Dietary Supplement Creatine for Adolescent Females with SSRI-Resistant Depression

描述(由申请人提供)：根据PAR-11-177提交的R21/R33组合申请，将旨在针对大脑能量代谢的膳食补充剂干预与缺乏情绪障碍的大脑高能代谢物的翻译神经成像测量配对。为患有难治性重度抑郁障碍(MDD)的女性青少年试行一种新的干预措施，同时量化其对机械性目标的参与，支持国家精神卫生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绘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，这种变化随着抑郁发作的解决而正常化。31-磷磁共振波谱成像(31P-MRSI)是一种安全和非侵入性的成像方法，可以在体内测量特定高能大脑代谢物的浓度。这些药物包括β-核苷三磷酸(！-NTP；主要是三磷酸腺苷，或称ATP)和磷酸肌酸(PCR)。对成年MDD患者的31P-MRSI研究显示了脑能量代谢的变化模式：PCR值增加，而！-NTP降低。在女性中更常见的是，这种模式与治疗初治期MDD对抗抑郁药物的反应增加，以及难治性MDD对甲状腺激素增加的可能性增加有关。有机酸肌酸是所有脊椎动物的内源性物质，在维持大脑和骨骼肌中的ATP供应方面起着至关重要的作用。在临床前动物模型中，补充肌酸以一种性别相关的方式改变了啮齿动物的抑郁行为，有利于雌性。在健康的成年人中，补充肌酸可增加脑组织总肌酸，并诱导上述PCR和！-NTP的变化模式，这表明使用肌酸促进MDD的治疗反应状态是可能的。在R21概念验证研究中，我们建议测试肌酸靶点和改变女性青少年选择性5-羟色胺再摄取抑制剂(SSRI)抵抗MDD的大脑能量代谢的假设。参与者将接受四种方案中的一种为期8周的治疗：安慰剂或肌酸每天2g、4g或10g。31P-MRSI的PCR和！-NTP的测量将在基线上进行，并在治疗8周后重复。如果达到了R21研究的里程碑，我们将继续进行R33先导研究。使用在R21研究中提供靶向参与和耐受性的最佳组合的肌酸剂量，将对患有SSRI抗药性MDD的青春期女性进行随机安慰剂对照的肌酸可行性研究。这个

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