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Effects of Creatine Monohydrate Augmentation on Brain Metabolic and Network Outcome Measures in Women With Major Depressive Disorder

Published:December 14, 2015DOI:https://doi.org/10.1016/j.biopsych.2015.11.027

      Abstract

      Background

      Creatine monohydrate (creatine) augmentation has the potential to accelerate the clinical responses to and enhance the overall efficacy of selective serotonin reuptake inhibitor treatment in women with major depressive disorder (MDD). Although it has been suggested that creatine augmentation may involve the restoration of brain energy metabolism, the mechanisms underlying its antidepressant efficacy are unknown.

      Methods

      In a randomized, double-blind, placebo-controlled trial, 52 women with MDD were assigned to receive either creatine augmentation or placebo augmentation of escitalopram; 34 subjects participated in multimodal neuroimaging assessments at baseline and week 8. Age-matched healthy women (n = 39) were also assessed twice at the same intervals. Metabolic and network outcomes were measured for changes in prefrontal N-acetylaspartate and changes in rich club hub connections of the structural brain network using proton magnetic resonance spectroscopy and diffusion tensor imaging, respectively.

      Results

      We found MDD-related metabolic and network dysfunction at baseline. Improvement in depressive symptoms was greater in patients receiving creatine augmentation relative to placebo augmentation. After 8 weeks of treatment, prefrontal N-acetylaspartate levels increased significantly in the creatine augmentation group compared with the placebo augmentation group. Increment in rich club hub connections was also greater in the creatine augmentation group than in the placebo augmentation group.

      Conclusions

      N-acetylaspartate levels and rich club connections increased after creatine augmentation of selective serotonin reuptake inhibitor treatment. Effects of creatine administration on brain energy metabolism and network organization may partly underlie its efficacy in treating women with MDD.

      Keywords

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      References

        • Kupfer D.J.
        • Frank E.
        • Phillips M.L.
        Major depressive disorder: New clinical, neurobiological, and treatment perspectives.
        Lancet. 2012; 379: 1045-1055
        • Trivedi M.H.
        • Rush A.J.
        • Wisniewski S.R.
        • Nierenberg A.A.
        • Warden D.
        • Ritz L.
        • et al.
        Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice.
        Am J Psychiatry. 2006; 163: 28-40
        • Andrews P.W.
        • Bharwani A.
        • Lee K.R.
        • Fox M.
        • Thomson Jr, J.A.
        Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response.
        Neurosci Biobehav Rev. 2015; 51: 164-188
        • Lyoo I.K.
        • Yoon S.
        • Kim T.S.
        • Hwang J.
        • Kim J.E.
        • Won W.
        • et al.
        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. 2012; 169: 937-945
        • Strakowski S.M.
        Bioenergetics for depression: Something different for depression.
        Am J Psychiatry. 2012; 169: 891-893
        • Allen P.J.
        • D’Anci K.E.
        • Kanarek R.B.
        • Renshaw P.F.
        Chronic creatine supplementation alters depression-like behavior in rodents in a sex-dependent manner.
        Neuropsychopharmacology. 2010; 35: 534-546
        • Iosifescu D.V.
        • Bolo N.R.
        • Nierenberg A.A.
        • Jensen J.E.
        • Fava M.
        • Renshaw P.F.
        Brain bioenergetics and response to triiodothyronine augmentation in major depressive disorder.
        Biol Psychiatry. 2008; 63: 1127-1134
        • Moore C.M.
        • Christensen J.D.
        • Lafer B.
        • Fava M.
        • Renshaw P.F.
        Lower levels of nucleoside triphosphate in the basal ganglia of depressed subjects: A phosphorous-31 magnetic resonance spectroscopy study.
        Am J Psychiatry. 1997; 154: 116-118
        • Renshaw P.F.
        • Parow A.M.
        • Hirashima F.
        • Ke Y.
        • Moore C.M.
        • Frederick Bde B.
        • et al.
        Multinuclear magnetic resonance spectroscopy studies of brain purines in major depression.
        Am J Psychiatry. 2001; 158: 2048-2055
        • Adhihetty P.J.
        • Beal M.F.
        Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases.
        Neuromolecular Med. 2008; 10: 275-290
        • Cao X.
        • Li L.P.
        • Wang Q.
        • Wu Q.
        • Hu H.H.
        • Zhang M.
        • et al.
        Astrocyte-derived ATP modulates depressive-like behaviors.
        Nat Med. 2013; 19: 773-777
        • Bullmore E.
        • Sporns O.
        The economy of brain network organization.
        Nat Rev Neurosci. 2012; 13: 336-349
        • Kapogiannis D.
        • Mattson M.P.
        Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease.
        Lancet Neurol. 2011; 10: 187-198
        • van den Heuvel M.P.
        • Sporns O.
        Rich-club organization of the human connectome.
        J Neurosci. 2011; 31: 15775-15786
        • Ball G.
        • Aljabar P.
        • Zebari S.
        • Tusor N.
        • Arichi T.
        • Merchant N.
        • et al.
        Rich-club organization of the newborn human brain.
        Proc Natl Acad Sci U S A. 2014; 111: 7456-7461
        • van den Heuvel M.P.
        • Kahn R.S.
        • Goni J.
        • Sporns O.
        High-cost, high-capacity backbone for global brain communication.
        Proc Natl Acad Sci U S A. 2012; 109: 11372-11377
        • Collin G.
        • Sporns O.
        • Mandl R.C.
        • van den Heuvel M.P.
        Structural and functional aspects relating to cost and benefit of rich club organization in the human cerebral cortex.
        Cereb Cortex. 2014; 24: 2258-2267
        • Kaiser R.H.
        • Andrews-Hanna J.R.
        • Wager T.D.
        • Pizzagalli D.A.
        Large-scale network dysfunction in major depressive disorder: A meta-analysis of resting-state functional connectivity.
        JAMA Psychiatry. 2015; 72: 603-611
        • Zhang J.
        • Wang J.
        • Wu Q.
        • Kuang W.
        • Huang X.
        • He Y.
        • et al.
        Disrupted brain connectivity networks in drug-naive, first-episode major depressive disorder.
        Biol Psychiatry. 2011; 70: 334-342
        • Korgaonkar M.S.
        • Fornito A.
        • Williams L.M.
        • Grieve S.M.
        Abnormal structural networks characterize major depressive disorder: A connectome analysis.
        Biol Psychiatry. 2014; 76: 567-774
        • Lyoo I.K.
        • Yoon S.
        • Jacobson A.M.
        • Hwang J.
        • Musen G.
        • Kim J.E.
        • et al.
        Prefrontal cortical deficits in type 1 diabetes mellitus: Brain correlates of comorbid depression.
        Arch Gen Psychiatry. 2012; 69: 1267-1276
        • Rajkowska G.
        • Miguel-Hidalgo J.J.
        • Wei J.
        • Dilley G.
        • Pittman S.D.
        • Meltzer H.Y.
        • et al.
        Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression.
        Biol Psychiatry. 1999; 45: 1085-1098
        • Cosgrove K.P.
        • Mazure C.M.
        • Staley J.K.
        Evolving knowledge of sex differences in brain structure, function, and chemistry.
        Biol Psychiatry. 2007; 62: 847-855
        • Shansky R.M.
        • Glavis-Bloom C.
        • Lerman D.
        • McRae P.
        • Benson C.
        • Miller K.
        • et al.
        Estrogen mediates sex differences in stress-induced prefrontal cortex dysfunction.
        Mol Psychiatry. 2004; 9: 531-538
        • Bracken B.K.
        • Rouse E.D.
        • Renshaw P.F.
        • Olson D.P.
        T2 relaxation effects on apparent N-acetylaspartate concentration in proton magnetic resonance studies of schizophrenia.
        Psychiatry Res. 2013; 213: 142-153
        • First M.B.
        • Gibbon M.
        • Spitzer R.L.
        • Williams JBW
        Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-II), version 2.
        Biometrics Research, New York State Psychiatric Institute, New York1996
        • Hamilton M.
        A rating scale for depression.
        J Neurol Neurosurg Psychiatry. 1960; 23: 56-62
        • Drevets W.C.
        Prefrontal cortical-amygdalar metabolism in major depression.
        Ann N Y Acad Sci. 1999; 877: 614-637
        • van den Heuvel M.P.
        • Sporns O.
        • Collin G.
        • Scheewe T.
        • Mandl R.C.
        • Cahn W.
        • et al.
        Abnormal rich club organization and functional brain dynamics in schizophrenia.
        JAMA Psychiatry. 2013; 70: 783-792
        • Provencher S.W.
        Automatic quantitation of localized in vivo 1H spectra with LCModel.
        NMR Biomed. 2001; 14: 260-264
        • Lyoo I.K.
        • Yoon S.J.
        • Musen G.
        • Simonson D.C.
        • Weinger K.
        • Bolo N.
        • et al.
        Altered prefrontal glutamate-glutamine-gamma-aminobutyric acid levels and relation to low cognitive performance and depressive symptoms in type 1 diabetes mellitus.
        Arch Gen Psychiatry. 2009; 66: 878-887
        • Desikan R.S.
        • Segonne F.
        • Fischl B.
        • Quinn B.T.
        • Dickerson B.C.
        • Blacker D.
        • et al.
        An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest.
        Neuroimage. 2006; 31: 968-980
        • Mori S.
        • Crain B.J.
        • Chacko V.P.
        • van Zijl P.C.
        Three-dimensional tracking of axonal projections in the brain by magnetic resonance imaging.
        Ann Neurol. 1999; 45: 265-269
        • Rubinov M.
        • Sporns O.
        Complex network measures of brain connectivity: Uses and interpretations.
        Neuroimage. 2010; 52: 1059-1069
        • Yoon S.
        • Lyoo I.K.
        • Renshaw P.F.
        Application of magnetic resonance spectroscopic imaging to addiction research.
        in: MacKilop J. de Wit H. The Wiley-Blackwell Handbook of Addiction Psychopharmacology. Wiley-Blackwell, Malden, MA2013: 707-750
        • Simes R.J.
        An improved Bonferroni procedure for multiple tests of significance.
        Biometrika. 1986; 73: 751-754
        • Hennen J.
        Statistical methods for longitudinal research on bipolar disorders.
        Bipolar Disord. 2003; 5: 156-168
        • Pizzagalli D.A.
        Frontocingulate dysfunction in depression: Toward biomarkers of treatment response.
        Neuropsychopharmacology. 2011; 36: 183-206
        • Bustillo J.R.
        Use of proton magnetic resonance spectroscopy in the treatment of psychiatric disorders: A critical update.
        Dialogues Clin Neurosci. 2013; 15: 329-337
        • Singh M.K.
        • Kesler S.R.
        • Hadi Hosseini S.M.
        • Kelley R.G.
        • Amatya D.
        • Hamilton J.P.
        • et al.
        Anomalous gray matter structural networks in major depressive disorder.
        Biol Psychiatry. 2013; 74: 777-785
        • Liao Y.
        • Huang X.
        • Wu Q.
        • Yang C.
        • Kuang W.
        • Du M.
        • et al.
        Is depression a disconnection syndrome? Meta-analysis of diffusion tensor imaging studies in patients with MDD.
        J Psychiatry Neurosci. 2013; 38: 49-56
        • Sexton C.E.
        • Mackay C.E.
        • Ebmeier K.P.
        A systematic review of diffusion tensor imaging studies in affective disorders.
        Biol Psychiatry. 2009; 66: 814-823
        • Vaynman S.
        • Ying Z.
        • Wu A.
        • Gomez-Pinilla F.
        Coupling energy metabolism with a mechanism to support brain-derived neurotrophic factor-mediated synaptic plasticity.
        Neuroscience. 2006; 139: 1221-1234
        • Mattson M.P.
        • Gleichmann M.
        • Cheng A.
        Mitochondria in neuroplasticity and neurological disorders.
        Neuron. 2008; 60: 748-766
        • Stoy M.
        • Schlagenhauf F.
        • Sterzer P.
        • Bermpohl F.
        • Hagele C.
        • Suchotzki K.
        • et al.
        Hyporeactivity of ventral striatum towards incentive stimuli in unmedicated depressed patients normalizes after treatment with escitalopram.
        J Psychopharmacol. 2012; 26: 677-688
        • Roy M.
        • Harvey P.O.
        • Berlim M.T.
        • Mamdani F.
        • Beaulieu M.M.
        • Turecki G.
        • et al.
        Medial prefrontal cortex activity during memory encoding of pictures and its relation to symptomatic improvement after citalopram treatment in patients with major depression.
        J Psychiatry Neurosci. 2010; 35: 152-162
        • Li B.S.
        • Wang H.
        • Gonen O.
        Metabolite ratios to assumed stable creatine level may confound the quantification of proton brain MR spectroscopy.
        Magn Reson Imaging. 2003; 21: 923-928
        • Jansen J.F.
        • Backes W.H.
        • Nicolay K.
        • Kooi M.E.
        1H MR spectroscopy of the brain: Absolute quantification of metabolites.
        Radiology. 2006; 240: 318-332
        • Hersch S.M.
        • Gevorkian S.
        • Marder K.
        • Moskowitz C.
        • Feigin A.
        • Cox M.
        • et al.
        Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2’dG.
        Neurology. 2006; 66: 250-252
        • Lyoo I.K.
        • Kong S.W.
        • Sung S.M.
        • Hirashima F.
        • Parow A.
        • Hennen J.
        • et al.
        Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate.
        Psychiatry Res. 2003; 123: 87-100
        • Kondo D.G.
        • Sung Y.H.
        • Hellem T.L.
        • Fiedler K.K.
        • Shi X.
        • Jeong E.K.
        • et al.
        Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: A 31-phosphorus magnetic resonance spectroscopy study.
        J Affect Disord. 2011; 135: 354-361
        • Hellem T.L.
        • Sung Y.H.
        • Shi X.F.
        • Pett M.A.
        • Latendresse G.
        • Morgan
        • et al.
        Creatine as a novel treatment for depression in females using methamphetamine: A pilot study.
        J Dual Diagn. 2015; 11: 189-202
        • Ongur D.
        • Prescot A.P.
        • Jensen J.E.
        • Rouse E.D.
        • Cohen B.M.
        • Renshaw P.F.
        • et al.
        T2 relaxation time abnormalities in bipolar disorder and schizophrenia.
        Magn Reson Med. 2010; 63: 1-8
        • Bhagwagar Z.
        • Wylezinska M.
        • Taylor M.
        • Jezzard P.
        • Matthews P.M.
        • Cowen P.J.
        Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor.
        Am J Psychiatry. 2004; 161: 368-370