Abstract
Impairments in bioenergetic function, cellular resiliency, and structural plasticity are associated with the pathogenesis of mood disorders. Preliminary evidence suggests that creatine, an ergogenic compound known to promote cell survival and influence the production and usage of energy in the brain, can improve mood in treatment-resistant patients. This study examined the effects of chronic creatine supplementation using the forced swim test (FST), an animal model selectively sensitive to antidepressants with clinical efficacy in human beings. Thirty male (experiment 1) and 36 female (experiment 2) Sprague–Dawley rats were maintained on either chow alone or chow blended with either 2% w/w creatine monohydrate or 4% w/w creatine monohydrate for 5 weeks before the FST. Open field exploration and wire suspension tests were used to rule out general psychostimulant effects. Male rats maintained on 4% creatine displayed increased immobility in the FST as compared with controls with no differences by diet in the open field test, whereas female rats maintained on 4% creatine displayed decreased immobility in the FST and less anxiety in the open field test compared with controls. Open field and wire suspension tests confirmed that creatine supplementation did not produce differences in physical ability or motor function. The present findings suggest that creatine supplementation alters depression-like behavior in the FST in a sex-dependent manner in rodents, with female rats displaying an antidepressant-like response. Although the mechanisms of action are unclear, sex differences in creatine metabolism and the hormonal milieu are likely involved.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Agren H, Niklasson F (1988). Creatinine and creatine in CSF: indices of brain energy metabolism in depression. J Neural Transm 74: 55–59.
Amital D, Vishne T, Roitman S, Kotler M, Levine J (2006). Open study of creatine monohydrate in treatment-resistant posttraumatic stress disorder. J Clin Psychiatry 67: 836–837.
Andres RH, Ducray AD, Schlattner U, Wallimann T, Widmer HR (2008). Functions and effects of creatine in the central nervous system. Brain Res Bull 76: 329–343.
Andres RH, Huber AW, Schlattner U, Perez-Bouza A, Krebs SH, Seiler RW et al (2005). Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue. Neuroscience 133: 701–713.
Armario A, Gavaldà A, Martí O (1988). Forced swimming test in rats: effect of desipramine administration and the period of exposure to the test on struggling behavior, swimming, immobility and defecation rate. Eur J Pharmacol 158: 207–212.
Bebbington P, Dunn G, Jenkins R, Lewis G, Brugha T, Farrell M et al (2003). The influence of age and sex on the prevalence of depressive conditions: report from the National Survey of Psychiatric Morbidity. Intern Rev Psychiatry 15: 74–83.
Bjørnebekk A, Mathé AA, Gruber SHM, Brené S (2007). Social isolation increases number of newly proliferated cells in hippocampus in female flinders sensitive line rats. Hippocampus 17: 1193–1200.
Brosnan JT, Brosnan ME (2007). Creatine: endogenous metabolite, dietary, and therapeutic supplement. Annu Rev Nutr 27: 241–261.
Brotto LA, Barr AM, Gorzalka BB (2000). Sex differences in forced-swim and open-field test behaviours after chronic administration of melatonin. Eur Neuropsychopharmacol 402: 87–93.
Brustovetsky N, Brustovetsky T, Dubinsky J (2001). On the mechanisms of neuroprotection by creatine and phosphocreatine. J Neurochem 76: 425–434.
Burroughs S, French D (2007). Depression and anxiety: role of mitochondria. Curr Anaesth Crit Care 18: 34–41.
Carlezon WA, Mague SD, Andersen SL (2003). Enduring behavioral effects of early exposure to methylphenidate in rats. Biol Psychiatry 54: 1330–1337.
Carranza-Lira S, Valentino-Figueroa ML (1999). Estrogen therapy for depression in postmenopausal women. Int J Gynaecol Obstet 65: 35–38.
Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H et al (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301: 386–389.
Chen JQ, Yager JD, Russo J (2005). Regulation of mitochondrial respiratory chain structure and function by estrogens/estrogen receptors and potential physiological/pathophysiological implications. BBA—Mol Cell Res 1746: 1–17.
Cohen LS, Soares CN, Poitras JR, Prouty J, Alexander AB, Shifren JL (2003). Short-term use of estradiol for depression in perimenopausal and postmenopausal women: a preliminary report. Am J Psychiatry 160: 1519–1522.
Crochemore C, Virgili M, Contestabile A (2005). Neurochemical correlates of differential neuroprotection by long-term dietary creatine supplementation. Brain Res 1058: 183–188.
