American Psychiatric Association., American Psychiatric Association. DSM-5 Task Force. Diagnostic and statistical manual of mental disorders: DSM-5. 5th edn. American Psychiatric Association: Washington, D.C., 2013, xliv, 947 p.pp.
Depression and Other Common Mental Disorders: Global Health Estimates. vol. Licence:CC BY-NC-SA 3.0 IGO. World Health Organization: Geneva, 2017, pp Licence:CC BY-NC-SA 3.0 IGO.
Collaborators GDaIIaP. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1545–602.
Finley CR, Chan DS, Garrison S, Korownyk C, Kolber MR, Campbell S, et al. What are the most common conditions in primary care? Systematic review. Can Fam Physician. 2018;64:832–40.
Rajan S, McKee M, Rangarajan S, Bangdiwala S, Rosengren A, Gupta R, et al. Association of symptoms of depression with cardiovascular disease and mortality in low-, middle-, and high-income countries. JAMA Psychiatry. 2020;77:1052–63.
Chen PC, Chan YT, Chen HF, Ko MC, Li CY. Population-based cohort analyses of the bidirectional relationship between type 2 diabetes and depression. Diabetes Care. 2013;36:376–82.
Smith DJ, Court H, McLean G, Martin D, Langan Martin J, Guthrie B, et al. Depression and multimorbidity: a cross-sectional study of 1,751,841 patients in primary care. J Clin Psychiatry. 2014;75:1202–8.
Cuijpers P, Smit F. Excess mortality in depression: a meta-analysis of community studies. J Affect Disord. 2002;72:227–36.
Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, 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.
Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354:1231–42.
Kessler RC. The costs of depression. Psychiatric Clin North Am. 2012;35:1–14.
Birnbaum HG, Kessler RC, Kelley D, Ben-Hamadi R, Joish VN, Greenberg PE. Employer burden of mild, moderate, and severe major depressive disorder: mental health services utilization and costs, and work performance. Depress Anxiety. 2010;27:78–89.
Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. Public Health Rep. 1985;100:126–31.
Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, Minson CT, Nigg CR, Salem GJ, et al. American College of Sports Medicine position stand. Exercise and physical activity for older adults. Med Sci Sports Exerc. 2009;41:1510–30.
Colberg SR, Sigal RJ, Fernhall B, Regensteiner JG, Blissmer BJ, Rubin RR, et al. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement. Diabetes Care. 2010;33:e147–167.
Garber CE, Blissmer B, Deschenes MR, Franklin BA, Lamonte MJ, Lee IM, et al. American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Med Sci Sports Exerc. 2011;43:1334–59.
Williams MA, Haskell WL, Ades PA, Amsterdam EA, Bittner V, Franklin BA, et al. Resistance exercise in individuals with and without cardiovascular disease: 2007 update: a scientific statement from the American Heart Association Council on Clinical Cardiology and Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2007;116:572–84.
Scott KM, Lim C, Al-Hamzawi A, Alonso J, Bruffaerts R, Caldas-de-Almeida JM, et al. Association of mental disorders with subsequent chronic physical conditions: World mental health surveys from 17 countries. JAMA Psychiatry. 2016;73:150–8.
Pedersen BK. Physical activity and muscle-brain crosstalk. Nat Rev Endocrinol. 2019;15:383–92.
Singh NA, Clements KM, Fiatarone MA. A randomized controlled trial of progressive resistance training in depressed elders. J Gerontol A Biol Sci Med Sci. 1997;52:M27–M35.
Dunn AL, Trivedi MH, Kampert JB, Clark CG, Chambliss HO. Exercise treatment for depression: efficacy and dose response. Am J Prev Med. 2005;28:1–8.
Singh NA, Stavrinos TM, Scarbek Y, Galambos G, Liber C, Fiatarone Singh MA. A randomized controlled trial of high versus low intensity weight training versus general practitioner care for clinical depression in older adults. J Gerontol A Biol Sci Med Sci. 2005;60:768–76.
Blumenthal JA, Babyak MA, Doraiswamy PM, Watkins L, Hoffman BM, Barbour KA, et al. Exercise and pharmacotherapy in the treatment of major depressive disorder. Psychosom Med. 2007;69:587–96.
Wewege MA, Thom JM, Rye KA, Parmenter BJ. Aerobic, resistance or combined training: A systematic review and meta-analysis of exercise to reduce cardiovascular risk in adults with metabolic syndrome. Atherosclerosis. 2018;274:162–71.
Ashton RE, Tew GA, Aning JJ, Gilbert SE, Lewis L, Saxton JM. Effects of short-term, medium-term and long-term resistance exercise training on cardiometabolic health outcomes in adults: systematic review with meta-analysis. Br J Sports Med. 2020;54:341–8.
Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007;30:464–72.
Herold F, Törpel A, Schega L, Müller NG. Functional and/or structural brain changes in response to resistance exercises and resistance training lead to cognitive improvements – a systematic review. Eur Rev Aging Phys Act. 2019;16:10.
