Effects of serum brain derived neurotrophic factor on exercise augmentation treatment of depression.
Open accessAbstract
Background Brain Derived Neurotrophic Factor (BDNF) has potential as a biomarker of depression treatment because serum BDNF in depressed human subjects is decreased and normalizes with treatment. The relationship between serum BDNF and exercise treatment of depression is not known. The Treatment with Exercise Augmentation for Depression (TREAD) study examined dosed exercise augmentation treatment of partial responders to antidepressants. Serum BDNF in TREAD subjects was analyzed to understand its relationship with exercise training.Methods Subjects were randomized to high (16 kcal/kg/week or KKW) or low (4 KKW) energy expenditure exercise over 12 weeks. Actual kcal/week expended and IDS-C scores were collected weekly. One hundred four subjects in TREAD provided baseline blood samples; a subset of 70 subjects also provided week 12 samples. Serum BDNF was determined using ELISA. Correlations were examined between change in BDNF and 1) mean kcal/week expended, and 2) change in IDS-C score. Mixed-effects ANOVA examined the effect of baseline BDNF on outcome.Results Resting serum BDNF was stable and did not correlate with energy expenditure (p = 0.15) or IDS-C improvement (p = 0.89). Subjects entering the study with higher BDNF improved more rapidly on the IDS-C (p = 0.003).Limitations Serum may not be the most sensitive blood fraction in which to measure BDNF change. Pre-treatment with medication may mask exercise effect on BDNF.Conclusions These results suggest that change in serum BDNF does not reflect efficacy of exercise augmentation treatment of MDD. Instead BDNF may function as an augmentation moderator. Pre-treatments that raise BDNF may improve the efficacy of exercise treatment of MDD.
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Antidepressant medications may be useful for priming patients with MDD to respond better to a subsequent AE intervention.
“This suggests that antidepressant medications may be useful for ‘priming’ patients with MDD to respond better to a subsequent AE intervention (Toups et al., 2011).”
From Aerobic Exercise as a Tool to Improve Hippocampal Plasticity and Function in Humans: Practical Implications for Mental Health Treatment (2016) · cites this paper as Toups et al., 2011
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“Acute exercise has consistently been shown to increase peripheral BDNF levels in healthy (104–106), those with MDD (107, 108), and elderly (109) individuals, whereas the long-term effects of exercise on resting BDNF concentrations have been mixed (64, 110).”
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“Physical activity may prevent the development of depression during the follow up according prospective studies (23, 100, 102), can reduce de the risk of anxiety (110) and may enhance the cognitive performance (97) contributing with antidepressant drugs and/or cognitivebehavioral therapy (111).”
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Salehi, I., Hosseini, S. M., Haghighi, M., Jahangard, L., Bajoghli, H., Gerber, M., Pühse, U., Holsboer‐Trachsler, E., & Brand, S. (2016) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2016.01.012 · Cited by 49 · see citing works
Szuhany, K. L., & Otto, M. W. (2019) · Cognitive Behaviour Therapy · doi:10.1080/16506073.2019.1641145 · Cited by 46 · see citing works
“…that the intervention yielded a completion rate of 68%, similar to other studies of exercise (e.g. 53–75%; Chalder et al., 2012; Smits et al., 2016; Toups et al., 2011) and brief BA (e.g. 76–81%; Hopko et al., 2011; Moshier & Otto, 2017) as well as clinical trials of antidepressants (74%;…”
ResultSalehi, I., Hosseini, S. M., Haghighi, M., Jahangard, L., Bajoghli, H., Gerber, M., Pühse, U., Kirov, R., Holsboer‐Trachsler, E., & Brand, S. (2014) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2014.06.018 · Cited by 43 · see citing works
“Toups et al. (2011) assessed 104 patients suffering from MDD and found no association between BDNF and the efficacy of an exercise augmentation treatment.”
BackgroundRetractedRelationship of depression and sleep quality, diseases and general characteristics
Jiang, Y., Jiang, T., Xu, L., & Lan, D. (2022) · World Journal of Psychiatry · doi:10.5498/wjp.v12.i5.722 · Cited by 45 · see citing works
Relationships between serum BDNF and the antidepressant effect of acute exercise in depressed women
Meyer, J. D., Koltyn, K. F., Stegner, A. J., Kim, J., & Cook, D. B. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.09.022 · Cited by 40 · see citing works
Feter, N., Alt, R., Dias, M., & Rombaldi, A. J. (2019) · Science & Sports · doi:10.1016/j.scispo.2019.02.001 · Cited by 40 · see citing works
Babaei, A., Nourshahi, M., Fani, M., Entezari, Z., Jameie, S. B., & Haghparast, A. (2021) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2021.02.006 · Cited by 37 · see citing works
Rethorst, C. D., GREER, T. L., Toups, M. S. P., Bernstein, I. H., Carmody, T. J., & Trivedi, M. H. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.104 · Cited by 36 · see citing works
Prediction of treatment outcomes to exercise in patients with non-remitted Major Depressive Disorder
Rethorst, C. D., South, C., Rush, A., Greer, T. L., & Trivedi, M. H. (2017) · Depression and Anxiety · doi:10.1002/da.22670 · Cited by 35 · see citing works
“Our previous analyses of the TREAD data found each were associated with treatment response (Rethorst, Toups, et al., 2013; Toups et al., 2011).”
MethodRethorst, C. D., Tu, J., Carmody, T. J., Greer, T. L., & Trivedi, M. H. (2016) · Journal of Affective Disorders · doi:10.1016/j.jad.2016.01.052 · Cited by 34 · see citing works
“Previous analyses indicate that hypersomnia and elevations in BMI are associated with better treatment outcomes to exercise (Rethorst et al., 2013; Toups et al., 2011).”
BackgroundEnette, L., Vogel, T., Fanon, J. L., & Lang, P. O. (2017) · Rejuvenation Research · doi:10.1089/rej.2016.1886 · Cited by 34 · see citing works
“This reinforces the results reported by Toups et al., 72 that, improvement of depressive symptoms is not necessarily associated with specific changes in the BDNF level.”
Campos, C., Rocha, N., Lattari, E., Nardi, A. E., & Machado, S. E. D. C. (2017) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527315666161223142918 · Cited by 33 · see citing works
Schuch, F. B., da Silveira, L. E., de Zeni, T. C., da Silva, D. P., Wollenhaupt-Aguiar, B., Ferrari, P., Reischak-Oliveira, Á., & Kapczinski, F. P. (2015) · Psychiatry Research · doi:10.1016/j.psychres.2015.07.072 · Cited by 32 · see citing works
“based on previous literature, were tested: age, maximal oxygen consumption (VO2 max), Body Mass Index (BMI) (Toups et al., 2011; Schuch et al., 2014), and presence of manic-depressive episode (Fernandes et al.”
MethodInsulin resistance as a marker for the immune-metabolic subtype of depression
Brouwer, A., van Raalte, D. H., Lamers, F., Rutters, F., Elders, P. J. M., Someren, E. J. W. V., Snoek, F. J., Beekman, A. T. F., & Bremmer, M. A. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.08.151 · Cited by 32 · see citing works
Optimizing the exercise prescription for depression: the search for biomarkers of response
Medina, J. L., Jacquart, J., & Smits, J. A. J. (2015) · Current Opinion in Psychology · doi:10.1016/j.copsyc.2015.02.003 · Cited by 29 · see citing works
Effect of Exercise on Cognition in Neurodegenerative Disorders: An Approach Focusing on BDNF
Gökçe, E., Güneş, E., & Nalçacı, E. (2019) · Nöro Psikiyatri Arşivi · doi:10.29399/npa.23369 · Cited by 28 · see citing works
Callaghan, C. K., Rouine, J., & O’Mara, S. M. (2017) · Physiology & Behavior · doi:10.1016/j.physbeh.2017.07.018 · Cited by 24 · see citing works
Affect Following First Exercise Session as a Predictor of Treatment Response in Depression
Suterwala, A. M., Rethorst, C. D., Carmody, T. J., Greer, T. L., Grannemann, B. D., Jha, M. K., & Trivedi, M. H. (2016) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.15m10104 · Cited by 22 · see citing works
Sundquist, K., Memon, A. A., Palmér, K., Sundquist, J., & Wang, X. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155646 · Cited by 21 · see citing works
Popel, N., Kennedy, K. G., Fıksenbaum, L., Mitchell, R. H. B., MacIntosh, B. J., & Goldstein, B. I. (2020) · Bipolar Disorders · doi:10.1111/bdi.12993 · Cited by 16 · see citing works
Rahman, M. S., Millischer, V., Zeebari, Z., Forsell, Y., & Lavebratt, C. (2017) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2017.05.007 · Cited by 16 · see citing works
“Accordingly, the relationship between antidepressive effect of PE and BDNF level se ms consistent in animal models but inconsistent in humans (Russo-Neustadt and Chen, 2005; Toups et al., 2011).”