Czéh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M et al (2001). Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci 98: 12796–12801.
Dager SR, Friedman SD, Parow A (2004). Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry 61: 450–458.
Dalbo VJ, Roberts M, Kerksick C, Stout J (2008). Putting the myth of creatine supplementation leading to muscle cramps and dehydration to rest. Br J Sports Med 42: 567–573.
Dalvi A, Lucki I (1999). Murine models of depression. Psychopharmacology 147: 14–16.
Detke MJ, Richels M, Lucki I (1995). Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology 121: 66–72.
Drossopoulou G, Antoniou K, Kitraki E, Papathanasiou G, Papalexi E, Dalla C et al (2004). Sex differences in behavioral, neurochemical and neuroendocrine effects induced by the forced swim test in rats. Neuroscience 126: 849–857.
Ducray AD, Schläppi JA, Qualls R, Andres RH, Seiler RW, Schlattner U et al (2007). Creatine treatment promotes differentiation of GABA-ergic neuronal precursors in cultured fetal rat spinal cord. J Neurosci Res 85: 1863–1875.
Duman RS, Malberg J, Thome J (1999). Neural plasticity to stress and antidepressant treatment. Biol Psychiatry 46: 1181–1191.
Duman RS, Monteggia LM (2006). A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59: 1116–1127.
Estrada-Camarena E, Fernandez-Guasti A, Lopez-Rubalcava C (2003). Antidepressant-like effect of different estrogenic compounds in the forced swimming test. Neuropsychopharmacology 28: 830–838.
Ferrier CH, Alarcon G, Glover A, Koutroumanidis M, Morris RG, Simmons A et al (2000). N-Acetylaspartate and creatine levels measured by (1) H-MRS relate to recognition memory. Neurology 55: 1874–1883.
Frey R, Gruber S, Reinfried L, Stadlbauer A, Mlnarik V, Kasper S et al (2003). Proton magnetic resonance spectroscopy in depression: elevated creatine and unaffected myo-inositol levels in the frontal brain. J Eur Coll Neuropsychopharmacol 13: S277.
Fuchs E, Czéh B, Kole M, Michaelis T, Lucassen P (2004). Alterations of neuroplasticity in depression: the hippocampus and beyond. Eur Neuropsychopharmacol 14: S481–S490.
Gabbay V, Hess DA, Liu S, Babb JS, Klein RG, Gonen O (2007). Lateralized caudate metabolic abnormalities in adolescent major depressive disorder: a proton MR spectroscopy study. Am J Psychiatry 164: 1881–1889.
Gledhill RF, Van Der Merwe CA, Greyling M, Van Niekerk MM (1988). Race-gender differences in serum creatine kinase activity: a study among South Africans. J Neurol Neurosurg Psychiatry 51: 301–304.
Grippo AJ, Wu KD, Hassan I, Carter CS (2008). Social isolation in prairie voles induces behaviors relevant to negative affect: toward the development of a rodent model focusing on co-occurring depression and anxiety. Depress Anxiety 25: E17–E26.
Halbreich U, Kahn LS (2001). Role of estrogen in the aetiology and treatment of mood disorders. CNS Drugs 15: 797–817.
Hamakawa H, Kato T, Shioiri T, Inubushi T, Kato N (1999). Quantitative proton magnetic resonance spectroscopy of the bilateral frontal lobes in patients with bipolar disorder. Psychol Med 29: 639–644.
Hamilton M (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry 23: 56–62.
Horn M, Frantz S, Remkes H, Laser A, Urban B, Mettenleiter A et al (1998). Effects of chronic dietary creatine feeding on cardiac energy metabolism and on creatine content in heart, skeletal muscle, brain, liver and kidney. J Mol Cell Cardiol 30: 277–284.
Iosifescu DV, Bolo NR, Nierenberg AA, Jensen E, Fava M, Renshaw P (2008). Brain bioenergetics and response to triiodothyronine augmentation in major depressive disorder. Biol Psychiatry 63: 1127–1134.
Kalia M (2005). Neurobiological basis of depression: an update. Metabolism 54: 24–27.
Kato T, Takahashi S (1994). Reduction of brain phosphocreatine in bipolar II disorder detected by phosphorus-31 magnetic resonance spectroscopy. J Affect Disord 31: 125–133.