Tipton CM. The history of “Exercise Is Medicine” in ancient civilizations. Adv Physiol Educ. 2014;38:109–17.
Berryman JW. Motion and rest: Galen on exercise and health. Lancet. 2012;380:210–1.
Bate J. The Anatomy of Melancholy revisited. Lancet. 2017;389:1790–1.
Knudson AB, Davis JE. Medically prescribed exercises for neuropsychiatric patients; the Veterans Administration program. J Am Med Assoc. 1949;140:1090–5.
Morgan WP. Selected physiological and psychomotor correlates of depression in psychiatric patients. Res Q. 1968;39:1037–43.
Morgan WP. A pilot investigation of physical working capacity in depressed and nondepressed psychiatric males. Res Q. 1969;40:859–61.
Morgan WP. Physical working capacity in depressed and non-depressed psychiatric females: a preliminary study. Am Correct Ther J. 1970;24:14–16.
Morgan WP, Roberts JA, Brand FR, Feinerman AD. Psychological effect of chronic physical activity. Med Sci Sports. 1970;2:213–7.
Greist JH, Klein MH, Eischens RR, Faris J, Gurman AS, Morgan WP. Running as treatment for depression. Compr Psychiatry. 1979;20:41–54.
Sexton H, Maere A, Dahl NH. Exercise intensity and reduction in neurotic symptoms. A controlled follow-up study. Acta Psychiatr Scand. 1989;80:231–5.
Doyne EJ, Ossip-Klein DJ, Bowman ED, Osborn KM, McDougall-Wilson IB, Neimeyer RA. Running versus weight lifting in the treatment of depression. J Consult Clin Psychol. 1987;55:748–54.
Chekroud SR, Gueorguieva R, Zheutlin AB, Paulus M, Krumholz HM, Krystal JH, et al. Association between physical exercise and mental health in 1·2 million individuals in the USA between 2011 and 2015: a cross-sectional study. Lancet Psychiatry. 2018;5:739–46.
Pearce M, Garcia L, Abbas A, Strain T, Schuch FB, Golubic R, et al. Association between physical activity and risk of depression: A systematic review and meta-analysis. JAMA Psychiatry. 2022;79:550–9.
Dishman RK, McDowell CP, Herring MP. Customary physical activity and odds of depression: a systematic review and meta-analysis of 111 prospective cohort studies. Br J Sports Med. 2021;55:926–34.
American College of Sports Medicine, Riebe D, Ehrman JK, Liguori G, Magal M. ACSM’s Guidelines for Exercise Testing and Prescription. 10 edn. Philadelphia: Wolters Kluwer; 2018.
Bull FC, Al-Ansari SS, Biddle S, Borodulin K, Buman MA-O, Cardon G, et al. World Health Organization 2020 guidelines on physical activity and sedentary behaviour. Br J Sports Med. 2020;54:1451–62.
Piercy KL, Troiano RP, Ballard RM, Carlson SA, Fulton JE, Galuska DA, et al. The physical activity guidelines for Americans. JAMA. 2018;320:2020–8.
Schuch FB, Vancampfort D, Richards J, Rosenbaum S, Ward PB, Stubbs B. Exercise as a treatment for depression: A meta-analysis adjusting for publication bias. J Psychiatr Res. 2016;77:42–51.
Kvam S, Kleppe CL, Nordhus IH, Hovland A. Exercise as a treatment for depression: A meta-analysis. J Affect Disord. 2016;202:67–86.
Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, et al. Exercise for depression. Cochrane Database Syst Rev. 2013;9:CD004366.
Lee J, Gierc M, Vila-Rodriguez F, Puterman E, Faulkner G. Efficacy of exercise combined with standard treatment for depression compared to standard treatment alone: A systematic review and meta-analysis of randomized controlled trials. J Affect Disord. 2021;295:1494–511.
Stubbs B, Vancampfort D, Rosenbaum S, Ward PB, Richards J, Ussher M, et al. Challenges establishing the efficacy of exercise as an antidepressant treatment: A systematic review and meta-analysis of control group responses in exercise Rrandomised controlled trials. Sports Med. 2016;46:699–713.
Blumenthal JA, Babyak MA, Moore KA, Craighead WE, Herman S, Khatri P, et al. Effects of exercise training on older patients with major depression. Arch Int Med. 1999;159:2349–56.
Krogh J, Videbech P, Thomsen C, Gluud C, Nordentoft M. DEMO-II trial. Aerobic exercise versus stretching exercise in patients with major depression-a randomised clinical trial. PLoS One. 2012;7:e48316.
Jacquart SD, Marshak HH, Dos Santos H, Luu SM, Berk LS, McMahon PT, et al. The effects of simultaneous exercise and psychotherapy on depressive symptoms in inpatient, psychiatric older adults. Adv Mind Body Med. 2014;28:8–17.
Oertel-Knochel V, Mehler P, Thiel C, Steinbrecher K, Malchow B, Tesky V, et al. Effects of aerobic exercise on cognitive performance and individual psychopathology in depressive and schizophrenia patients. Eur Arch Psychiatry Clin Neurosci. 2014;264:589–604.
