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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants Phase II (R33)
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Special Emphasis Panel (ZMH1-ERB-F (01))
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Avenevoli, Shelli A
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University of Utah
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Salt Lake City
United States
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Kondo, Douglas G; Forrest, Lauren N; Shi, Xianfeng et al. (2016) Creatine target engagement with brain bioenergetics: a dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression. Amino Acids 48:1941-54
Sung, Young-Hoon; Yurgelun-Todd, Deborah A; Kondo, Douglas G et al. (2015) Gender differences in the effect of tobacco use on brain phosphocreatine levels in methamphetamine-dependent subjects. Am J Drug Alcohol Abuse 41:281-9
Hellem, Tracy L; Sung, Young-Hoon; Shi, Xian-Feng et al. (2015) Creatine as a Novel Treatment for Depression in Females Using Methamphetamine: A Pilot Study. J Dual Diagn 11:189-202
Shi, Xian-Feng; Forrest, Lauren N; Kuykendall, M Danielle et al. (2014) Anterior cingulate cortex choline levels in female adolescents with unipolar versus bipolar depression: a potential new tool for diagnosis. J Affect Disord 167:25-9
Kondo, D G; Hellem, T L; Shi, X-F et al. (2014) A review of MR spectroscopy studies of pediatric bipolar disorder. AJNR Am J Neuroradiol 35:S64-80
Shi, Xian-Feng; Carlson, Paul J; Kim, Tae-Suk et al. (2014) Effect of altitude on brain intracellular pH and inorganic phosphate levels. Psychiatry Res 222:149-56
Sung, Young-Hoon; Yurgelun-Todd, Deborah A; Shi, Xian-Feng et al. (2013) Decreased frontal lobe phosphocreatine levels in methamphetamine users. Drug Alcohol Depend 129:102-9
Allen, Patricia J; D'Anci, Kristen E; Kanarek, Robin B et al. (2012) Sex-specific antidepressant effects of dietary creatine with and without sub-acute fluoxetine in rats. Pharmacol Biochem Behav 101:588-601
Lyoo, In Kyoon; Yoon, Sujung; Kim, Tae-Suk et al. (2012) A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder. Am J Psychiatry 169:937-945
Kondo, Douglas G; Sung, Young-Hoon; Hellem, Tracy L et al. (2011) Open-label uridine for treatment of depressed adolescents with bipolar disorder. J Child Adolesc Psychopharmacol 21:171-5

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