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: 10045272
• 负责人: Brent Michael Kious
• 金额: $ 38.11万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045272
• 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 Airway Disease; Clinical; Clinical Trials; Complementary Health; Creatine; Creatine Supplement; Depression and Suicide; Development; Disease; Double-Blind Method; Effectiveness; Energy Metabolism; Epidemiology; Exhibits; Functional Magnetic Resonance Imaging; Funding; Hamilton Rating Scale for Depression; Health; Hippocampus (Brain); Hypoxia; Image; Integrative Medicine; Intervention; Intervention Studies; Link; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Measures; Mediating; Medical; Mental Depression; Metabolism; Mitochondria; N-acetylaspartate; Nucleotides; Oral; Outcome; Oxygen; Participant; Patients; Persons; Phase; Phosphocreatine; Phosphorus; Physiological; Placebos; Prevalence; Production; Productivity; Prosencephalon; Protons; Randomized; Research; Resistance; Rest; Risk; Rodent; Sea; Selective Serotonin Reuptake Inhibitor; Serotonin; Smoking; Structure; Suicide; Supplementation; Tryptophan; Tryptophan 5-monooxygenase; United States; Utah; Whole Blood; Work; accomplished suicide; cingulate cortex; clinical care; depressed patient; depressive symptoms; dietary supplements; disability; emotion regulation; 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.

项目总结/文摘