Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2016 Aug;48(8):1941-54.
doi: 10.1007/s00726-016-2194-3. Epub 2016 Feb 23.

Creatine target engagement with brain bioenergetics: a dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression

Douglas G Kondo  1 , Lauren N Forrest  2 , Xianfeng Shi  3 , Young-Hoon Sung  3 , Tracy L Hellem  2 , Rebekah S Huber  2 , Perry F Renshaw  3
Affiliations
Randomized Controlled Trial

Creatine target engagement with brain bioenergetics: a dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression

Douglas G Kondo et al. Amino Acids. 2016 Aug.

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.

Keywords: Adolescent depression; Bioenergetics; Creatine monohydrate; Mitochondrial function; Phosphocreatine; Phosphorus-31 magnetic resonance spectroscopy; Women’s health.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Frontal lobe region of interest for phosphorus-31 magnetic resonance spectroscopy scans and a representative 31P-MRS spectrum. NTP alpha, gamma and beta-nucleoside triphosphate, PCr phosphocreatine, PDE phosphodiesters, Pi inorganic phosphate, PME phosphomonoesters
Fig. 2
Fig. 2
Participant flow diagram: screening, randomization and disposition of adolescent females with treatment-resistant major depressive disorder. FU follow-up, SSRI selective serotonin reuptake inhibitor, WC withdrew consent
Fig. 3
Fig. 3
Pre- versus post-treatment frontal lobe phosphocreatine (PCr/TP) in participants randomized to treatment with placebo or creatine 2, 4 or 10 g daily (N = 28)
Fig. 4
Fig. 4
Correlation between Children’s Depression Rating Scale-Revised (CDRS-R) scores and frontal lobe phosphocreatine (PCr/TP) and in participants randomized to placebo (left) versus active treatment (right) with creatine 2, 4 or 10 g (*p = 0.03)
Fig. 5
Fig. 5
Correlation between Children’s Depression Rating Scale-Revised (CDRS-R) scores and frontal lobe phosphocreatine (PCr/TP) and in the entire sample (p = 0.02). Right panel scatter plot of the correlation between Children’s Depression Rating Scale-Revised (CDRS-R) scores and frontal lobe PCr/TP, displayed by treatment group: placebo, 2 g creatine, 4 g creatine and 10 g creatine. Left panel negative correlation between changes in Children’s Depression Rating Scale-Revised (CDRS-R) scores and frontal lobe phosphocreatine/total phosphorus signal (PCr/TP) across all phosphorus magnetic resonance spectroscopy scans, i.e., lower depression scores correlate with higher PCr/TP concentrations (*p = 0.02)
Fig. 6
Fig. 6
Percent Change in Children’s Depression Rating Scale-Revised (CDRS-R) scores from baseline to week 8, displayed by treatment group (N = 28)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Adzic M, Lukic I, Mitic M, Djordjevic J, Elakovic I, Djordjevic A, Krstic-Demonacos M, Matic G, Radojcic M. Brain region- and sex-specific modulation of mitochondrial glucocorticoid receptor phosphorylation in fluoxetine treated stressed rats: effects on energy metabolism. Psychoneuroendocrinology. 2013;38:2914–2924. doi: 10.1016/j.psyneuen.2013.07.019. - DOI - PubMed
    1. Agarwal N, Port JD, Bazzocchi M, Renshaw PF. Update on the use of MR for assessment and diagnosis of psychiatric diseases. Radiology. 2010;255:23–41. doi: 10.1148/radiol.09090339. - DOI - PubMed
    1. Allen PJ. Creatine metabolism and psychiatric disorders: does creatine supplementation have therapeutic value? Neurosci Biobehav Rev. 2012;36:1442–1462. doi: 10.1016/j.neubiorev.2012.03.005. - DOI - PMC - PubMed
    1. Allen PJ, D’Anci KE, Kanarek RB, Renshaw PF. Chronic creatine supplementation alters depression-like behavior in rodents in a sex-dependent manner. Neuropsychopharmacology. 2010;35:534–546. doi: 10.1038/npp.2009.160. - DOI - PMC - PubMed
    1. Allen PJ, D’Anci KE, Kanarek RB, Renshaw PF. Sex-specific antidepressant effects of dietary creatine with and without sub-acute fluoxetine in rats. Pharmacol Biochem Behav. 2012;101(4):588–601. doi: 10.1016/j.pbb.2012.03.005. - DOI - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources