A randomized, double-blind, placebo-controlled, proof-of-concept trial of creatine monohydrate as adjunctive treatment for bipolar depression

Ricardo Alexandre Toniolo, Michelle Silva, Francy de Brito Ferreira Fernandes, José Antonio de Mello Siqueira Amaral, Rodrigo da Silva Dias, Beny Lafer, Ricardo Alexandre Toniolo, Michelle Silva, Francy de Brito Ferreira Fernandes, José Antonio de Mello Siqueira Amaral, Rodrigo da Silva Dias, Beny Lafer

Abstract

Depressive episodes are a major cause of morbidity and dysfunction in individuals suffering from bipolar disorder. Currently available treatments for this condition have limited efficacy and new therapeutic options are needed. Extensive research in the pathophysiology of bipolar disorder points to the existence of mitochondrial and bioenergetic dysfunction. We hypothesized that creatine monohydrate, a nutraceutical that works as a mitochondrial modulator, would be effective as an adjunctive therapy for bipolar depression. We conducted a double-blind trial in which 35 patients with bipolar disorder type I or II in a depressive episode by DSM-IV criteria and in use of regular medication for the treatment of this phase of the disease were randomly allocated into two adjunctive treatment groups for 6 weeks: creatine monohydrate 6 g daily (N = 17) or placebo (N = 18). Primary efficacy was assessed by the change in the Montgomery-Åsberg Depression Rating Scale (MADRS). We did not find a statistically significant difference in the comparison between groups for the change in score on the MADRS after 6 weeks in an intention-to-treat (ITT) analysis (p = 0.560; Cohen's d = 0.231). However, we found significant superiority of creatine add-on vs. placebo when we considered the remission criterion of a MADRS score ≤ 12 at week 6 analyzing the outcome of the 35 randomized patients on ITT (52.9% remission in the creatine group vs. 11.1% remission in the placebo group) and of the 23 completers (66.7% remission in the creatine group vs. 18.2% remission in the placebo group) (p = 0.012; OR = 9.0 and p = 0.036; OR = 9.0, respectively). Two patients who received creatine switched to hypomania/mania early in the trial. No clinically relevant physical side-effects were reported or observed. This proof-of-concept study, aiming to restore brain bioenergetics using an adjunctive mitochondrial modulator, is not conclusive on the efficacy of creatine add-on for bipolar depression, but suggests that this compound may have a role in the adjunctive treatment of this phase of the illness. Further investigation through randomized controlled trials with larger samples should be conducted to verify the efficacy of creatine supplementation for bipolar depression and also for subsyndromal depressive symptoms.

Trial registration: ClinicalTrials.gov NCT01655030.

Keywords: Adjunctive therapy; Bipolar disorder; Creatine monohydrate; Depression; Double-blind method; Randomized controlled trial.

Conflict of interest statement

RA.T., M.S., F.B.F.F., J.A.M.S.A., R.S.D. and B.L. report no potential conflicts of interest.

Figures

Fig. 1
Fig. 1
Screening, randomization and disposition of 35 patients with bipolar depression assigned to adjunctive treatment with creatine monohydrate or placebo
Fig. 2
Fig. 2
Observed and last observation carried forward Montgomery–Åsberg Depression Rating Scale (MADRS) scores at each treatment week for 27 patients with bipolar depression assigned to a 6-week adjunctive treatment with creatine monohydrate or placebo

References

    1. Allen PJ, D’Anci KE, Darrell C, Galinko L, Salvatore J, Kanarek RB, Renshaw PF (2010) Creatine supplementation offsets depressive behavior in female rats independent of fluoxetine. In: Society for Neuroscience 40th annual meeting, San Diego
    1. Bartoli F, Dell’Osso B, Crocamo C, Fiorillo A, Ketter TA, Suppes T, Clerici M, Carrà G. Benefits and harms of low and high second-generation antipsychotics doses for bipolar depression: a meta-analysis. J Psychiatr Res. 2017;88:38–46. doi: 10.1016/j.jpsychires.2016.12.021.
    1. Bauer M, Glenn T, Conell J, Rasgon N, Marsh W, Sagduyu K, et al. Common use of dietary supplements for bipolar disorder: a naturalistic, self-reported study. Int J Bipolar Disord. 2015;3(1):29.
    1. Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64(6):468–475. doi: 10.1016/j.biopsych.2008.04.022.
    1. Brown NC, Andreazza AC, Young LT. An updated meta-analysis of oxidative stress markers in bipolar disorder. Psychiatry Res. 2014;218(1–2):61–68. doi: 10.1016/j.psychres.2014.04.005.
    1. Calabrese JR, Keck PE, Jr, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, Cutler AJ, McCoy R, Wilson E, Mullen J. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351–1360. doi: 10.1176/appi.ajp.162.7.1351.
    1. Carneiro AM, Fernandes F, Moreno RA. Hamilton depression rating scale and Montgomery–Asberg depression rating scale in depressed and bipolar I patients: psychometric properties in a Brazilian sample. Health Qual Life Outcomes. 2015;13:42. doi: 10.1186/s12955-015-0235-3.
    1. Clay HB, Sillivan S, Konradi C. Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int J Dev Neurosci. 2011;29(3):311–324. doi: 10.1016/j.ijdevneu.2010.08.007.
    1. Cunha MP, Pazini FL, Ludka FK, Rosa JM, Oliveira Á, Budni J, et al. The modulation of NMDA receptors and l-arginine/nitric oxide pathway is implicated in the anti-immobility effect of creatine in the tail suspension test. Amino Acids. 2015;47(4):795811. doi: 10.1007/s00726-014-1910-0.
    1. Dean OM, Turner A, Malhi GS, Ng C, Cotton SM, Dodd S, et al. Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression. Rev Bras Psiquiatr. 2015;37(1):3–12. doi: 10.1590/1516-4446-2013-1341.
    1. Dechent P, Pouwels PJ, Wilken B, Hanefeld F, Frahm J. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol. 1999;277(3 Pt 2):R698–R704.
    1. Dudley J, DelBello MP, Weber WA, Adler CM, Strakowski SM, Lee JH. Tissue-dependent cerebral energy metabolism in adolescents with bipolar disorder. J Affect Disord. 2016;191:248–255. doi: 10.1016/j.jad.2015.11.045.
    1. Fava M. Implications of a biosignature study of the placebo response in major depressive disorder. JAMA Psychiatry. 2015;72(11):1073–1074. doi: 10.1001/jamapsychiatry.2015.1727.
    1. First MB, Spitzer RL, Gibbon M, Williams Janet BW. Structured clinical interview for DSM-IV axis I disorders, clinician version (SCID-CV) Washington, DC: American Psychiatric Press; 1996.
    1. Forester BP, Harper DG, Georgakas J, Ravichandran C, Ph D, Madurai N, Cohen BM. Antidepressant effects of open label treatment with Coenzyme Q10 in Geriatric Bipolar Depression. J Clin Psychopharmacol. 2015;35(3):338–340. doi: 10.1097/JCP.0000000000000326.
    1. Gardner A, Boles RG. Beyond the serotonin hypothesis: mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):730–743. doi: 10.1016/j.pnpbp.2010.07.030.
    1. Guy W (ed) (1976) Clinical global impressions. In: ECDEU assessment manual for psychopharmacology, revised. National Institute of Mental Health, Rockville
    1. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967;6(4):278–296. doi: 10.1111/j.2044-8260.1967.tb00530.x.
    1. Iosifescu DV, Bolo NR, Nierenberg AA, Jensen JE, Fava M, Renshaw PF. Brain bioenergetics and response to triiodothyronine augmentation in major depressive disorder. Biol Psychiatry. 2008;63(12):1127–1134. doi: 10.1016/j.biopsych.2007.11.020.
    1. Iovieno N, Nierenberg AA, Parkin SR, Hyung Kim DJ, Walker RS, Fava M, Papakostas GI. Relationship between placebo response rate and clinical trial outcome in bipolar depression. J Psychiatr Res. 2016;74:38–44. doi: 10.1016/j.jpsychires.2015.12.016.
    1. Jensen JE, Daniels M, Haws C, Bolo NR, Lyoo IK, Yoon SJ, Cohen BM, Stoll AL, Rusche JR, Renshaw PF. Triacetyluridine (TAU) decreases depressive symptoms and increases brain pH in bipolar patients. Exp Clin Psychopharmacol. 2008;16(3):199–206. doi: 10.1037/1064-1297.16.3.199.
    1. Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59(6):530–537. doi: 10.1001/archpsyc.59.6.530.
    1. Kato T. Neurobiological basis of bipolar disorder: Mitochondrial dysfunction hypothesis and beyond. Schizophr Res. 2016;183:63–66.
    1. Kato T, Takahashi S, Shioiri T, Murashita J, Hamakawa H, Inubushi T. Reduction of brain phosphocreatine in bipolar II disorder detected by phosphorus-31 magnetic resonance spectroscopy. J Affect Disord. 1994;31(2):125–133. doi: 10.1016/0165-0327(94)90116-3.
    1. Kato T, Shioiri T, Murashita J, Hamakawa H, Takahashi Y, Inubushi T, et al. Lateralized abnormality of high energy phosphate metabolism in the frontal lobes of patients with bipolar disorder detected by phase-encoded 31P-MRS. Psychol Med. 1995;25(3):557–566. doi: 10.1017/S003329170003347X.
    1. Kim HJ, Kim CK, Carpentier A, Poortmans JR. Studies on the safety of creatine supplementation. Amino Acids. 2011;40(5):1409–1418. doi: 10.1007/s00726-011-0878-2.
    1. Kondo DG, Sung Y, Hellem TL, Fiedler KK, Shi X, Jeong E, Renshaw PF. 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(10):354–361. doi: 10.1016/j.jad.2011.07.010.
    1. Kondo DG, Forrest LN, Shi X, Sung YH, Hellem TL, Huber RS, Renshaw PF. Creatine target engagement with brain bioenergetics: a dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression. Amino Acids. 2016;48(8):1941–1954. doi: 10.1007/s00726-016-2194-3.
    1. Lawler JM, Barnes WS, Wu G, Song W, Demaree S. Direct antioxidant properties of creatine. Biochem Biophys Res Commun. 2002;290(1):47–52. doi: 10.1006/bbrc.2001.6164.
    1. Loebel A, Cucchiaro J, Silva R, Kroger H, Hsu J, Sarma K, Sachs G. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):160–168. doi: 10.1176/appi.ajp.2013.13070984.
    1. Lyoo IK, Kong SW, Sung SM, 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 Neuroimaging. 2003;123(2):87–100. doi: 10.1016/S0925-4927(03)00046-5.
    1. Lyoo I, Yoon S, Kim TS, Hwang J, Kim JE, 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(9):937–945. doi: 10.1176/appi.ajp.2012.12010009.
    1. McElroy SL, Weisler RH, Chang W, Olausson B, Paulsson B, Brecher M, Agambaram V, Merideth C, Nordenhem A, Young AH. EMBOLDEN II (Trial D1447C00134) Investigators. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II) J Clin Psychiatry. 2010;71(2):163–174. doi: 10.4088/JCP.08m04942gre.
    1. Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134(4):382–389. doi: 10.1192/bjp.134.4.382.
    1. Morris G, Walder K, McGee SL, Dean OM, Tye SJ, Maes M, Berk M. A model of the mitochondrial basis of bipolar disorder. Neurosci Biobehav Rev. 2017;74(Pt A):1–20. doi: 10.1016/j.neubiorev.2017.01.014.
    1. Nierenberg AA, Kansky C, Brennan BP, Shelton RC, Perlis R, Iosifescu DV. Mitochondrial modulators for bipolar disorder: a pathophysiologically informed paradigm for new drug development. Aust N Z J Psychiatry. 2013;47(1):26–42. doi: 10.1177/0004867412449303.
    1. Post RM, Altshuler LL, Frye MA, Suppes T, Keck PE, Jr, McElroy SL, et al. Complexity of pharmacologic treatment required for sustained improvement in outpatients with bipolar disorder. J Clin Psychiatry. 2010;71(9):1176–1186. doi: 10.4088/JCP.08m04811yel.
    1. Renshaw PF, Parow AM, Hirashima F, Ke Y, Moore CM, Frederick Bde B, et al. Multinuclear magnetic resonance spectroscopy studies of brain purines in major depression. Am J Psychiatry. 2001;158(12):2048–2055. doi: 10.1176/appi.ajp.158.12.2048.
    1. Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve. 2007;35(2):235–242. doi: 10.1002/mus.20688.
    1. Roitman S, Green T, Oshe Y, Kami N, Levine J. Creatine monohydrate in resistant depression: a preliminary study. Bipolar Disord. 2007;9(7):754–758. doi: 10.1111/j.1399-5618.2007.00532.x.
    1. Rosa AR, Sánchez-Moreno J, Martínez-Aran A, Salamero M, Torrent C, Reinares M, et al. Validity and reliability of the Functioning Assessment Short Test (FAST) in bipolar disorder. Clin Pract Epidemiol Ment Health. 2007;3:5. doi: 10.1186/1745-0179-3-5.
    1. Royes LF, Figher MR, Furian AF, Oliveira MS, Fiorenza NG, Ferreira J, et al. Neuromodulatory effect of creatine on extracellular action potentials in rat hippocampus: role of NMDA receptors. Neurochem Int. 2008;53(1):33–37. doi: 10.1016/j.neuint.2008.04.008.
    1. Sarris J, Mischoulon D, Schweitzer I. Adjunctive nutraceuticals with standard pharmacotherapies in bipolar disorder: a systematic review of clinical trials. Bipolar Disord. 2011;13(5–6):454–465. doi: 10.1111/j.1399-5618.2011.00945.x.
    1. Sarris J, Murphy Mischoulon D, Papakostas GI, Fava M, Berk M, Ng CH. Adjunctive nutraceuticals for depression: a systematic review and meta-analyses. Am J Psychiatry. 2016;173(6):575–587. doi: 10.1176/appi.ajp.2016.15091228.
    1. Scaini G, Rezin GT, Carvalho AF, Streck EL, Berk M, Quevedo J. Mitochondrial dysfunction in bipolar disorder: evidence, pathophysiology and translational implications. Neurosci Biobehav Rev. 2016;68:694–713. doi: 10.1016/j.neubiorev.2016.06.040.
    1. Sestili P, Martinelli C, Bravi G, Piccoli G, Curci R, Battistelli M, et al. Validity and reliability of the Functioning Assessment Short Test (FAST) in bipolar disorder. Free Radic Biol Med. 2006;40(5):837–849. doi: 10.1016/j.freeradbiomed.2005.10.035.
    1. Sonawalla SB, Renshaw PF, Moore CM, Alpert JE, Nierenberg A, Rosenbaum JF, Fava M. Compounds containing cytosolic choline in the basal ganglia: a potential biological marker of true drug response to fluoxetine. Am J Psychiatry. 1999;156(10):1638–1640. doi: 10.1176/ajp.156.10.1638.
    1. Tarnopolsky MA. The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochondrial cytopathies. Adv Drug Deliv Rev. 2008;60(1314):1561–1567. doi: 10.1016/j.addr.2008.05.001.
    1. Taylor DM, Cornelius V, Smith L, Young AH. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand. 2014;130(6):452–469. doi: 10.1111/acps.12343.
    1. Tohen M, Frank E, Bowden CL, Colom F, Ghaemi SN, Yatham LN, Malhi GS, Calabrese JR, Nolen WA, Vieta E, Kapczinski F, Goodwin GM, Suppes T, Sachs GS, Chengappa KR, Grunze H, Mitchell PB, Kanba S, Berk M. The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders. Bipolar Disord. 2009;11(5):453–473. doi: 10.1111/j.1399-5618.2009.00726.x.
    1. Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev. 2000;80(3):1107–1213. doi: 10.1152/physrev.2000.80.3.1107.
    1. Yoon S, Kim JE, Hwang J, Kim TS, Kang HJ, Namgung E, et al. Effects of creatine monohydrate augmentation on brain metabolic and network outcome measures in women with major depressive disorder. Biol Psychiatry. 2016;80(6):439–447. doi: 10.1016/j.biopsych.2015.11.027.
    1. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–435. doi: 10.1192/bjp.133.5.429.
    1. Young AH, McElroy SL, Bauer M, Philips N, Chang W, Olausson B, Paulsson B, Brecher M, EMBOLDEN I (Trial 001) Investigators A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I) J Clin Psychiatry. 2010;71(2):150–162. doi: 10.4088/JCP.08m04995gre.
    1. Yuksel C, Du F, Ravichandran Goldbach JR, Thida T, Lin P, et al. Abnormal high-energy phosphate molecule metabolism during regional brain activation in patients with bipolar disorder. Mol Psychiatry. 2015;20(9):1079–1084. doi: 10.1038/mp.2015.13.

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