{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:47:24Z","timestamp":1785836844089,"version":"3.56.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:p>Depression represents a multifaceted neuropsychiatric disorder distinguished by disruptions in cerebral energy metabolism, neurotransmitter communication, neuroplasticity, and cognitive processes. An increasing body of literature indicates that integrative non-pharmacological interventions aimed at metabolic and neurochemical pathways may present promising adjunctive strategies for ameliorating depressive manifestations and concomitant cognitive impairments. This review explores the prospective combined effects of creatine supplementation, branched-chain amino acids (BCAAs), and physical exercise as a multimodal bioenergetic intervention for the management of depression. Creatine is pivotal in maintaining neuronal energy equilibrium via the phosphocreatine system, thereby facilitating mitochondrial functionality and adenosine triphosphate availability within neural cells. BCAAs may influence central fatigue and exercise performance through competitive inhibition of tryptophan transport across the blood-brain barrier. Importantly, this mechanism primarily reflects acute exercise-related serotonergic responses associated with central fatigue and should not be considered mechanistically equivalent to the chronic serotonergic dysfunction observed in major depressive disorder. Accordingly, within the context of depression, BCAAs are discussed as indirect modulators of mental health outcomes through their effects on fatigue perception, exercise tolerance, and adherence to physical activity, rather than as direct serotonergic antidepressant interventions. Concurrently, consistent engagement in physical exercise activates critical neuroplasticity-associated signaling pathways, which are instrumental in promoting hippocampal neurogenesis and enhancing stress resilience. Emerging empirical evidence derived from both experimental and clinical investigations suggests that the combined application of these interventions may exert complementary influences on brain bioenergetics, neuroplasticity, exercise capacity, and cognitive function. Collectively, this integrative paradigm highlights the potential of creatine supplementation, BCAAs, and physical exercise to support depression-related outcomes through distinct yet complementary mechanisms involving bioenergetic regulation, enhanced exercise capacity, neuroplastic adaptations, and improved cognitive and emotional functioning.<\/jats:p>","DOI":"10.3389\/fpsyt.2026.1830803","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:22:27Z","timestamp":1785835347000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Reprogramming brain bioenergetics in depression: an integrative framework linking creatine, branched-chain amino acids, and exercise to neuroplasticity, cognitive function, and depression-related outcomes"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaoqin","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Physical Education, Hunan International Economics University","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Physical Education, Hunan First Normal University","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.encep.2016.02.004","article-title":"Depression","volume":"392","author":"Malhi","year":"2018","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"16065","DOI":"10.1038\/nrdp.2016.65","article-title":"Major depressive disorder","volume":"2","author":"Otte","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2013.00199","article-title":"Synaptic activity and bioenergy homeostasis: implications in brain trauma and neurodegenerative diseases","volume":"4","author":"Khatri","year":"2013","journal-title":"Front Neurol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci13121610","article-title":"Exploring the role of neuroplasticity in development, aging, and neurodegeneration","volume":"13","author":"Marzola","year":"2023","journal-title":"Brain Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4050","article-title":"Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants","volume":"22","author":"Duman","year":"2016","journal-title":"Nat Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1586\/14737175.8.1.93","article-title":"The underlying neurobiology of bipolar disorder","volume":"2","author":"Manji","year":"2003","journal-title":"World Psy: Off J World Psychiatr Assoc (WPA)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/s12916-015-0310-y","article-title":"The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders","volume":"13","author":"Morris","year":"2015","journal-title":"BMC Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsaf090.0807","article-title":"Major depressive disorder","volume":"358","author":"Saini","year":"2008","journal-title":"N Engl J Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/7854_2012_210","article-title":"Emotional processing and antidepressant action","volume":"14","author":"Harmer","year":"2013","journal-title":"Curr Topics Behav Neurosci"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-012-1330-y","article-title":"Large neutral amino acids: dietary effects on brain neurochemistry and function","volume":"45","author":"Fernstrom","year":"2013","journal-title":"Amino Acids"},{"key":"B11","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1007\/s007260170063","article-title":"Amino acids and central fatigue","volume":"20","author":"Blomstrand","year":"2001","journal-title":"Amino Acids"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/136.2.544s","article-title":"A role for branched-chain amino acids in reducing central fatigue","volume":"136","author":"Blomstrand","year":"2006","journal-title":"J Nutr"},{"key":"B13","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1097\/00005768-200105001-01538","article-title":"Central fatigue: the serotonin hypothesis and beyond","volume":"36","author":"Meeusen","year":"2006","journal-title":"Sports Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1123\/ijsnem.17.s1.s37","article-title":"Amino