Kerling A, Tegtbur U, Gutzlaff E, Kuck M, Borchert L, Ates Z, et al. Effects of adjunctive exercise on physiological and psychological parameters in depression: a randomized pilot trial. J Affect Disord. 2015;177:1–6.
Pilu A, Sorba M, Hardoy MC, Floris AL, Mannu F, Seruis ML, et al. Efficacy of physical activity in the adjunctive treatment of major depressive disorders: preliminary results. Clin Pract Epidemiol Ment Health. 2007;3:8.
Mota-Pereira J, Silverio J, Carvalho S, Ribeiro JC, Fonte D, Ramos J. Moderate exercise improves depression parameters in treatment-resistant patients with major depressive disorder. J Psychiatr Res. 2011;45:1005–11.
Danielsson L, Papoulias I, Petersson EL, Carlsson J, Waern M. Exercise or basic body awareness therapy as add-on treatment for major depression: a controlled study. J Affect Disord. 2014;168:98–106.
Belvederi Murri M, Amore M, Menchetti M, Toni G, Neviani F, Cerri M, et al. Physical exercise for late-life major depression. Br J Psychiatry. 2015;207:235–42.
Carneiro LS, Fonseca AM, Vieira-Coelho MA, Mota MP, Vasconcelos-Raposo J. Effects of structured exercise and pharmacotherapy vs. pharmacotherapy for adults with depressive symptoms: A randomized clinical trial. J Psychiatr Res. 2015;71:48–55.
Legrand FD, Neff EM. Efficacy of exercise as an adjunct treatment for clinically depressed inpatients during the initial stages of antidepressant pharmacotherapy: An open randomized controlled trial. J Affect Disord. 2016;191:139–44.
Salehi I, Hosseini SM, Haghighi M, Jahangard L, Bajoghli H, Gerber M, et al. Electroconvulsive therapy (ECT) and aerobic exercise training (AET) increased plasma BDNF and ameliorated depressive symptoms in patients suffering from major depressive disorder. J Psychiatr Res. 2016;76:1–8.
Siqueira CC, Valiengo LL, Carvalho AF, Santos-Silva PR, Missio G, de Sousa RT, et al. Antidepressant efficacy of adjunctive aerobic activity and associated biomarkers in major depression: A 4-Week, randomized, single-blind, controlled clinical trial. PLoS One. 2016;11:e0154195.
Gujral S, Aizenstein H, Reynolds CF 3rd, Butters MA, Grove G, Karp JF, et al. Exercise for depression: A feasibility trial exploring neural mechanisms. Am J Geriatr Psychiatry. 2019;27:611–6.
Moraes HS, Silveira HS, Oliveira NA, Matta Mello Portugal E, Araújo NB, Vasques PE, et al. Is strength training as effective as aerobic training for depression in older adults? A randomized controlled trial. Neuropsychobiology. 2020;79:141–9.
Martinsen EW, Medhus A, Sandvik L. Effects of aerobic exercise on depression: a controlled study. Br Med J (Clin Res Ed). 1985;291:109.
Veale D, Le Fevre K, Pantelis C, de Souza V, Mann A, Sargeant A. Aerobic exercise in the adjunctive treatment of depression: a randomized controlled trial. J R Soc Med. 1992;85:541–4.
Knubben K, Reischies FM, Adli M, Schlattmann P, Bauer M, Dimeo F. A randomised, controlled study on the effects of a short-term endurance training programme in patients with major depression. Br J Sports Med. 2007;41:29–33.
Krogh J, Saltin B, Gluud C, Nordentoft M. The DEMO trial: a randomized, parallel-group, observer-blinded clinical trial of strength versus aerobic versus relaxation training for patients with mild to moderate depression. J Clin Psychiatry. 2009;70:790–800.
Doose M, Ziegenbein M, Hoos O, Reim D, Stengert W, Hoffer N, et al. Self-selected intensity exercise in the treatment of major depression: A pragmatic RCT. Int J Psychiatry Clin Pract. 2015;19:266–75.
Hallgren M, Kraepelien M, Öjehagen A, Lindefors N, Zeebari Z, Kaldo V, et al. Physical exercise and internet-based cognitive-behavioural therapy in the treatment of depression: randomised controlled trial. Br J Psychiatry. 2015;207:227–34.
Schuch FB, Vasconcelos-Moreno MP, Borowsky C, Zimmermann AB, Rocha NS, Fleck MP. Exercise and severe major depression: effect on symptom severity and quality of life at discharge in an inpatient cohort. J Psychiatr Res. 2015;61:25–32.
Helgadóttir B, Hallgren M, Ekblom Ö, Forsell Y. Training fast or slow? Exercise for depression: A randomized controlled trial. Prev Med. 2016;91:123–31.
Olson RL, Brush CJ, Ehmann PJ, Alderman BL. A randomized trial of aerobic exercise on cognitive control in major depression. Clin Neurophysiol. 2017;128:903–13.