ResultBlood-Based Biomarkers in Depression: Emerging Themes in Clinical Research
Uddin, M. (2014) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-014-0108-1 · Cited by 15 · see citing works
“Although there was no observed effect of exercise on BDNF, the authors speculated that pretreatments that raise resting BDNF levels might improve the efficacy of exercise treatment for MDD [19].”
BackgroundJaehne, E. J., Kent, J. N., Lam, N., Schonfeld, L., Spiers, J. G., Begni, V., Rosa, F. D., Riva, M. A., & van den Buuse, M. (2022) · Developmental Psychobiology · doi:10.1002/dev.22347 · Cited by 12 · see citing works
Silva, R. C., Meattini, M., Perusi, G., Carletto, S., Bortolomasi, M., Gennarelli, M., Baune, B. T., & Minelli, A. (2025) · Psychological Medicine · doi:10.1017/s0033291725100743 · Cited by 16 · see citing works
“In the neurotrophic domain, higher baseline concentrations of BDNF were associated with a faster symptom improvement in patients partially responding to anti-depressants who received adjunctive exercise (Toups et al., 2011).”
Lamego, M. K., Moura, A. D. S., Paes, F., Rocha, N., Filho, A. S. S., Lattari, E., Rimes, R., Manochio, J., Budde, H., Wegner, M., et al. (2015) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527315666151111125402 · Cited by 11 · see citing works
Nasstasia, Y., Baker, A., Halpin, S. A., Lewin, T. J., Hides, L. M., Kelly, B. J., & Callister, R. (2016) · The Journal of Nervous and Mental Disease · doi:10.1097/nmd.0000000000000611 · Cited by 10 · see citing works
“Exercise helps promote brain health, synaptic growth, and neurogenesis, particularly within the hippocampus, and facilitates monoamine neurotransmission not dissimilar to effects observed with antidepressant medication (Toups et al., 2011).”
BackgroundExercise and sleep - Review and future directions
Uchida, S., Shioda, K., Morita, Y., Kubota, C., Ganeko, M., & Takeda, N. (2012) · The Journal of Physical Fitness and Sports Medicine · doi:10.7600/jpfsm.1.317 · Cited by 9 · see citing works
Etxaniz‐Oses, J., Iriarte‐Yoller, N., Tous‐Espelosin, M., & Maldonado‐Martín, S. (2023) · F1000Research · doi:10.12688/f1000research.140970.1 · Cited by 8 · see citing works
Exercise for Mood and Anxiety Disorders
Szuhany, K. L., Smits, J. A. J., Asmundson, G. J. G., & Otto, M. W. (2014) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780199935291.013.20 · Cited by 8 · see citing works
Chen, C., Du, S., Shao, Q., Fu, X., Lin, J., Zhou, S. L., & Li, Y. (2024) · Journal of Bodywork and Movement Therapies · doi:10.1016/j.jbmt.2024.10.068 · Cited by 6 · see citing works
Shen, Z., Zhu, J.-H., Liu, B.-P., & Jia, C.-X. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.08.195 · Cited by 4 · see citing works
Etxaniz‐Oses, J., Iriarte‐Yoller, N., Tous‐Espelosin, M., & Maldonado‐Martín, S. (2024) · F1000Research · doi:10.12688/f1000research.140970.2 · Cited by 3 · see citing works
The Treatment with Exercise Augmentation for Depression (TREAD) study
Rethorst, C. D., Greer, T. L., & Trivedi, M. H. (2016) · Cambridge University Press eBooks · doi:10.1017/cbo9781316157565.008 · Cited by 3 · see citing works
Sundquist, K., Palmér, K., Memon, A. A., Sundquist, J., & Wang, X. (2020) · Mindfulness · doi:10.1007/s12671-020-01352-3 · Cited by 2 · see citing works
PSYCHOLOGICAL BENEFITS OF EXERCISE AND PHYSICAL ACTIVITY IN OLDER ADULTS
Dolenc, P., & Petrič, M. (2019) · Annales Kinesiologiae · doi:10.35469/ak.2018.167 · Cited by 2 · see citing works
“Therefore, this hypothesis suggests that PA can work in a similar way as anti-depressants, medications that can help relieve symptoms of depression (Toups et al., 2011).”
