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

项目总结/摘要 此R61/R33应用程序响应由国家补充和认证中心发布的PAR-18-829。 综合健康（NCCIH）。在R61阶段，该奖项将支持开发一种三臂 评估5-羟色氨酸（5-HTP）、肌酸一水合物及其组合的能力的临床试验 改变已经服用抗抑郁药的人的三种不同的抑郁生物标志物：1）额叶皮层 通过磷磁共振波谱测量的生物能量学; 2）膝下扣带皮层 通过静息状态功能磁共振成像测量的功能连接;和3）整体- 血清素水平这项研究的动机是有证据表明，相对缺氧有助于抑郁症的风险。 已经反复证明，患有缺氧医学病症（如哮喘和慢性呼吸道疾病）的人， 阻塞性肺疾病患者抑郁和自杀的风险高于健康对照组， 无缺氧医疗条件的人。同样，据观察，与其他国家相比， 在美国，像犹他州这样的山区州有更高的重度抑郁症和自杀率， 其他社会人口因素无法解释。由于居住海拔而导致的慢性缺氧可能 通过改变大脑生物能量学或血清素合成来调节这一点。这些缺陷可以通过以下方式加以纠正： 分别补充肌酸和5-HTP。在R61阶段，我们将进行随机， 双盲、三臂试验，以研究（目的1）补充5- HTP和肌酸对生活在高海拔地区的未患抑郁症的人的光谱标记物的影响 对标准抗抑郁药反应充分，以及（目标2）静息状态功能改变 抑郁症患者的连通性。评估5-HTP补充剂影响血清素的能力 为了综合，我们还将（目的3）测量受试者在治疗8周之前和之后的血液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症和靶点相关。 参与与抗抑郁反应有关。我们假设，双增强与 肌酸和5-HTP与单独使用任何一种药物相比， 通过临床结局测量的MDD患者的反应。我们进一步假设， 对联合治疗有反应的患者将表现出脑能量代谢标志物的正常化 通过31 P-MRS测量和正常化的膝下扣带回静息状态功能连接。的 这里描述的研究计划将为随后的安慰剂对照R 01资助的研究奠定基础 建议进一步评估研究干预治疗MDD患者的有效性， 对一线药物没有反应的抑郁症。本提案和后续R 01级提案将 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.