Buschert V, Prochazka D, Bartl H, Diemer J, Malchow B, Zwanzger P, et al. Effects of physical activity on cognitive performance: a controlled clinical study in depressive patients. Eur Arch Psychiatry Clin Neurosci. 2019;269:555–63.
Chau RMW, Tsui AYY, Wong EYW, Cheung EYY, Chan DYC, Lau PMY, et al. Effectiveness of a structured physical rehabilitation program on the physical fitness, mental health and pain for Chinese patients with major depressive disorders in Hong Kong – a randomized controlled trial with 9-month follow-up outcomes. Disabil Rehabil. 2020. Advance online publication. https://doi.org/10.1080/09638288.2020.1800833.
Haussleiter IS, Bolsinger B, Assion HJ, Juckel G. Adjuvant guided exercise therapy versus self-organized activity in patients with major depression. J Nerv Ment Dis. 2020;208:982–8.
La Rocque CL, Mazurka R, Stuckless TJR, Pyke K, Harkness KL. Randomized controlled trial of bikram yoga and aerobic exercise for depression in women: Efficacy and stress-based mechanisms. J Affect Disord. 2021;280:457–66.
Schulz JM, Birmingham TB, Atkinson HF, Woehrle E, Primeau CA, Lukacs MJ, et al. Are we missing the target? Are we aiming too low? What are the aerobic exercise prescriptions and their effects on markers of cardiovascular health and systemic inflammation in patients with knee osteoarthritis? A systematic review and meta-analysis. Br J Sports Med. 2020;54:771–5.
Stubbs B, Vancampfort D, Rosenbaum S, Ward PB, Richards J, Soundy A, et al. Dropout from exercise randomized controlled trials among people with depression: A meta-analysis and meta regression. J Affect Disord. 2016;190:457–66.
Rethorst CD, Trivedi MH. Evidence-based recommendations for the prescription of exercise for major depressive disorder. J Psychiatr Pract. 2013;19:204–12.
Stubbs B, Vancampfort D, Hallgren M, Firth J, Veronese N, Solmi M, et al. EPA guidance on physical activity as a treatment for severe mental illness: a meta-review of the evidence and Position Statement from the European Psychiatric Association (EPA), supported by the International Organization of Physical Therapists in Mental Health (IOPTMH). Eur Psychiatry. 2018;54:124–44.
Firth J, Stubbs B, Vancampfort D, Schuch F, Lagopoulos J, Rosenbaum S, et al. Effect of aerobic exercise on hippocampal volume in humans: A systematic review and meta-analysis. NeuroImage. 2018;166:230–8.
Schatzberg AF. Pharmacological principles of antidepressant efficacy. Hum Psychopharmacol. 2002;17:S17–22.
Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR. Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry. 1990;47:411–8.
Miller HL, Delgado PL, Salomon RM, Berman R, Krystal JH, Heninger GR, et al. Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry. 1996;53:117–28.
Nutt DJ. The neuropharmacology of serotonin and noradrenaline in depression. Int Clin Psychopharmacol. 2002;17:S1–12.
Delgado PL, Price LH, Miller HL, Salomon RM, Aghajanian GK, Heninger GR, et al. Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients. Arch Gen Psychiatry. 1994;51:865–74.
Berman RM, Sanacora G, Anand A, Roach LM, Fasula MK, Finkelstein CO, et al. Monoamine depletion in unmedicated depressed subjects. Biol Psychiatry. 2002;51:469–73.
Praschak-Rieder N, Wilson AA, Hussey D, Carella A, Wei C, Ginovart N, et al. Effects of tryptophan depletion on the serotonin transporter in healthy humans. Biol Psychiatry. 2005;58:825–30.
Ruhé HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry. 2007;12:331–59.
Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry. 2022. Advance online publication. https://doi.org/10.1038/s41380-022-01661-0.
Vreeburg SA, Hoogendijk WJ, van Pelt J, Derijk RH, Verhagen JC, van Dyck R, et al. Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. Arch Gen Psychiatry. 2009;66:617–26.
Bus BA, Molendijk ML, Tendolkar I, Penninx BW, Prickaerts J, Elzinga BM, et al. Chronic depression is associated with a pronounced decrease in serum brain-derived neurotrophic factor over time. Mol Psychiatry. 2015;20:602–8.
Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732–41.
Ronaldson A, Carvalho LA, Kostich K, Lazzarino AI, Urbanova L, Steptoe A. The effects of six-day SSRI administration on diurnal cortisol secretion in healthy volunteers. Psychopharmacology (Berl). 2018;235:3415–22.
Hinkelmann K, Moritz S, Botzenhardt J, Muhtz C, Wiedemann K, Kellner M, et al. Changes in cortisol secretion during antidepressive treatment and cognitive improvement in patients with major depression: a longitudinal study. Psychoneuroendocrinology. 2012;37:685–92.