acids and the brain: do they play a role in \"central fatigue\"","author":"Meeusen","year":"2007","journal-title":"Int J Sport Nutr Exerc Metab"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/wps.20229","article-title":"What has serotonin to do with depression","volume":"14","author":"Cowen","year":"2015","journal-title":"World Psy: Off J World Psychiatr Assoc (WPA)"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1056\/nejm195907232610406","article-title":"The neurobiology of depression--revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms","volume":"367","author":"Albert","year":"2012","journal-title":"Philos Trans R Soc Lond Ser B Biol Sci"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2012.03.005","article-title":"Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value","volume":"36","author":"Allen","year":"2012","journal-title":"Neurosci Biobehav Rev"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2016.10.037","article-title":"Neurobiological basis of bipolar disorder: Mitochondrial dysfunction hypothesis and beyond","volume":"187","author":"Kato","year":"2017","journal-title":"Schizophr Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1017\/s0033291713002535","article-title":"Cognitive impairment in depression: a systematic review and meta-analysis","volume":"44","author":"Rock","year":"2014","journal-title":"Psychol Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.jpsychires.2016.02.023","article-title":"Exercise as a treatment for depression: a meta-analysis adjusting for publication bias","volume":"77","author":"Schuch","year":"2016","journal-title":"J Psychiatr Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1015950108","article-title":"Exercise training increases size of hippocampus and improves memory","volume":"108","author":"Erickson","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-019-0174-x","article-title":"Physical activity and muscle-brain crosstalk","volume":"15","author":"Pedersen","year":"2019","journal-title":"Nat Rev Endocrinol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2000.80.3.1107","article-title":"Creatine and creatinine metabolism","volume":"80","author":"Wyss","year":"2000","journal-title":"Physiol Rev"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.20900\/jpbs.20250006","article-title":"Creatine supplementation: More is likely better for brain bioenergetics, health and function","volume":"10","author":"Fabiano","year":"2025","journal-title":"J Psychiatry Brain Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19040954","article-title":"Branched chain amino acids: Beyond nutrition metabolism","volume":"19","author":"Nie","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ynstr.2019.100170","article-title":"Branched-chain amino acids mediate resilience to chronic social defeat stress by activating BDNF\/TRKB signaling","volume":"11","author":"Nasrallah","year":"2019","journal-title":"Neurobiol Stress"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.4103\/ijpvm.ijpvm_59_23","article-title":"Role of branched and aromatic amino acids, diet inflammatory index, and anthropometric indices on mental health","volume":"15","author":"Majdizadeh","year":"2024","journal-title":"Int J Prev Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-011-0877-3","article-title":"The creatine kinase system and pleiotropic effects of creatine","volume":"40","author":"Wallimann","year":"2011","journal-title":"Amino Acids"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.71638","article-title":"Creatine supplementation in depression: a review of mechanisms, efficacy, clinical outcomes, and future directions","volume":"16","author":"Juneja","year":"2024","journal-title":"Cureus"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.20463\/jenb.2018.0009","article-title":"Regular exercise and creatine supplementation prevent chronic mild stress-induced decrease in hippocampal neurogenesis via Wnt\/GSK3\u03b2\/\u03b2-catenin pathway","volume":"22","author":"Leem","year":"2018","journal-title":"J Exercise Nutr Biochem"},{"key":"B31","doi-asserted-by":"publisher","first-page":"24","DOI":"10.20463\/jenb.2016.09.20.3.4","article-title":"Effects of creatine monohydrate supplementation and exercise on depression-like behaviors and raphe 5-HT neurons in mice","volume":"20","author":"Ahn","year":"2016","journal-title":"J Exercise Nutr Biochem"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0076301","article-title":"Creatine supplementation associated or not with strength training upon emotional and cognitive measures in older women: a randomized double-blind study","volume":"8","author":"Alves","year":"2013","journal-title":"PloS One"},{"key":"B33","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/s00213-005-0269-z","article-title":"Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol","volume":"185","author":"McMorris","year":"2006","journal-title":"Psychopharmacol (Berl)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.70252\/EKHJ1489","article-title":"Effects of creatine supplementation and progressive resistance training in stroke survivors","volume":"15","author":"Butchart","year":"2022","journal-title":"Int J Exerc Sci"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1186\/1550-2783-5-14","article-title":"Brain serotonin and dopamine modulators, perceptual responses and endurance performance during exercise in the heat following creatine supplementation","volume":"5","author":"Hadjicharalambous","year":"2008","journal-title":"J Int Soc Sports Nutr"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/nu16060766","article-title":"The effect of creatine nitrate and caffeine individually or combined on exercise performance and cognitive function: a randomized, crossover, double-blind, placebo-controlled trial","volume":"16","author":"Mabrey","year":"2024","journal-title":"Nutrients"},{"key":"B37","first-page":"6","article-title":"Creatine supplementation on cognitive performance following exercise in female Muay Thai athletes","volume":"1","author":"Pires","year":"2021","journal-title":"J For Sports