Research Progress on Comorbid Depression in Epilepsy
DOI:
https://doi.org/10.71204/bxrffv91Keywords:
Epilepsy, Depression, Comorbidity, PathogenesisAbstract
Comorbid depression in epilepsy is a prevalent and severe clinical condition that significantly increases the psychosocial burden of patients. In recent years, with advances in research on its pathological mechanisms, the core biological processes underlying comorbid depression in epilepsy have become increasingly clarified. Its pathogenesis involves multiple pathways, including neurotransmitter imbalance, inflammation, genetic variations, and neuroendocrine abnormalities. This review summarizes the core pathological mechanisms of comorbid depression in epilepsy from four perspectives: neurotransmission, neuroendocrinology, hippocampal structure, and neuroinflammation, aiming to provide theoretical support for clinical diagnosis and treatment.
References
Aljafen, B. N., Alneseyan, R., Muayqil, T., et al. (2024). Evaluating the prevalence and risk factors for depression in patients with temporal lobe epilepsy with hippocampal sclerosis: A cross-sectional multicenter study. Epilepsy & Behavior, 154, 109782. DOI: https://doi.org/10.1016/j.yebeh.2024.109782
Bal-Price, A., & Brown, G. C. (2001). Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. Journal of Neuroscience, 21(17), 6480–6491. DOI: https://doi.org/10.1523/JNEUROSCI.21-17-06480.2001
Basu, T., Antonoudiou, P., Weiss, G. L., et al. (2022). Hypothalamic-pituitary-adrenal axis dysfunction worsens epilepsy outcomes and increases SUDEP risk. bioRxiv. https://doi.org/10.1101/2022.03.15.484525 DOI: https://doi.org/10.1101/2022.03.15.484525
Birioukova, L. M., van Luijtelaar, G., & Midzyanovskaya, I. S. (2024). D1-like and D2-like dopamine receptors in the rat prefrontal cortex: Impacts of genetic generalized epilepsies and social behavioral deficits. Receptors, 3(1), 36–57. DOI: https://doi.org/10.3390/receptors3010004
Bølling-Ladegaard, E., Dreier, J. W., Kessing, L. V., Budtz-Jørgensen, E., Lolk, K., & Christensen, J. (2023). Directionality of the association between epilepsy and depression: A nationwide register-based cohort study. Neurology, 100(9). https://doi.org/10.1212/WNL.0000000000201542 DOI: https://doi.org/10.1212/WNL.0000000000201542
Bozzi, Y., & Borrelli, E. (2013). The role of dopamine signaling in epileptogenesis. Frontiers in Cellular Neuroscience, 7, 1–12. DOI: https://doi.org/10.3389/fncel.2013.00157
Brodovskaya, A., & Kapur, J. (2021). Anticonvulsant dopamine type 2 receptor agonist activates inhibitory parvalbumin interneurons. Epilepsia, 62(9), 147-152. DOI: https://doi.org/10.1111/epi.17004
Cai, L., He, Q., Luo, H., et al. (2023). Is depression in patients with temporal lobe epilepsy related to hippocampal sclerosis? A meta-analysis. Clinical Neurology and Neurosurgery, 225, 107602. DOI: https://doi.org/10.1016/j.clineuro.2023.107602
Chen, X., Zhang, K., Li, Y., Wang, C., Lou, H., & Yu, S. (2025). Stress induces behavioral disorders by promoting microglial phagocytosis via decreasing neuronal Dkk3. Molecular Psychiatry, 30(12), 5731–5748. DOI: https://doi.org/10.1038/s41380-025-03314-4
Choy, M., Dadgar-Kiani, E., Cron, G. O., et al. (2022). Repeated hippocampal seizures lead to brain-wide reorganization of circuits and seizure propagation pathways. Neuron, 110(2), 221–236. DOI: https://doi.org/10.1016/j.neuron.2021.10.010
de Kloet, E. R. (2022). Brain mineralocorticoid and glucocorticoid receptor balance in neuroendocrine regulation and stress-related psychiatric etiopathologies. Current Opinion in Endocrine and Metabolic Research, 24, 100352. DOI: https://doi.org/10.1016/j.coemr.2022.100352
De Luca, P., Mele, M., Tanqueiro, S., et al. (2025). Synaptic accumulation of GluN2B-containing NMDA receptors mediates the effects of BDNF-TrkB signalling on synaptic plasticity and in hyperexcitability during status epilepticus. Journal of Biomedical Science, 32(1), 82. DOI: https://doi.org/10.1186/s12929-025-01164-4
