Olivia Norrell

Background: Depression is a debilitating mental health disorder that affects approximately 280 million people worldwide.¹ Causes of depression are multifactorial, but are linked to stress, socioeconomic status, and imbalances of neurotransmitters in key areas of the brain: the prefrontal cortex and hippocampus.^1,2 Current treatments consist of cognitive behavioral therapy as well as antidepressant medications such as SSRIs, SNRIs, MAOIs, and tricyclic antidepressants.^1,3 However, depression can be elusive to current treatment options. Exercise is a known alternative to alleviate depressive symptoms.^1,2 The mechanisms by which exercise ameliorates depression are studied here and provide promising future therapeutic options for those with depression.

Objective: This review serves to identify key metabolites produced during exercise, their neuroprotective mechanisms, and their application as alternatives for treatment-resistant depression. Key metabolites include irisin, lactate, and kynurenine aminotransferase.

Search Methods: Articles were sourced from the PubMed database from 2017 to 2025 using MeSH terms “Exercise,” “Depression,” “Myokines,” and keywords “Irisin,” “Lactate,” and “Kynurenine”.

Results: A study on human prefrontal cortex samples with major depressive disorder (MDD) and major depressive disorder with psychotic features (MDD-P) identified a significant decrease in FNDC5 mRNA expression, a protein from which the myokine irisin is derived.⁴ Irisin has been linked to an upregulation of brain-derived neurotrophic factor (BDNF) which promotes neurogenesis and synaptogenesis, both of which may help prevent depression.⁵ This same study used mouse models of depression and found that depressed mice had increased feelings of helplessness and correspondingly reduced FNDC5 mRNA levels in the frontal cortex.⁴ Together, these findings show a decrease in irisin in depression models. Alternatively, a study on exercised rats found an increase in spatial memory, learning, and locomotion with a decrease in anxiety, all of which are associated with a reduction in depressive symptoms.⁶ qRT-PCR of the rat’s hippocampi found a significant increase in mRNA concentrations of PGC1α, FNDC5, and BDNF.⁶ A separate study on mice found that subcutaneous irisin injections had anxiolytic and antidepressive effects.⁷ qRT-PCR showed that gene expression of FNDC5 and PGC1α were also significantly increased in the hippocampus and prefrontal cortex of these mice.⁷ Another study on exercised mice showed an increase in spatial learning and memory formation, both signs of a healthy hippocampus, in connection to the lactate/SIRT1/BDNF pathway.⁸ In this study, mice were also injected with lactate and were found to have a significant increase in BDNF expression.⁸ SIRT1 knockdown also exposed a direct connection to BDNF expression.⁸ Further study using primary neurons and sirtinol found that SIRT1 induction of BDNF is PGC1α/FNDC5 dependent.⁸ Finally, a 12-week exercise study on human males found significantly increased kynurenine aminotransferase levels via muscle biopsies and qRT-PCR.⁹ Kynurenine aminotransferase converts kynurenine to kynurenic acid which cannot cross the blood-brain barrier (BBB).⁹ The alternative is a neurotoxic pathway that creates metabolites capable of crossing the BBB.⁹  

Conclusion: Overall, exercise may alleviate depression through upregulating the production of the neuroprotective metabolites irisin, lactate, and kynurenine aminotransferase. Irisin and lactate exert their positive effects through upregulating BDNF while kynurenine aminotransferase decreases the formation of neurotoxic metabolites. Additionally, irisin and lactate offer promising injectable therapeutic options in the treatment of depression.^7,8,10 Further studies are needed to determine efficacy of injectable exercise metabolites in humans, differences in male and female response to treatment, and the exact mechanism by which BDNF ameliorates depression.

Works Cited:

1. Alizadeh Pahlavani H. Possible role of exercise therapy on depression: Effector neurotransmitters as key players. Behav Brain Res. 2024;459:114791. doi:10.1016/j.bbr.2023.114791
2. Nay K, Smiles WJ, Kaiser J, McAloon LM, Loh K, Galic S, Oakhill JS, Gundlach AL, Scott JW. Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders. International Journal of Molecular Sciences. 2021; 22(8):4052. https://doi.org/10.3390/ijms22084052
3. Wu D, Qu S, Sun H, et al. Unveiling the brain mechanism underlying depression: 12 Years of insights from bibliometric and visualization analysis. Brain Res Bull. Published online February 11, 2025. doi:10.1016/j.brainresbull.2025.111246
4. Lima-Filho R, Fortuna JS, Cozachenco D, et al. Brain FNDC5/Irisin Expression in Patients and Mouse Models of Major Depression. eNeuro. 2023;10(2):ENEURO.0256-22.2023. Published 2023 Feb 13. doi:10.1523/ENEURO.0256-22.2023
5. Paoletti I, Coccurello R. Irisin: A Multifaceted Hormone Bridging Exercise and Disease Pathophysiology. Int J Mol Sci. 2024;25(24):13480. Published 2024 Dec 16. doi:10.3390/ijms252413480
6. Belviranlı M, Okudan N. Exercise Training Protects Against Aging-Induced Cognitive Dysfunction via Activation of the Hippocampal PGC-1α/FNDC5/BDNF Pathway. Neuromolecular Med. 2018;20(3):386-400. doi:10.1007/s12017-018-8500-3
7. Pignataro P, Dicarlo M, Suriano C, et al. Once-Daily Subcutaneous Irisin Administration Mitigates Depression- and Anxiety-like Behavior in Young Mice. Int J Mol Sci. 2023;24(7):6715. Published 2023 Apr 4. doi:10.3390/ijms24076715
8. El Hayek L, Khalifeh M, Zibara V, et al. Lactate Mediates the Effects of Exercise on Learning and Memory through SIRT1-Dependent Activation of Hippocampal Brain-Derived Neurotrophic Factor (BDNF). J Neurosci. 2019;39(13):2369-2382. doi:10.1523/JNEUROSCI.1661-18.2019
9. Allison DJ, Nederveen JP, Snijders T, et al. Exercise training impacts skeletal muscle gene expression related to the kynurenine pathway. Am J Physiol Cell Physiol. 2019;316(3):C444-C448. doi:10.1152/ajpcell.00448.2018
10. Liu Y, Fu X, Zhao X, Cui R, Yang W. The role of exercise-related FNDC5/irisin in depression. Front Pharmacol. 2024;15:1461995. Published 2024 Oct 17. doi:10.3389/fphar.2024.1461995