Matrisciano F, Bonaccorso S, Ricciardi A, Scaccianoce S, Panaccione I, Wang L, et al. Changes in BDNF serum levels in patients with major depression disorder (MDD) after 6 months treatment with sertraline, escitalopram, or venlafaxine. J Psychiatric Res. 2009;43:247–54.
Molendijk ML, Bus BA, Spinhoven P, Penninx BW, Kenis G, Prickaerts J, et al. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry. 2011;16:1088–95.
Wang L, Wang R, Liu L, Qiao D, Baldwin DS, Hou R. Effects of SSRIs on peripheral inflammatory markers in patients with major depressive disorder: A systematic review and meta-analysis. Brain Behav Immun. 2019;79:24–38.
Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007;45:27–37.
Enache D, Pariante CM, Mondelli V. Markers of central inflammation in major depressive disorder: A systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue. Brain Behav Immun. 2019;81:24–40.
Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.
Pedersen BK, Akerström TC, Nielsen AR, Fischer CP. Role of myokines in exercise and metabolism. J Appl Physiol (1985). 2007;103:1093–8.
Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol (1985). 2005;98:1154–62.
Pedersen BK. Muscles and their myokines. J Exp Biol. 2011;214:337–46.
Wen L, Jin Y, Li L, Sun S, Cheng S, Zhang S, et al. Exercise prevents raphe nucleus mitochondrial overactivity in a rat depression model. Physiol Behav. 2014;132:57–65.
Lu Q, Mouri A, Yang Y, Kunisawa K, Teshigawara T, Hirakawa M, et al. Chronic unpredictable mild stress-induced behavioral changes are coupled with dopaminergic hyperfunction and serotonergic hypofunction in mouse models of depression. Behav Brain Res. 2019;372:112053.
Ahmad A, Rasheed N, Banu N, Palit G. Alterations in monoamine levels and oxidative systems in frontal cortex, striatum, and hippocampus of the rat brain during chronic unpredictable stress. Stress. 2010;13:355–64.
Shen M, Yang Y, Wu Y, Zhang B, Wu H, Wang L, et al. L-theanine ameliorate depressive-like behavior in a chronic unpredictable mild stress rat model via modulating the monoamine levels in limbic-cortical-striatal-pallidal-thalamic-circuit related brain regions. Phytother Res. 2019;33:412–21.
Wu GF, Ren S, Tang RY, Xu C, Zhou JQ, Lin SM, et al. Antidepressant effect of taurine in chronic unpredictable mild stress-induced depressive rats. Sci Rep. 2017;7:4989.
Daniele TMDC, de Bruin PFC, Rios ERV, de Bruin VMS. Effects of exercise on depressive behavior and striatal levels of norepinephrine, serotonin and their metabolites in sleep-deprived mice. Behav Brain Res. 2017;332:16–22.
Lee H, Ohno M, Ohta S, Mikami T. Regular moderate or intense exercise prevents depression-like behavior without change of hippocampal tryptophan content in chronically tryptophan-deficient and stressed mice. PLoS One. 2013;8:e66996.
Kiuchi T, Lee H, Mikami T. Regular exercise cures depression-like behavior via VEGF-Flk-1 signaling in chronically stressed mice. Neuroscience. 2012;207:208–17.
Otsuka T, Nishii A, Amemiya S, Kubota N, Nishijima T, Kita I. Effects of acute treadmill running at different intensities on activities of serotonin and corticotropin-releasing factor neurons, and anxiety- and depressive-like behaviors in rats. Behav Brain Res. 2016;298:44–51.
Lechin F, van der Dijs B, Orozco B, Lechin ME, Báez S, Lechin AE, et al. Plasma neurotransmitters, blood pressure, and heart rate during supine-resting, orthostasis, and moderate exercise conditions in major depressed patients. Biol Psychiatry. 1995;38:166–73.
Zimmer P, Stritt C, Bloch W, Schmidt FP, Hübner ST, Binnebößel S, et al. The effects of different aerobic exercise intensities on serum serotonin concentrations and their association with Stroop task performance: a randomized controlled trial. Eur J Appl Physiol. 2016;116:2025–34.
Carneiro LS, Mota MP, Vieira-Coelho MA, Alves RC, Fonseca AM, Vasconcelos-Raposo J. Monoamines and cortisol as potential mediators of the relationship between exercise and depressive symptoms. Eur Arch Psychiatry Clin Neurosci. 2017;267:117–21. Germany
Payne JK, Held J, Thorpe J, Shaw H. Effect of exercise on biomarkers, fatigue, sleep disturbances, and depressive symptoms in older women with breast cancer receiving hormonal therapy. Oncol Nurs Forum. 2008;35:635–42.
Wipfli B, Landers D, Nagoshi C, Ringenbach S. An examination of serotonin and psychological variables in the relationship between exercise and mental health. Scand J Med Sci Sports. 2011;21:474–81.
Melancon MO, Lorrain D, Dionne IJ. Changes in markers of brain serotonin activity in response to chronic exercise in senior men. Appl Physiol Nutr Metab. 2014;39:1250–6.