Erritzoe, D., Godlewska, B. R., Rizzo, G., et al. (2023). Brain serotonin release is reduced in patients with depression: A [11C] Cimbi-36 positron emission tomography study with a d-amphetamine challenge. Biological Psychiatry, 93(12), 1089–1098. DOI: https://doi.org/10.1016/j.biopsych.2022.10.012
Fang, W., Chen, S., Xia, X., et al. (2024). Interictal interleukin-6 and tumor necrosis factor α levels are associated with seizure recurrence in adults with epilepsy. Epilepsy & Behavior, 155, 109786. DOI: https://doi.org/10.1016/j.yebeh.2024.109786
Ferreira, R., Xapelli, S., Santos, T., et al. (2010). Neuropeptide Y modulation of interleukin-1β (IL-1β)-induced nitric oxide production in microglia. Journal of Biological Chemistry, 285(53), 41921–41934. DOI: https://doi.org/10.1074/jbc.M110.164020
Galvis-Montes, D. S., van Loo, K. M. J., van Waardenberg, A. J., et al. (2023). Highly dynamic inflammatory and excitability transcriptional profiles in hippocampal CA1 following status epilepticus. Scientific Reports, 13(1), 22187. DOI: https://doi.org/10.1038/s41598-023-49310-y
González-Arias, C., Sánchez-Ruiz, A., Esparza, J., et al. (2023). Dysfunctional serotonergic neuron-astrocyte signaling in depressive-like states. Molecular Psychiatry, 28(9), 3856–3873. DOI: https://doi.org/10.1038/s41380-023-02269-8
Gu, S., Xu, D., Huang, J., Zhou, X., Liu, Y., & Zhang, Z. (2025). Photoelectrochemical biosensor with single atom sites for norepinephrine sensing and brain region synergy in epilepsy. Nature Communications, 16(1), 4765. DOI: https://doi.org/10.1038/s41467-025-60148-y
Gulyaeva, N. V. (2021). Stress-associated molecular and cellular hippocampal mechanisms common for epilepsy and comorbid depressive disorders. Biochemistry Moscow, 86(6), 641–656. DOI: https://doi.org/10.1134/S0006297921060031
Gunaydin, L. A., Grosenick, L., Finkelstein, J. C., et al. (2014). Natural neural projection dynamics underlying social behavior. Cell, 157(7), 1535–1551. DOI: https://doi.org/10.1016/j.cell.2014.05.017
Han, K., Wang, Q., Wang, C., et al. (2018). Ghrelin improves pilocarpine-induced cerebral cortex inflammation in epileptic rats by inhibiting NF-κB and TNF-α. Molecular Medicine Reports, 18, 3563-3568. DOI: https://doi.org/10.3892/mmr.2018.9381
Han, Y. M., Kim, M. S., Jo, J., et al. (2021). Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior. Molecular Psychiatry, 26(9), 5087–5096. DOI: https://doi.org/10.1038/s41380-021-01016-1
Harris, A. P., Holmes, M. C., de Kloet, E. R., Chapman, K. E., & Seckl, J. R. (2013). Mineralocorticoid and glucocorticoid receptor balance in control of HPA axis and behaviour. Psychoneuroendocrinology, 38(5), 648–658. DOI: https://doi.org/10.1016/j.psyneuen.2012.08.007
Hyder, S. K., Lazarini-Lopes, W., Toib, J., Williams, G., Sukharev, A., & Forcelli, P. A. (2025). Optogenetic stimulation of the dorsal striatum bidirectionally controls seizures. Proceedings of the National Academy of Sciences, 122(14), e2419178122. DOI: https://doi.org/10.1073/pnas.2419178122
Jin, K., Lu, J., Yu, Z., et al. (2020). Linking peripheral IL-6, IL-1β and hypocretin-1 with cognitive impairment from major depression. Journal of Affective Disorders, 277, 204–211. DOI: https://doi.org/10.1016/j.jad.2020.08.024
Joëls, M. (2001). Corticosteroid actions in the hippocampus. Journal of Neuroendocrinology, 13(8), 657–669. DOI: https://doi.org/10.1046/j.1365-2826.2001.00688.x
Kaczorowska, M., Czekuć-Kryśkiewicz, E., Dądalski, M., & Kotulska, K. (2023). Immunological markers of drug resistant epilepsy and its response to immunomodulatory therapy with ACTH in children. Folia Neuropathologica, 61(4), 360–370. DOI: https://doi.org/10.5114/fn.2023.131662
Kim, Y. K., Na, K. S., Myint, A. M., & Leonard, B. E. (2016). The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 64, 277–284. DOI: https://doi.org/10.1016/j.pnpbp.2015.06.008
Kumar, U., Medel-Matus, J., Redwine, H. M., et al. (2016). Effects of selective serotonin and norepinephrine reuptake inhibitors on depressive- and impulsive-like behaviors and on monoamine transmission in experimental temporal lobe epilepsy. Epilepsia, 57(3), 506–515. DOI: https://doi.org/10.1111/epi.13321
Lai, S., Zhang, L., Tu, X., et al. (2024). Termination of convulsion seizures by destabilizing and perturbing seizure memory engrams. Science Advances, 10(12), eadk9484. DOI: https://doi.org/10.1126/sciadv.adk9484
Leschik, J., Gentile, A., Cicek, C., et al. (2022). Brain-derived neurotrophic factor expression in serotonergic neurons improves stress resilience and promotes adult hippocampal neurogenesis. Progress in Neurobiology, 217, 102333. DOI: https://doi.org/10.1016/j.pneurobio.2022.102333
Li, B., Sun, Q., Ding, F., et al. (2025). Anti-seizure effects of norepinephrine-induced free fatty acid release. Cell Metabolism, 37(1), 223–238. DOI: https://doi.org/10.1016/j.cmet.2024.10.011
Li, R., Geng, R., Xu, X., Wang, C., Tao, Y., & Dai, Y. (2025). Clinical efficacy of lacosamide monotherapy in children with focal epilepsy and comorbid depression and its impact on peripheral blood interleukin-6 and serotonin expression. Epilepsy Research, 216, 107587. DOI: https://doi.org/10.1016/j.eplepsyres.2025.107587
Li, X. Y., Zhang, S. Y., Hong, Y. Z., et al. (2024). TGR5-mediated lateral hypothalamus-dCA3-dorsolateral septum circuit regulates depressive-like behavior in male mice. Neuron, 112(11), 1795–1814. DOI: https://doi.org/10.1016/j.neuron.2024.02.019
Li, Y., Tian, J., Wei, J., et al. (2026). Hippocampal chandelier cells modulate seizure susceptibility and severity. Advanced Science, 13(4), e01066. DOI: https://doi.org/10.1002/advs.202501066
Lin, Y. L., Wei, C. W., Lerdall, T. A., Nhieu, J., & Wei, L. N. (2021). Crabp1 modulates HPA axis homeostasis and anxiety-like behaviors by altering FKBP5 expression. International Journal of Molecular Sciences, 22(22), 12240. h DOI: https://doi.org/10.3390/ijms222212240
Linsen, F., Broeder, C., Sep, M. S. C., et al. (2023). Glucocorticoid receptor (GR) antagonism as disease-modifying treatment for MDD with childhood trauma: Protocol of the RESET-medication randomized controlled trial. BMC Psychiatry, 23(1), 331. DOI: https://doi.org/10.1186/s12888-023-04830-9
Lisgaras, C. P., Oliva, A., McKenzie, S., LaFrancois, J., Siegelbaum, S. A., & Scharfman, H. E. (2023). Hippocampal area CA2 controls seizure dynamics, interictal EEG abnormalities and social comorbidity in mouse models of temporal lobe epilepsy. bioRxiv. https://doi.org/10.1101/2023.01.15.524149 DOI: https://doi.org/10.1101/2023.01.15.524149
Ma, X., Shin, J. W., Cho, J. H., Han, S. W., & Kim, D. H. (2024). IL-6 expression-suppressing Lactobacillus reuteri strains alleviate gut microbiota-induced anxiety and depression in mice. Letters in Applied Microbiology, 77(1), 144. DOI: https://doi.org/10.1093/lambio/ovad144
Martino, P. L., Pulopulos, M. M., Canto, C. D., Dupanlou, M. L., Rubio, S. M., & Bonet, J. L. (2025). High levels of TNF-α are associated with symptoms of depression in health professionals at a hospital. Spanish Journal of Psychiatry and Mental Health, 18(3), 169–173. DOI: https://doi.org/10.1016/j.rpsm.2021.10.002
Medel-Matus, J., Shin, D., Sankar, R., & Mazarati, A. (2017). Inherent vulnerabilities in monoaminergic pathways predict the emergence of depressive impairments in an animal model of chronic epilepsy. Epilepsia, 58(8), 116-121. DOI: https://doi.org/10.1111/epi.13822
Pereira, G. C., Piton, E., Ramanzini, G., Camargo, L. F. M., & Bochi, G. V. (2022). Microglia and HPA axis in depression: An overview of participation and relationship. Journal of Neuroendocrinology, 34(7), e13289.