Kato T, Takahashi S, Shioiri T, Inubushi T (1992). Brain phosphorous metabolism in depressive disorders detected by phosphorus-31 magnetic resonance spectroscopy. J Affect Disord 26: 223–230.
Kessler RC (2003). Epidemiology of women and depression. J Affect Disord 74: 5–13.
Klinge CM (2008). Estrogenic control of mitochondrial function and biogenesis. Cell Biochem 105: 1342–1351.
Koga Y, Takahashi H, Oikawa D, Tachibana T, Denbow DM, Furuse M (2005). Brain creatine functions to attenuate acute stress responses through GABAnergic system in chicks. Neuroscience 132: 65–71.
Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI et al (2000). Gender differences in chronic major and double depression. J Affect Disord 60: 1–11.
Kuzhikandathil EV, Molloy GR (1994). Transcription of the brain creatine kinase gene in glial cells is modulated by cyclic amp-dependent protein kinase. J Neuroscience Res 39: 70–82.
Lahmame A, Gomez F, Armario A (1996). Fawn-hooded rats show enhanced active behaviour in the forced swimming test, with no evidence for pituitary-adrenal axis hyperactivity. Psychopharmacology 125: 74–78.
Leussis MP, Andersen SL (2008). Is adolescence a sensitive period for depression? Behavioral and neuroanatomical findings from a social stress model. Synapse 62: 22–30.
Lifschytz T, Shalom G, Lerer B, Newman M (2006). Sex-dependent effects of fluoxetine and trioodothyronine in the forced swim test in rats. Eur Neuropsychopharmacol 16: 115–121.
Lyoo IK, Kong SW, Sung SM, Hirashima F, Parow A, Hennen J et al (2003). Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate. Psychiatry Res 123: 87–100.
Malnick SD, Shaer A, Soreq H, Kaye AM (1983). Estrogen-induced creatine kinase in the reproductive system of the immature female rat. Endocrinology 113: 1907–1909.
Manji HK, Drevets WC, Charney DS (2001). The cellular neurobiology of depression. Nat Med 7: 541–547.
Manji HK, Moore GJ, Rajkowska G, Chen G (2000). Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry 5: 578–593.
Matthews RT, Ferrante RJ, Klivenyi P, Yang L, Klein AM, Mueller G et al (1999). Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol 157: 142–149.
Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddaurah-Daouk R et al (1998). Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's Disease. J Neuroscience 18: 156–163.
McEwen BS (2005). Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 54: 20–23.
McLeish MJ, Kenyon GL (2005). Relating structure to mechanism in creatine kinase. Crit Rev Biochem Mol Biol 40: 1–20.
McMorris T, Harris RC, Swain J, Corbett J, Collard K, Dyson RJ et al (2006). Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology 186: 93–103.
Meltzer HY (1971). Factors affecting serum creatine phosphokinase levels in the general population: the role of race, activity and age. Clin Chim Acta 33: 165–172.
Moretti A, Gorini A, Villa RF (2003). Affective disorders, antidepressant drugs and brain metabolism. Mol Psychiatry 8: 773–785.
Moore CM, Christensen JD, Lafer B, Fava M, Renshaw PF (1997). Lower levels of nucleoside triphosphate in the basal ganglia of depressed subjects: a phosphorous-31 magnetic resonance spectroscopy study. Am J Psychiatry 154: 116–118.
Niklasson F, Agren H (1984). Brain energy metabolism and blood-brain barrier permeability in depressive patients: analyses of creatine, creatinine, urate, and albumin in CSF and blood. Biol Psychiatry 19: 1183–1206.
Nolen-Hoeksema S (1987). Sex differences in unipolar depression: evidence and theory. Psychol Bull 101: 259–282.
Overstreet DH, Keeney A, Hogg S (2004). Antidepressant effects of citalopram and CRF receptor antagonist CP-154,526 in a rat model of depression. Eur J Pharmacol 492: 195–201.
Ozkan O, Duman O, Haspolat S, Ozgentas HE, Dikici MB, Gürer I et al (2005). Effect of systemic creatine monohydrate on denervated muscle during reinnervation: experimental study in the rat. J Reconstr Microsurg 21: 573–579.
Page ME, Detke MJ, Dalvi A, Kirby LG, Lucki I (1999). Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test. Psychopharmacology 147: 162–167.
Peña-Altamira E, Crochemore C, Virgili M, Contestabile A (2005). Neurochemical correlates of differential neuroprotection by long-term dietary creatine supplementation. Brain Res 1058: 183–188.