Neurosci"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/nu17243831","article-title":"Effects of creatine monohydrate loading on sleep metrics, physical performance, cognitive function, and recovery in physically active men: a randomized, double-blind, placebo-controlled, crossover trial","volume":"17","author":"Ben Maaoui","year":"2025","journal-title":"Nutrients"},{"key":"B39","article-title":"The effect of creatine monohydrate consumption on men's cognitive function with anaerobic exercise","volume":"11","author":"Hariyanto","year":"2025","journal-title":"J Sport Sci Fitness"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2019.00107","article-title":"A multi-ingredient nutritional supplement in combination with resistance exercise and high-intensity interval training improves cognitive function and increases N-3 index in healthy older men: a randomized controlled trial","volume":"11","author":"Bell","year":"2019","journal-title":"Front Aging Neurosci"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1080\/15502783.2025.2542369","article-title":"Acute creatine supplementation enhances technical performance in adolescent basketball players under cognitive-motor dual-task condition","volume":"22","author":"Wu","year":"2025","journal-title":"J Int Soc Sports Nutr"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2018.05.014","article-title":"Physiological and pathological roles of branched-chain amino acids in the regulation of protein and energy metabolism and neurological functions","volume":"133","author":"Shimomura","year":"2018","journal-title":"Pharmacol Res"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-45328-2_10","article-title":"Metabolism of amino acids in the brain and their roles in regulating food intake","volume":"1265","author":"He","year":"2020","journal-title":"Adv Exp Med Biol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1097\/00005768-199701000-00008","article-title":"Possible mechanisms of central nervous system fatigue during exercise","volume":"29","author":"Davis","year":"1997","journal-title":"Med Sci Sports Exerc"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3390\/dietetics4030032","article-title":"Branched-chain amino acids combined with exercise improves physical function and quality of life in older adults: results from a pilot randomized controlled trial","volume":"4","author":"Robbins","year":"2025","journal-title":"Dietetics (Bsl Switz)"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2021.111592","article-title":"Effect of a 40-weeks multicomponent exercise program and branched chain amino acids supplementation on functional fitness and mental health in frail older persons","volume":"155","author":"Caldo-Silva","year":"2021","journal-title":"Exp Gerontol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.4077\/cjp.2011.amk075","article-title":"Effects of BCAA, arginine and carbohydrate combined drink on post-exercise biochemical response and psychological condition","volume":"54","author":"Hsu","year":"2011","journal-title":"Chin J Physiol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-013-1566-1","article-title":"Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines","volume":"45","author":"Choi","year":"2013","journal-title":"Amino Acids"},{"key":"B49","article-title":"The supplementation of branched-chain amino acids, arginine, and citrulline improves endurance exercise performance in two consecutive days","volume":"15","author":"Cheng","year":"2016","journal-title":"J Sports Sci Med"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/136.2.548s","article-title":"Exercise-dependent preference for a mixture of branched-chain amino acids and homeostatic control of brain serotonin in exercising rats","volume":"136","author":"Smriga","year":"2006","journal-title":"J Nutr"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1080\/10284150290028936","article-title":"Preference for a solution of branched-chain amino acids plus glutamine and arginine correlates with free running activity in rats: involvement of serotonergic-dependent processes of lateral hypothalamus","volume":"5","author":"Smriga","year":"2002","journal-title":"Nutr Neurosci"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2023.1266422","article-title":"Acute consumption of a branched chain amino acid and vitamin B-6 containing sports drink does not improve multiple sprint exercise performance, but increases post-exercise blood glucose","volume":"10","author":"Farra","year":"2023","journal-title":"Front Nutr"},{"key":"B53","doi-asserted-by":"publisher","first-page":"22644","DOI":"10.1038\/s41598-023-49781-z","article-title":"Essential amino acid supplements ingestion has a positive effect on executive function after moderate-intensity aerobic exercise","volume":"13","author":"Dora","year":"2023","journal-title":"Sci Rep"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/nu13041106","article-title":"Effect of training-detraining phases of multicomponent exercises and BCAA supplementation on inflammatory markers and albumin levels in frail older persons","volume":"13","author":"Caldo-Silva","year":"2021","journal-title":"Nutrients"},{"key":"B55","article-title":"Branched-chain amino acid supplementation during 30-km competitive run: mood and cognitive performance","volume":"10","author":"Hassm\u00e9n","year":"1994","journal-title":"Nutrition"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3390\/nu15071716","article-title":"The preventive effect of exercise and oral branched-chain amino acid supplementation on obesity-induced brain changes in Ldlr-\/-.Leiden mice","volume":"15","author":"Lohkamp","year":"2023","journal-title":"Nutrients"}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2026.1830803\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:22:29Z","timestamp":1785835349000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2026.1830803\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":56,"alternative-id":["10.3389\/fpsyt.2026.1830803"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2026.1830803","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]},"article-number":"1830803"}}