Dietary Supplement Creatine for Adolescent Females with SSRI-Resistant Depression

描述（由申请人提供）：根据PAR-11-177提交，该R21/R33联合申请将膳食补充剂干预与情绪障碍中缺乏的大脑高能代谢物的转化神经成像测量相结合，旨在靶向大脑中的能量代谢。试点一项针对患有难治性重度抑郁症（MDD）的女性青少年的新干预措施，同时量化其对机械目标的参与，支持国家心理健康研究所和膳食补充剂办公室战略计划中概述的具体战略。这项研究计划的长期目标是描述与情绪障碍相关的线粒体大脑能量代谢的变化。越来越多的证据表明，抑郁症与大脑能量代谢的变化有关，这种变化随着抑郁症发作的缓解而正常化。31-磷磁共振光谱成像（31P-MRSI）是一种安全、无创的成像方法，可以在体内测量特定高能脑代谢物的浓度。这些包括-三磷酸核苷（ntp；主要是三磷酸腺苷或ATP）和磷酸肌酸（PCr）。成年重度抑郁症患者的31P-MRSI研究显示了脑组织能量代谢的变化模式：PCr增加，-NTP减少。在女性中更常见，这种模式与对治疗初期MDD的抗抑郁药物和治疗抵抗性MDD的甲状腺激素增强的反应增加的可能性有关。有机酸肌酸是所有脊椎动物的内源性物质，在维持脑和骨骼肌ATP供应方面起着至关重要的作用。在临床前动物模型中，补充肌酸改变了啮齿类动物的抑郁行为，这种行为以性别依赖的方式有利于雌性。在健康成人中，膳食补充肌酸可增加总脑肌酸，并诱导PCr和！-NTP如上所述，提示使用肌酸促进重度抑郁症治疗反应状态的可能性。在R21概念验证研究中，我们提出验证肌酸靶向并改变女性青少年选择性5 -羟色胺再摄取抑制剂（SSRI）抵抗性重度抑郁症的脑组织能量代谢的假设。参与者将使用四种方案中的一种进行8周的治疗：每天服用安慰剂或肌酸2g、4g或10g。31P-MRSI测量PCr和！ntp将在基线进行，并在治疗8周后重复。如果达到R21研究里程碑，我们将继续进行R33试点研究。使用R21研究中提供最佳靶标参与和耐受性组合的肌酸剂量，将对患有ssri抗性MDD的青春期女性进行肌酸随机安慰剂对照可行性研究。这项研究的公共卫生相关性源于这样一个事实，即到19岁时重度抑郁症的累积患病率为15-24%，以及现有治疗方法的局限性。此外，青春期是发育的关键时期，在这一时期，女性患重度抑郁症的比例翻了一番，在整个育龄期，女性患重度抑郁症的比例是男性的两倍。最后，女性抑郁症与几种主要的医学疾病有关。因此，一种针对患有重度抑郁症的青春期女性的新型干预措施有可能广泛影响公共卫生，超越精神病学的界限。

DESCRIPTION (provided by applicant): Submitted in response to PAR-11-177, this combined R21/R33 application pairs a dietary supplement intervention intended to target energy metabolism in the brain with translational neuroimaging measures of brain high-energy metabolites that are deficient in mood disorders. Piloting a novel intervention for female adolescents with treatment-resistant major depressive disorder (MDD), while quantifying its engagement of a mechanistic target, supports specific strategies outlined in the strategic plans of the National Institute of Mental Health and the Office of Dietary Supplements. The long-term goal of this research program is to delineate the alterations in mitochondrial brain energy metabolism that are associated with mood disorders. Converging lines of evidence suggest that depression is associated with changes in brain energy metabolism that normalize with resolution of a depressive episode. 31-Phosphorus Magnetic Resonance Spectroscopic Imaging (31P-MRSI), a safe and non-invasive imaging method, allows in vivo measurement of concentrations in specific high-energy cerebral metabolites. These include beta-nucleoside triphosphate (!-NTP; largely adenosine triphosphate, or ATP) and phosphocreatine (PCr). 31P-MRSI studies of adults with MDD show a pattern of changes in brain energy metabolism: increased PCr and decreased !-NTP. More common in females, this pattern is associated with an increased likelihood of response to both antidepressants in treatment-naive MDD, and thyroid hormone augmentation in treatment-resistant MDD. The organic acid creatine is endogenous to all vertebrates, and is known to play a vital role in maintaining ATP supplies in brain and skeletal muscle. In preclinical animal models, creatine supplementation alters rodent depression-like behaviors in a gender-dependent manner that favors females. In healthy adults, dietary supplementation with creatine increases total brain creatine, and induces the pattern of alterations in PCr and !-NTP noted above, suggesting the possibility of using creatine to promote a treatment-responsive state in MDD. In the R21 proof- of-concept study, we propose to test the hypothesis that creatine targets and alters brain energy metabolism in female adolescents selective serotonin reuptake inhibitor (SSRI)-resistant MDD. Participants will be treated for 8 weeks with one of four regimens: placebo or creatine 2g, 4g or 10g daily. 31P-MRSI measurements of PCr and !-NTP will be performed at baseline, and repeated after 8 weeks of treatment. If the R21 study milestones are met, we will proceed to an R33 pilot study. Using the dose of creatine that offered the best combination of target engagement and tolerability in the R21 study, a randomized placebo-controlled feasibility study of creatine for adolescent females with SSRI-resistant MDD will be conducted. The public health relevance of this research stems from the fact that the cumulative prevalence of MDD is 15-24% by age nineteen, and the limitations of available treatments. Furthermore, adolescence marks a critical developmental period in which the rate of MDD in females doubles, remaining twice that of males throughout women's reproductive years. Finally, depression in women is linked to several major medical illnesses. Thus, a novel intervention for adolescent females with MDD has the potential to broadly impact public health, beyond the boundaries of psychiatry. PUBLIC HEALTH RELEVANCE: This research addresses a significant public health problem, medication-resistant adolescent major depressive disorder, through development of the novel dietary supplement intervention creatine. Treatment response will be measured with magnetic resonance spectroscopy brain scans in addition to standard clinical assessments. This translational approach is designed to improve knowledge of the underlying biology of adolescent depression and recovery.