Pittenger C, Duman RS (2008). Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33: 88–109.
Porsolt RD (1978). ‘Behavioral despair’ in rats and mice: strain differences and the effects of imipramine. Eur J Pharmacol 51: 291–294.
Porsolt RD, Deniel M, Jalfre M (1978). Forced swimming in rats: hypothermia, immobility and the effects of imipramine. Eur J Pharmacol 57: 431–436.
Porsolt RD, Le Pichon M, Jalfre M (1977). Depression: a new animal model sensitive to antidepressant treatments. Nature 266: 730–732.
Rae C, Digney AL, McEwan SR, Bates TC (2003). Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial. Proc Biol Sci 270: 2147–2150.
Ramirez O, Jimenez E (2002). Sexual dimorphism in rat cerebrum and cerebellum: different patterns of catalytically active creatine kinase isoenzymes during postnatal development and aging. Int J Devl Neuroscience 20: 627–639.
Reiss NA, Kaye AM (1981). Identification of the major component of the estrogen-induced protein of rat uterus as the BB isozyme of creatine kinase. J Biol Chem 256: 5741–5749.
Renshaw PF, Parow AM, Hirashima F, Ke Y, Moore CM, Frederick Bde B et al (2001). Multinuclear magnetic resonance spectroscopy studies of brain purines in major depression. Am J Psychiatry 158: 2048–2055.
Rezin GT, Amboni G, Zugno AI, Quevedo J, Streck EL (2008). Mitochondrial dysfunction and psychiatric disorders. Neurochem Res 34: 1021–1029.
Rocha BA, Fleischer R, Schaeffer JM, Rohrer SP, Hickey GJ (2005). 17β-estradiol-induced antidepressant-like effect in the forced swim test is absent in estrogen receptor-β knockout (Berko) mice. Psychopharmacologia 179: 637–643.
Rodriguez-Landa JF, Contreras CM, Bernal-Morales B, Gutierrez-Garcia AG, Saavedra M (2007). Allopregnanolone reduces immobility in the forced swimming test and increases the firing rate of the lateral septal neurons through actions on the GABA-A receptor in the rat. Psychopharmacology 21: 76–84.
Roitman S, Green T, Osher Y, Karni N, Levine J (2007). Creatine monohydrate in resistant depression: a preliminary study. Bipol Disord 9: 754–758.
Rooney K, Bryson J, Phuyal J, Denyer G, Caterson I, Thompson C (2002). Creatine supplementation alters insulin secretion and glucose homeostasis in vivo. Metabolism 51: 518–522.
Roy BD, Bourgeois JM, Mahoney DJ, Tarnopolsky MA (2002). Dietary supplementation with creatine monohydrate prevents corticosteroid-induced attenuation of growth in young rats. Can J Physiol Pharmacol 80: 1008–1014.
Sáenz JCB, Villagra OR, Trías JF (2006). Factor analysis of forced swimming test, sucrose preference test and open field test on enriched, social, and isolated reared rats. Behav Brain Res 169: 57–65.
Sapolsky R (2000). The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry 48: 755–765.
Schiller L, Jahkel M, Oehler J (2006). The influence of sex and social isolation housing on pre- and postsynaptic 5-HT1A receptors. Brain Res 1103: 76–87.
Segal M, Avital A, Drobot M, Lukanin A, Derevenski A, Sandbank S et al (2007). Serum creatine kinase level in unmedicated nonpsychotic, psychotic, bipolar, and schizoaffective depressed patients. Eur Neuropsychopharmacol 17: 194–198.
Shao L, Marin MV, Watson SJ, Schatzberg A, Akil H, Myers RM et al (2008). Mitochondrial involvement in psychiatric disorders. Ann Med 40: 281–295.
Stine OC, Luu SU, Zito M, Casanova M (1993). The possible association between affective disorder and partially deleted mitochondrial DNA. Biol Psychiatry 33: 141–142.
Streijger F, Pluk H, Oerlemans F, Beckers G, Bianco AC, Ribeiro MO et al (2009). Mice lacking brain-type creatine kinase activity show defective thermoregulation. Physiol Behav 97: 76–86.
Sullivan PG, Geiger JD, Mattson MP, Scheff SW (2000). Dietary supplement creatine protects against traumatic brain injury. Ann Neurol 48: 723–729.
Vasudevan N, Pfaff DW (2008). Non-genomic actions of estrogens and their interaction with genomic actions in the brain. Front Neuroendocrinol 29: 238–257.
Volz HP, Rzanny R, Riehemann S, May S, Hegewald H, Preussler B et al (1998). 31P magnetic resonance spectroscopy in the frontal lobe of major depressed patients. Eur Arch Psychiatry Clin Neurosci 248: 289–295.
Walf AA, Frye CA (2006). A review and update of mechanisms of estrogen in the hippocampus and amygdala for anxiety and depression behavior. Neuropsychopharmacology 31: 1097–1111.
Walf AA, Koonce CJ, Frye CA (2009). Adult female wildtype, but not oestrogen receptor β knockout, mice have decreased depression-like behavior during pro-oestrus and following administration of oestradiol or diarylpropionitrile. J Psychopharmacology 23: 442–450.
Walf AA, Rhodes ME, Frye CA (2004). Antidepressant effects of ERbeta-selective estrogen receptor modulators in the forced swim test. Pharmacol Biochem Behav 78: 523–529.
Walliman T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM (1992). Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem J 281: 21–40.
Wang R, Xu Y, Wu H, Li Y, Guo J, Li X (2008). The antidepressant effects of curcumin in the forced swimming test involve 5-HT1 and 5-HT2 receptors. Eur J Pharmacol 578: 43–50.
Watanabe A, Kato N, Kato T (2002). Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neurosci Res 42: 279–285.
Wilken B, Ramirez JM, Richter DW, Hanefeld F (1996). Creatine protects the central respiratory network of mammals under anoxic conditions. Pediatr Res 43: 8–14.
Willner P (1997). Validity, reliability, and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology 134: 319–329.
Willner P, Towell A, Sampson D, Sophokleous S, Muscat R (1987). Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology 93: 358–364.
Wong ET, Cobb C, Umehara MK, Wolff GA, Haywood LJ, Greenberg T et al (1983). Heterogeneity of serum creatine kinase activity among racial and gender groups of the population. Am J Clin Pathol 79: 582–586.
Wongwitdecha N, Kasemsook C, Plasen S (2006). Social isolation alters the effect of desipramine in the rat forced swimming test. Behav Brain Res 167: 232–236.
Wyss M, Kaddurah-Daouk R (2000). Creatine and creatinine metabolism. Physiol Rev 80: 1107–1213.
Yamashita H, Ohira Y, Wakatsuki T, Yamamoto M, Kizaki T, Oh-ishi S et al (1995). Increased growth of brown adipose tissue but its reduced thermogenic activity in creatine–depleted rats fed β-guanidinopropionic acid. BBA—Bioenergetics 1230: 69–73.
Yang SH, Liu R, Perez EJ, Wen Y, Stevens SM, Valencia T et al (2004). Mitochondrial localization of estrogen receptor β. Proc Natl Acad Sci 101: 4130–4135.
Acknowledgements
These studies were supported in part by grants DA015116 and MH058681 from the National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Additional information
DISCLOSURE
PF Renshaw is a consultant for Novartis, GSK, Roche, and Kyowa Hakko. He receives or has received research support from GSK, Roche, and Eli Lilly. PF Renshaw is an inventor on a patent application filed by McLean Hospital (Belmont, MA, USA) in 2001 that describes this use of creatine as a treatment for depression. No patent has issued, and this application has not been licensed. PJ Allen, KE D'Anci, and RB Kanarek have no financial or competing interests to declare.
Rights and permissions
About this article
Cite this article
Allen, P., D'Anci, K., Kanarek, R. et al. Chronic Creatine Supplementation Alters Depression-like Behavior in Rodents in a Sex-Dependent Manner. Neuropsychopharmacol 35, 534–546 (2010). https://doi.org/10.1038/npp.2009.160
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2009.160
Keywords
This article is cited by
-
Dietary creatine intake and depression risk among U.S. adults
Translational Psychiatry (2020)
-
Creatine, Similar to Ketamine, Counteracts Depressive-Like Behavior Induced by Corticosterone via PI3K/Akt/mTOR Pathway
Molecular Neurobiology (2016)
-
Creatine for women: a review of the relationship between creatine and the reproductive cycle and female-specific benefits of creatine therapy
Amino Acids (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 (2016)
-
Involvement of PI3K/Akt Signaling Pathway and Its Downstream Intracellular Targets in the Antidepressant-Like Effect of Creatine
Molecular Neurobiology (2016)