Savitz J. The kynurenine pathway: a finger in every pie. Mol Psychiatry. 2020;25:131–47.
Agudelo LZ, Femenía T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, et al. Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell. 2014;159:33–45.
Contrepois K, Wu S, Moneghetti KJ, Hornburg D, Ahadi S, Tsai MS, et al. Molecular choreography of acute exercise. Cell. 2020;181:1112–30.
Binder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth factors (Chur, Switzerland). 2004;22:123–31.
Qiao H, An SC, Xu C, Ma XM. Role of proBDNF and BDNF in dendritic spine plasticity and depressive-like behaviors induced by an animal model of depression. Brain Res. 2017;1663:29–37.
Lu Y, Ho CS, McIntyre RS, Wang W, Ho RC. Effects of vortioxetine and fluoxetine on the level of Brain Derived Neurotrophic Factors (BDNF) in the hippocampus of chronic unpredictable mild stress-induced depressive rats. Brain Res Bull. 2018;142:1–7.
Lapmanee S, Charoenphandhu J, Teerapornpuntakit J, Krishnamra N, Charoenphandhu N. Agomelatine, venlafaxine, and running exercise effectively prevent anxiety- and depression-like behaviors and memory impairment in restraint stressed rats. PLoS One. 2017;12:e0187671.
Eldomiaty MA, Almasry SM, Desouky MK, Algaidi SA. Voluntary running improves depressive behaviours and the structure of the hippocampus in rats: A possible impact of myokines. Brain Res. 2017;1657:29–42.
Matthews VB, Astrom MB, Chan MH, Bruce CR, Krabbe KS, Prelovsek O, et al. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia. 2009;52:1409–18.
Rasmussen P, Brassard P, Adser H, Pedersen MV, Leick L, Hart E, et al. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp Physiol. 2009;94:1062–9.
Gustafsson G, Lira CM, Johansson J, Wisen A, Wohlfart B, Ekman R, et al. The acute response of plasma brain-derived neurotrophic factor as a result of exercise in major depressive disorder. Psychiatry Res. 2009;169:244–8.
Kallies G, Rapp MA, Fydrich T, Fehm L, Tschorn M, Teran C, et al. Serum brain-derived neurotrophic factor (BDNF) at rest and after acute aerobic exercise in major depressive disorder. Psychoneuroendocrinology. 2018;102:212–5.
Ross RE, Saladin ME, George MS, Gregory CM. High-intensity aerobic exercise acutely increases brain-derived neurotrophic factor. Med Sci Sports Exerc. 2019;51:1698–709.
Meyer JD, Koltyn KF, Stegner AJ, Kim JS, Cook DB. Relationships between serum BDNF and the antidepressant effect of acute exercise in depressed women. Psychoneuroendocrinology. 2016;74:286–94.
Yarrow JF, White LJ, McCoy SC, Borst SE. Training augments resistance exercise induced elevation of circulating brain derived neurotrophic factor (BDNF). Neurosci Lett. 2010;479:161–5.
Church DD, Hoffman JR, Mangine GT, Jajtner AR, Townsend JR, Beyer KS, et al. Comparison of high-intensity vs. high-volume resistance training on the BDNF response to exercise. J Appl Physiol (1985). 2016;121:123–8.
Dinoff A, Herrmann N, Swardfager W, Gallagher D, Lanctot KL. The effect of exercise on resting concentrations of peripheral brain-derived neurotrophic factor (BDNF) in major depressive disorder: A meta-analysis. J Psychiatric Res. 2018;105:123–31.
Szuhany KL, Otto MW. Assessing BDNF as a mediator of the effects of exercise on depression. J Psychiatr Res. 2020;123:114–8.
Pereira DS, de Queiroz BZ, Miranda AS, Rocha NP, Felício DC, Mateo EC, et al. Effects of physical exercise on plasma levels of brain-derived neurotrophic factor and depressive symptoms in elderly women–a randomized clinical trial. Arch Phys Med Rehabil. 2013;94:1443–50.
Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimäki M. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav Immun. 2015;49:206–15.
Shi Y, Song R, Wang L, Qi Y, Zhang H, Zhu J, et al. Identifying Plasma Biomarkers with high specificity for major depressive disorder: A multi-level proteomics study. J Affect Disord. 2020;277:620–30.
Zavvari F, Nahavandi A. Fluoxetine increases hippocampal neural survival by improving axonal transport in stress-induced model of depression male rats. Physiol Behav. 2020;227:113140.
Lu Y, Xu X, Jiang T, Jin L, Zhao XD, Cheng JH, et al. Sertraline ameliorates inflammation in CUMS mice and inhibits TNF-α-induced inflammation in microglia cells. Int Immunopharmacol. 2019;67:119–28.
Liu W, Sheng H, Xu Y, Liu Y, Lu J, Ni X. Swimming exercise ameliorates depression-like behavior in chronically stressed rats: relevant to proinflammatory cytokines and IDO activation. Behav Brain Res. 2013;242:110–6.
Boettger S, Müller HJ, Oswald K, Puta C, Donath L, Gabriel HH, et al. Inflammatory changes upon a single maximal exercise test in depressed patients and healthy controls. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:475–8.
Pedersen BK, Febbraio M. Muscle-derived interleukin-6–a possible link between skeletal muscle, adipose tissue, liver, and brain. Brain Behav Immun. 2005;19:371–6.
Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 2003;17:884–6.
Steensberg A, Fischer CP, Keller C, Møller K, Pedersen BK. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab. 2003;285:E433–437.
Hallberg L, Janelidze S, Engstrom G, Wisén AG, Westrin A, Brundin L. Exercise-induced release of cytokines in patients with major depressive disorder. J Affect Disord. 2010;126:262–7.
Colbert LH, Visser M, Simonsick EM, Tracy RP, Newman AB, Kritchevsky SB, et al. Physical activity, exercise, and inflammatory markers in older adults: findings from the Health, Aging and Body Composition Study. J Am Geriatr Soc. 2004;52:1098–104.
Kohut ML, McCann DA, Russell DW, Konopka DN, Cunnick JE, Franke WD, et al. Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and psychosocial factors in older adults. Brain Behav Immun. 2006;20:201–9.
Krogh J, Benros ME, Jørgensen MB, Vesterager L, Elfving B, Nordentoft M. The association between depressive symptoms, cognitive function, and inflammation in major depression. Brain Behav Immun. 2014;35:70–76.
Euteneuer F, Dannehl K, Del Rey A, Engler H, Schedlowski M, Rief W. Immunological effects of behavioral activation with exercise in major depression: an exploratory randomized controlled trial. Transl Psychiatry. 2017;7:e1132.
Lavebratt C, Herring MP, Liu JJ, Wei YB, Bossoli D, Hallgren M, et al. Interleukin-6 and depressive symptom severity in response to physical exercise. Psychiatry Res. 2017;252:270–6.
Rethorst CD, Toups MS, Greer TL, Nakonezny PA, Carmody TJ, Grannemann BD, et al. Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder. Mol Psychiatry. 2013;18:1119–24.
Trivedi MH, Greer TL, Church TS, Carmody TJ, Grannemann BD, Galper DI, et al. Exercise as an augmentation treatment for nonremitted major depressive disorder: a randomized, parallel dose comparison. J Clin Psychiatry. 2011;72:677–84.
Köhler CA, Freitas TH, Stubbs B, Maes M, Solmi M, Veronese N, et al. Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis. Mol Neurobiol. 2018;55:4195–206.
Molendijk ML, Spinhoven P, Polak M, Bus BA, Penninx BW, Elzinga BM. Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N=9484). Mol Psychiatry. 2014;19:791–800.
Zhou C, Zhong J, Zou B, Fang L, Chen J, Deng X, et al. Meta-analyses of comparative efficacy of antidepressant medications on peripheral BDNF concentration in patients with depression. PLoS One. 2017;12:e0172270.
Schuch FB, Deslandes AC, Stubbs B, Gosmann NP, Silva CT, Fleck MP. Neurobiological effects of exercise on major depressive disorder: A systematic review. Neurosci Biobehav Rev. 2016;61:1–11.
Krogh J, Nordentoft M, Mohammad-Nezhad M, Westrin A. Growth hormone, prolactin and cortisol response to exercise in patients with depression. J Affect Disord. 2010;125:189–97.
Toups MS, Greer TL, Kurian BT, Grannemann BD, Carmody TJ, Huebinger R, et al. Effects of serum Brain Derived Neurotrophic Factor on exercise augmentation treatment of depression. J Psychiatric Res. 2011;45:1301–6.
Krogh J, Rostrup E, Thomsen C, Elfving B, Videbech P, Nordentoft M. The effect of exercise on hippocampal volume and neurotrophines in patients with major depression–a randomized clinical trial. J Affect Disord. 2014;165:24–30.
Schuch FB, Vasconcelos-Moreno MP, Borowsky C, Zimmermann AB, Wollenhaupt-Aguiar B, Ferrari P, et al. The effects of exercise on oxidative stress (TBARS) and BDNF in severely depressed inpatients. Eur Arch Psychiatry Clin Neurosci. 2014;264:605–13.
Kerling A, Kuck M, Tegtbur U, Grams L, Weber-Spickschen S, Hanke A, et al. Exercise increases serum brain-derived neurotrophic factor in patients with major depressive disorder. J Affect Disord. 2017;215:152–5.
Rahman MS, Millischer V, Zeebari Z, Forsell Y, Lavebratt C. BDNF Val66Met and childhood adversity on response to physical exercise and internet-based cognitive behavioural therapy in depressed Swedish adults. J Psychiatr Res. 2017;93:50–58.
Gourgouvelis J, Yielder P, Clarke ST, Behbahani H, Murphy BA. Exercise leads to better clinical outcomes in those receiving medication plus cognitive behavioral therapy for major depressive disorder. Front Psychiatry. 2018;9:37.
Gerber M, Imboden C, Beck J, Brand S, Colledge F, Eckert A, et al. Effects of aerobic exercise on cortisol stress reactivity in response to the trier social stress test in inpatients with major depressive disorders: a randomized controlled trial. J Clin Med. 2020;9:1419.
Wolkowitz OM, Wolf J, Shelly W, Rosser R, Burke HM, Lerner GK, et al. Serum BDNF levels before treatment predict SSRI response in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1623–30.
Mikoteit T, Beck J, Eckert A, Hemmeter U, Brand S, Bischof R, et al. High baseline BDNF serum levels and early psychopathological improvement are predictive of treatment outcome in major depression. Psychopharmacology (Berl). 2014;231:2955–65.
Leong DP, Teo KK, Rangarajan S, Lopez-Jaramillo P, Avezum A, Orlandini A, et al. Prognostic value of grip strength: findings from the Prospective Urban Rural Epidemiology (PURE) study. Lancet. 2015;386:266–73.
Rethorst CD, South CC, Rush AJ, Greer TL, Trivedi MH. Prediction of treatment outcomes to exercise in patients with nonremitted major depressive disorder. Depress Anxiety. 2017;34:1116–22.
Więdłocha M, Marcinowicz P, Krupa R, Janoska-Jaździk M, Janus M, Dębowska W, et al. Effect of antidepressant treatment on peripheral inflammation markers – A meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2018;80:217–26.
Uher R, Tansey KE, Dew T, Maier W, Mors O, Hauser J, et al. An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am J Psychiatry. 2014;171:1278–86.
Jha MK, Minhajuddin A, Gadad BS, Greer T, Grannemann B, Soyombo A, et al. Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial. Psychoneuroendocrinology. 2017;78:105–13.
Carboni L, McCarthy DJ, Delafont B, Filosi M, Ivanchenko E, Ratti E, et al. Biomarkers for response in major depression: comparing paroxetine and venlafaxine from two randomised placebo-controlled clinical studies. Transl Psychiatry. 2019;9:182.
Lavin KM, Perkins RK, Jemiolo B, Raue U, Trappe SW, Trappe TA. Effects of aging and lifelong aerobic exercise on basal and exercise-induced inflammation. J Appl Physiol (1985). 2020;128:87–99.
Cabral-Santos C, de Lima Junior EA, Fernandes IMDC, Pinto RZ, Rosa-Neto JC, Bishop NC, et al. Interleukin-10 responses from acute exercise in healthy subjects: A systematic review. J Cell Physiol. 2019;234:9956–65.
Krabbe KS, Nielsen AR, Krogh-Madsen R, Plomgaard P, Rasmussen P, Erikstrup C, et al. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia. 2007;50:431–8.
Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A, et al. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes. 2003;52:1799–805.
Dias JP, Joseph JJ, Kluwe B, Zhao S, Shardell M, Seeman T, et al. The longitudinal association of changes in diurnal cortisol features with fasting glucose: MESA. Psychoneuroendocrinology. 2020;119:104698.
Zhou L, Sutton GM, Rochford JJ, Semple RK, Lam DD, Oksanen LJ, et al. Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab. 2007;6:398–405.
Sarwar N, Butterworth AS, Freitag DF, Gregson J, Willeit P, Gorman DN, et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet. 2012;379:1205–13.
Kaess BM, Preis SR, Lieb W, Beiser AS, Yang Q, Chen TC, et al. Circulating brain-derived neurotrophic factor concentrations and the risk of cardiovascular disease in the community. J Am Heart Assoc. 2015;4:e001544.
Nijm J, Kristenson M, Olsson AG, Jonasson L. Impaired cortisol response to acute stressors in patients with coronary disease. Implications for inflammatory activity. J Intern Med. 2007;262:375–84.
Mahmood Z, Davidsson A, Olsson E, Leanderson P, Lundberg AK, Jonasson L. The effect of acute exercise on interleukin-6 and hypothalamic-pituitary-adrenal axis responses in patients with coronary artery disease. Sci Rep. 2020;10:21390.
O’Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biological Psychiatry. 2007;62:1208–16.
Husain MM, Rush AJ, Fink M, Knapp R, Petrides G, Rummans T, et al. Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report. J Clin Psychiatry. 2004;65:485–91.
Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475:91–5.
Pearson S, Schmidt M, Patton G, Dwyer T, Blizzard L, Otahal P, et al. Depression and insulin resistance: cross-sectional associations in young adults. Diabetes Care. 2010;33:1128–33.
Rethorst CD, Greer TL, Toups MS, Bernstein I, Carmody TJ, Trivedi MH. IL-1β and BDNF are associated with improvement in hypersomnia but not insomnia following exercise in major depressive disorder. Transl Psychiatry. 2015;5:e611.
Szuhany KL, Otto MW. Efficacy evaluation of exercise as an augmentation strategy to brief behavioral activation treatment for depression: a randomized pilot trial. Cogn Behav Ther. 2020;49:228–41.