Dietary Supplement Creatine for Adolescent Females with SSRI-Resistant Depression

膳食补充剂肌酸治疗患有 SSRI 抗性抑郁症的青春期女性

• 批准号: 8282376
• 负责人: PERRY FRANKLIN RENSHAW
• 金额: $ 22.24万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282376
• 关键词: Address; Adenosine Triphosphate; Adolescence; Adolescent; Adult; Affect; Age; American; Animal Model; Antidepressive Agents; Behavior; Bioenergetics; Biology; Blood - brain barrier anatomy; Brain; Brain Chemistry; Brain scan; Buffers; Cells; Cerebrum; Child; Childhood; Clinical assessments; Concentration measurement; Creatine; Development; Dietary Supplementation; Dose; Energy Metabolism; Failure; Feasibility Studies; Female; Female Adolescents; Functional disorder; Gender; Goals; Image; Intervention; Knowledge; Link; Literature; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Measurement; Measures; Medical; Mental Depression; Metabolic; Methods; Mitochondria; Mood Disorders; National Institute of Mental Health; Neurodegenerative Disorders; Neuromodulator; Neuroprotective Agents; Oral; Participant; Patients; Pattern; Pharmaceutical Preparations; Phase; Phosphocreatine; Phosphorus; Pilot Projects; Placebo Control; Placebos; Play; Population; Prevalence; Procedures; Psychiatry; Psychotherapy; Public Health; Randomized; Recommendation; Recovery; Regimen; Research; Resistance; Resolution; Rodent; Role; Scanning; Schools; Selective Serotonin Reuptake Inhibitor; Severities; Site; Skeletal Muscle; Spectrum Analysis; Staging; Strategic Planning; Substance abuse problem; Supplementation; Testing; Thyroid Gland; Thyroid Hormones; Vertebrates; Woman; critical developmental period; depressive symptoms; design; dietary supplements; healthy volunteer; imaging modality; improved; in vivo; inorganic phosphate; magnetic resonance spectroscopic imaging; male; meetings; neuroimaging; novel; nucleoside triphosphate; organic acid; pre-clinical; programs; public health relevance; reproductive; response; stem; suicidal behavior; translational approach; treatment response; venlafaxine

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.

描述（由申请人提供）：根据 PAR-11-177 提交，该 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措施与缺乏情绪障碍的大脑高能代谢物的转化神经影像测量相结合。对患有难治性重度抑郁症 (MDD) 的女性青少年试行一种新颖的干预措施，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策略。该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。一系列证据表明，抑郁症与大脑能量代谢的变化有关，而大脑能量代谢的变化随着抑郁发作的缓解而恢复正常。 31-磷磁共振波谱成像 (31P-MRSI) 是一种安全且非侵入性的成像方法，可以在体内测量特定高能脑代谢物的浓度。其中包括 β-三磷酸核苷 (!-NTP；主要是三磷酸腺苷，或 ATP) 和磷酸肌酸 (PCr)。对患有 MDD 的成人进行的 31P-MRSI 研究显示，大脑能量代谢发生了变化：PCr 增加，!-NTP 减少。这种模式在女性中更为常见，与未接受治疗的 MDD 中的抗抑郁药物以及难治性 MDD 中的甲状腺激素增强反应的可能性增加有关。有机酸肌酸是所有脊椎动物的内源性，并且已知在维持大脑和骨骼肌中的 ATP 供应方面发挥着至关重要的作用。在临床前动物模型中，肌酸补充剂以有利于雌性的性别依赖性方式改变啮齿类动物的抑郁样行为。在健康成年人中，膳食补充肌酸会增加脑肌酸总量，并诱导上述 PCr 和 !-NTP 的改变模式，这表明使用肌酸促进 MDD 治疗反应状态的可能性。在 R21 概念验证研究中，我们建议检验以下假设：肌酸针对并改变对选择性血清素再摄取抑制剂 (SSRI) 耐药的女性青少年 MDD 的大脑能量代谢。参与者将接受四种方案之一为期 8 周的治疗：安慰剂或肌酸每天 2g、4g 或 10g。 PCr 和 !-NTP 的 31P-MRSI 测量将在基线时进行，并在治疗 8 周后重复。如果达到 R21 研究里程碑，我们将进行 R33 试点研究。使用 R21 研究中提供最佳目标参与和耐受性组合的肌酸剂量，将针对患有 SSRI 耐药性 MDD 的青少年女性进行肌酸随机安慰剂对照可行性研究。这项研究与公共卫生的相关性源于以下事实：到 19 岁时，MDD 的累积患病率为 15-24%，并且现有治疗方法存在局限性。此外，青春期标志着一个关键的发育时期，在此期间，女性 MDD 的发病率加倍，在女性整个育龄期间仍是男性的两倍。最后，女性抑郁症与多种重大疾病有关。因此，针对患有 MDD 的青少年女性的新型干预措施有可能超越精神病学的界限，广泛影响公共健康。 公共健康相关性：本研究通过开发新型膳食补充剂干预肌酸，解决了一个重大的公共健康问题，即耐药性青少年重度抑郁症。除了标准临床评估之外，还将通过磁共振波谱脑扫描来测量治疗反应。这种转化方法旨在提高对青少年抑郁症和康复的基础生物学的了解。