BackgroundTassone, V. K., Quesnel, D. A., Parkington, K. B., Rueda, A., Martin, J., Lee, G. H., Teixeira, A., deJonge, M. L., Lou, W. Y. W., Wiljer, D., et al. (2025) · PLoS ONE · doi:10.1371/journal.pone.0330848 · Cited by 1 · see citing works
Etxaniz‐Oses, J., Iriarte‐Yoller, N., Tous‐Espelosin, M., & Maldonado‐Martín, S. (2024) · F1000Research · doi:10.12688/f1000research.140970.4 · Cited by 1 · see citing works
Motivation and physical activity in individuals with severe mental illness
Farholm, A. (2017) · NORA - Norwegian Open Research Archives · Cited by 1 · see citing works
Exercise as an Adjunct to Treating Depression
Carson, R. (2015) · CRC Press eBooks · doi:10.1201/b19089-22
Rethorst, C. D. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-812605-9.00015-0
Gourgouvelis, J. (2017) · e-scholar@UOIT (University of Ontario Institute of Technology)
総合学科高校のカリキュラムと生徒の進路選択 : 何が「進学」と「就職」を決めるのか
小西, 尚. (2012) · Medical Entomology and Zoology
Exercise Effect on Mental Health in Isolating or Quarantining Adults
Chu, V., & Newman, D. G. (2023) · Aerospace Medicine and Human Performance · doi:10.3357/amhp.6073.2023
Etxaniz‐Oses, J., Iriarte‐Yoller, N., Tous‐Espelosin, M., & Maldonado‐Martín, S. (2024) · F1000Research · doi:10.12688/f1000research.140970.3
Etxaniz‐Oses, J., Iriarte‐Yoller, N., Tous‐Espelosin, M., & Maldonado‐Martín, S. (2024) · F1000Research · doi:10.12688/f1000research.140970.5
Etxaniz‐Oses, J., Iriarte‐Yoller, N., Tous‐Espelosin, M., & Maldonado‐Martín, S. (2025) · F1000Research · doi:10.12688/f1000research.140970.6
Etxaniz‐Oses, J., Iriarte‐Yoller, N., Tous‐Espelosin, M., & Maldonado‐Martín, S. (2026) · F1000Research · doi:10.12688/f1000research.140970.7
Etxaniz‐Oses, J., Iriarte‐Yoller, N., Tous‐Espelosin, M., & Maldonado‐Martín, S. (2026) · F1000Research · doi:10.12688/f1000research.140970.8
“…Oxford ’ s Evidence levels were 1b in six articles (Greer et al. , 2016; Mather et al. , 2002; Rethorst et al. , 2013a, 2016; Toups et al. , 2017; Trivedi et al. , 2011) and five 2b (Carta et al. , 2008; Greer et al. , 2014; Mota-Pereira et al. , 2011; Rethorst et al. , 2013b; Toups et al. , 2011).”
Influential
- Authors
- Toups, M. S. P., Greer, T. L., Kurian, B. T., Grannemann, B. D., Carmody, T. J., Huebinger, R., Rethorst, C., & Trivedi, M. H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Trivedi, Madhukar H.
- ORCID
- Venue
- Journal of Psychiatric Research
- Publisher
- Elsevier BV
- Published
- 2011-10
- Volume
- 45
- Issue
- 10
- Pages
- 1301-1306
- ISSN
- 0022-3956 (ISSN-L)
- PMC
- PMC9900870
- OpenAlex
- W2103491713
- Cited by
- 85
- References
- 30
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 7 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 4 · 2017: 9 · 2016: 12 · 2015: 7 · 2014: 8 · 2013: 1 · 2012: 8
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Psychiatric Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIMH (#5-R01-MH067692)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Physiology › Physical Activity and Health
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- brain-derived neurotrophic factor, serum BDNF, depression, major depressive disorder, energy expenditure, treatment moderators, biomarkers
- MeSH terms
- Adolescent, Adult, Aged, Combined Modality Therapy, Depression, Exercise Therapy, Female, Humans, Male, Middle Aged, Exercise, Treatment Outcome, Brain-Derived Neurotrophic Factor, Young Adult
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