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

项目摘要/摘要 此R61/R33应用程序响应由国家补充和支持中心发布的PAR-18-829 综合健康(NCCIH)。在R61阶段，该奖项将支持开发一款三臂 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物的患者的三个不同的抑郁症生物标志物：1)额叶皮质 磷磁共振波谱测定的生物能量学；2)扣带回亚区 通过静息状态功能磁共振成像测量的功能连通性；以及3)整体- 血液中的5-羟色胺水平。这项研究的动机是有证据表明，相对低氧会导致抑郁风险。 已经多次证明，患有哮喘和慢性病等缺氧性疾病的人 阻塞性肺病患抑郁症和自杀的风险比健康对照组和 患有非缺氧性疾病的人。同样，人们观察到，与其他国家相比， 美国，像犹他州这样的山区州有更高的严重抑郁障碍和自杀率，这是 其他社会人口学因素不能完全解释。因居住海拔高度引起的慢性低氧可能 通过改变大脑生物能量学或5-羟色胺合成来调节这一过程。这些缺陷可以通过以下方式得到纠正 分别补充肌酸和5-羟色胺。在R61阶段，我们将进行随机、 双盲三臂试验研究(目的1)补充5-羟色胺的效果 HTP和肌酸在高海拔人群抑郁症的光谱标志物上的作用 对标准抗抑郁药以及(目标2)静息状态功能改变的反应充分 抑郁症受试者的连接性。评价补充5-羟色胺对5-羟色胺的影响 综合，我们还将(目标3)测量受试者在治疗前和治疗8周后的血液5-羟色胺水平。 在R33阶段，我们将评估上述神经化学物质是否与抑郁和靶点相关 参与与抗抑郁反应有关。我们假设双重增强与 与单独使用肌酸和5-HTP相比，肌酸和5-HTP可以增强抗抑郁剂的作用 根据临床结果衡量MDD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大脑能量代谢标志的正常化 31P-MRS测量及亚膝扣带回静息状态功能连接正常化。这个 这里描述的研究计划将构成随后的安慰剂对照R01资助研究的基础 关于进一步评估研究干预对慢性阻塞性肺病患者治疗的有效性的建议 对第一线代理人没有反应的抑郁症。本建议书和后续的R01级建议书将 直接告知MDD的临床护理，同时帮助阐明其基础机制。

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.