Prinz, M., Jung, S., & Priller, J. (2019). Microglia biology: One century of evolving concepts. Cell, 179(2), 292–311. DOI: https://doi.org/10.1016/j.cell.2019.08.053
Sălcudean, A., Bodo, C. R., Popovici, R. A., et al. (2025). Neuroinflammation—A crucial factor in the pathophysiology of depression—A comprehensive review. Biomolecules, 15(4), 502. DOI: https://doi.org/10.3390/biom15040502
Schönhoff, K., von Rüden, E. L., Koska, I., Seiffert, I., & Potschka, H. (2021). Hippocampal and septal 5-HT1A receptor expression in two rat models of temporal lobe epilepsy. Neuroscience, 465, 219–230. DOI: https://doi.org/10.1016/j.neuroscience.2021.03.026
Shen, S., Liang, L., Shi, T., et al. (2025). Microglia-derived interleukin-6 triggers astrocyte apoptosis in the hippocampus and mediates depression-like behavior. Advanced Science, 12(11), 2412556. DOI: https://doi.org/10.1002/advs.202412556
Song, N., Liu, Z., Gao, Y., Lu, S., Yang, S., & Yuan, C. (2024). NAc-DBS corrects depression-like behaviors in CUMS mouse model via disinhibition of DA neurons in the VTA. Molecular Psychiatry, 29(5), 1550–1566. DOI: https://doi.org/10.1038/s41380-024-02476-x
Sun, S., Han, Y., Liu, X., et al. (2024). Reduced serum neurotrophic factors and monoamine neurotransmitters in epilepsy patients with comorbid depression. Frontiers in Neurology, 15, 1480854. DOI: https://doi.org/10.3389/fneur.2024.1480854
Tarwani, R. S., Awathale, S. N., Goyal, S. N., Sherikar, A. K., Bawane, P. P., & Nakhate, K. T. (2025). Bempedoic acid mitigates BCG-induced depression in mice by modulating TNF-α/NF-κB signaling and restoring brain serotonin contents. Brain Research, 1869, 150031. DOI: https://doi.org/10.1016/j.brainres.2025.150031
Tian, S., Liu, M., Yang, C., et al. (2024). The impact of ACTH levels on neurotransmitters and antioxidants in patients with major depressive disorder: A novel investigation. Journal of Affective Disorders, 365, 587–596. DOI: https://doi.org/10.1016/j.jad.2024.08.142
Tugba, E. K., Medine, G. I. O., Ozlem, A., Deniz, K., & Filiz, O. Y. (2022). Prolongation of absence seizures and changes in serotonergic and dopaminergic neurotransmission by nigrostriatal pathway degeneration in genetic absence epilepsy rats. Pharmacology Biochemistry and Behavior, 213, 173317. DOI: https://doi.org/10.1016/j.pbb.2021.173317
Van Heesch, F., Prins, J., Korte-Bouws, G. A. H., et al. (2013). Systemic tumor necrosis factor-alpha decreases brain stimulation reward and increases metabolites of serotonin and dopamine in the nucleus accumbens of mice. Behavioural Brain Research, 253, 191–195. DOI: https://doi.org/10.1016/j.bbr.2013.07.038
Vieira, É. L. M., de Oliveira, G. N. M., Lessa, J. M. K., et al. (2015). Interleukin-1β plasma levels are associated with depression in temporal lobe epilepsy. Epilepsy & Behavior, 53, 131–134. DOI: https://doi.org/10.1016/j.yebeh.2015.09.035
Visoná De Figueiredo, N. S., Jardim, A. P., Mazetto, L., et al. (2021). Do hippocampal neurons really count for comorbid depression in patients with mesial temporal lobe epilepsy and hippocampal sclerosis? A histopathological study. Frontiers in Integrative Neuroscience, 15, 747237. DOI: https://doi.org/10.3389/fnint.2021.747237
Wang, C., Zhang, N., Shao, Y., et al. (2025). Pathway-selective 5-HT1AR agonist as a rapid antidepressant strategy. Cell, 188(25), 7222–7237. DOI: https://doi.org/10.1016/j.cell.2025.10.022
