药物进行增强相比，增强抗抑郁药 通过临床结果衡量的MDD的人反应。我们进一步假设人 对组合治疗的反应者将表现出脑能量代谢标记的标准化 通过31p-MRS测量以及亚基因扣带静止状态功能连接的归一化。这 此处描述的研究计划将构成随后的安慰剂对照R01资助的研究的基础 提议进一步评估研究干预措施对MDD治疗的有效性 尚未对一线特工做出反应的抑郁症。该建议和随后的R01级建议将 直接通知MDD的临床护理，同时帮助阐明了其基础的机制。