title: Creatine target engagement with brain bioenergetics: a dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression.
abstract: Major depressive disorder (MDD) often begins during adolescence and is projected to become the leading cause of global disease burden by the year 2030. Yet, approximately 40 % of depressed adolescents fail to respond to standard antidepressant treatment with a selective serotonin reuptake inhibitor (SSRI). Converging evidence suggests that depression is related to brain mitochondrial dysfunction. Our previous studies of MDD in adult and adolescent females suggest that augmentation of SSRI pharmacotherapy with creatine monohydrate (CM) may improve MDD outcomes. Neuroimaging with phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) can measure the high-energy phosphorus metabolites in vivo that reflect mitochondrial function. These include phosphocreatine (PCr), a substrate for the creatine kinase reaction that produces adenosine triphosphate. As part of the National Institute of Mental Health's experimental medicine initiative, we conducted a placebo-controlled dose-ranging study of adjunctive CM for adolescent females with SSRI-resistant MDD. Participants were randomized to receive placebo or CM 2, 4 or 10 g daily for 8 weeks. Pre- and post-treatment (31)P-MRS scans were used to measure frontal lobe PCr, to assess CM's target engagement with cerebral energy metabolism. Mean frontal lobe PCr increased by 4.6, 4.1 and 9.1 % in the 2, 4 and 10 g groups, respectively; in the placebo group, PCr fell by 0.7 %. There was no group difference in adverse events, weight gain or serum creatinine. Regression analysis of PCr and depression scores across the entire sample showed that frontal lobe PCr was inversely correlated with depression scores (p = 0.02). These results suggest that CM achieves target engagement with brain bioenergetics and that the target is correlated with a clinical signal. Further study of CM as a treatment for adolescent females with SSRI-resistant MDD is warranted.
authors.affiliation: Department of Psychiatry, University of Utah School of Medicine, 501 Chipeta Way, Salt Lake City, UT, 84108, USA. doug.kondo@hsc.utah.edu.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Kondo
authors.affiliation: The Brain Institute, 383 Colorow Drive, Salt Lake City, UT, 84108, USA.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Forrest
authors.affiliation: Department of Psychiatry, University of Utah School of Medicine, 501 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Psychiatry, University of Utah School of Medicine, 501 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Sung
authors.affiliation: The Brain Institute, 383 Colorow Drive, Salt Lake City, UT, 84108, USA.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Hellem
authors.affiliation: The Brain Institute, 383 Colorow Drive, Salt Lake City, UT, 84108, USA.
authors.forename: Rebekah S
authors.initials: RS
authors.lastname: Huber
authors.affiliation: Department of Psychiatry, University of Utah School of Medicine, 501 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Perry F
authors.initials: PF
authors.lastname: Renshaw
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D003404:Creatinine / Q000008:administration & dosage*; D003865:Major Depressive Disorder / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D004351:Drug Resistance / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006801:Humans; D059906:Neuroimaging; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage
chemical_list: D003404:Creatinine; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Adolescent depression; Bioenergetics; Creatine monohydrate; Mitochondrial function; Phosphocreatine; Phosphorus-31 magnetic resonance spectroscopy; Women’s health