Wang, W., Wang, D., Zhao, D., et al. (2024). Dorsal raphe dopaminergic neurons target CaMKII+ neurons in dorsal bed nucleus of the stria terminalis for mediating depression-related behaviors. Translational Psychiatry, 14(1), 408. DOI: https://doi.org/10.1038/s41398-024-03093-6
Wei, Y., Chen, T., Bosco, D. B., et al. (2021). The complement C3-C3AR pathway mediates microglia-astrocyte interaction following status epilepticus. Glia, 69(5), 1155–1169. DOI: https://doi.org/10.1002/glia.23955
Whitebirch, A. C., LaFrancois, J. J., Jain, S., et al. (2022). Enhanced excitability of the hippocampal CA2 region and its contribution to seizure activity in a mouse model of temporal lobe epilepsy. Neuron, 110(19), 3121–3138. DOI: https://doi.org/10.1016/j.neuron.2022.07.020
Wu, Y., Tang, Y., Mei, Y., et al. (2026). Decoding depression: Stress-derived formaldehyde initiates depressive symptoms in mouse and human. Molecular Psychiatry, 31, 2868–2879 DOI: https://doi.org/10.1038/s41380-025-03405-2
Xiao, H., Cao, Y., Lizano, P., et al. (2024). Interleukin-1β moderates the relationships between middle frontal-mACC/insular connectivity and depressive symptoms in bipolar II depression. Brain, Behavior, and Immunity, 120, 44–53. DOI: https://doi.org/10.1016/j.bbi.2024.05.029
Xin, Q., Wang, J., Zheng, J., et al. (2024). Neuron-astrocyte coupling in lateral habenula mediates depressive-like behaviors. bioRxiv. https://doi.org/10.1101/2024.11.03.621722 DOI: https://doi.org/10.1101/2024.11.03.621722
Xu, Q., Xu, X., Gu, L., et al. (2025). An efficient neural network of cooperating serotonergic and noradrenergic neurons in modulating sudden unexpected death in epilepsy. International Journal of Biological Sciences, 21(14), 6452–6481. DOI: https://doi.org/10.7150/ijbs.114659
Yu, J., Cheng, Y., Cui, Y., et al. (2022). Anti-seizure and neuronal protective effects of irisin in kainic acid-induced chronic epilepsy model with spontaneous seizures. Neuroscience Bulletin, 38(11), 1347–1364. DOI: https://doi.org/10.1007/s12264-022-00914-w
Yu, Y. M., Jin, G. H., Zhong, C., et al. (2024). Exploring the role of interleukin-6 receptor blockade in epilepsy and associated neuropsychiatric conditions through a mendelian randomization study. World J Psychiatry, 14(8),1244–1253. DOI: https://doi.org/10.5498/wjp.v14.i8.1244
Zapukhliak, O., Netsyk, O., Romanov, A., et al. (2021). Mecamylamine inhibits seizure-like activity in CA1-CA3 hippocampus through antagonism to nicotinic receptors. PLOS ONE, 16(3), e0240074. DOI: https://doi.org/10.1371/journal.pone.0240074
Zhang, K., Wang, F., Zhai, M., et al. (2023). Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression. Theranostics, 13(3), 1059–1075. DOI: https://doi.org/10.7150/thno.81067
Zhu, Z. A., Li, Y. Y., Xu, J., et al. (2023). CDKL5 deficiency in adult glutamatergic neurons alters synaptic activity and causes spontaneous seizures via TrkB signaling. Cell Reports, 42(10), 113202. DOI: https://doi.org/10.1016/j.celrep.2023.113202
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Xiangfei Meng, Shaoqun Luan, Xin Wu, Sanhui Xu, Ming Zhou (Author)
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles published in this journal are licensed under the Creative Commons Attribution 4.0 International License (CC BY 4.0). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are properly credited. Authors retain copyright of their work, and readers are free to copy, share, adapt, and build upon the material for any purpose, including commercial use, as long as appropriate attribution is given.
How to Cite
