- 1. Hunan University of Chinese Medicine, Changsha 410208, China;
- 2. Epilepsy Center, Hunan Brain Hospital, the Second People’s Hospital of Hunan Province, Changsha 410007, China;
LI Zhenguang,
Email: 405291204@qq.com
Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are highly comorbid in the pediatric population, with a comorbidity rate of ADHD among children with epilepsy ranging from 13% to 70% worldwide. The co-occurrence of epilepsy and ADHD can significantly exacerbate cognitive impairment, reduce quality of life and treatment adherence, and impose a heavy burden on families and society. To systematically review advances in the pathogenesis of this co-morbidity, this study searched high-quality clinical and basic research articles published between 2018 to 2026 in databases such as PubMed, Web of Science, and CNKI. The results indicate that the mechanisms underlying this comorbidity are complex and multifaceted, involving imbalances in neurotransmitter systems, shared genetic susceptibility factors, abnormalities in brain structure and functional networks, neuroinflammation and oxidative stress processes, as well as the synergistic interaction of multiple pathways such as the hypothalamic-pituitary-adrenal axis and mitochondrial dysfunction, ultimately leading to the disruption of the excitatory-inhibitory homeostasis of the central nervous system. This review integrates the pathogenesis, treatment strategies, and research controversies surrounding the co-occurrence of epilepsy and ADHD from multiple perspectives, aiming to provide a theoretical framework for precision diagnosis and treatment, early intervention, and future basic research.
Citation： WANG Qianxi, LI Zhenguang. Recent advances in research on the pathogenesis of co-occurring epilepsy and attention-deficit/hyperactivity disorder. Journal of Epilepsy, 2026, 12(5): 414-421. doi: 10.7507/2096-0247.202604014 Copy
Copyright ? the editorial department of Journal of Epilepsy of West China Medical Publisher. All rights reserved
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| 2. | Symonds JD, Elliott KS, Shetty J, et al. Early childhood epilepsies: Epidemiology, classification, aetiology, and socio-economic determinants[J]. Brain, 2021, 144(9): 2879-2891. |
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- 1. Karadag N, Shadrin AA, O’Connell KS, et al. Identification of novel genomic risk loci shared between common epilepsies and psychiatric disorders[J]. Brain, 2023, 146(8): 3392-3403.
- 2. Symonds JD, Elliott KS, Shetty J, et al. Early childhood epilepsies: Epidemiology, classification, aetiology, and socio-economic determinants[J]. Brain, 2021, 144(9): 2879-2891.
- 3. Ono KE, Bearden DJ, Lee SM, et al. Interventions for ADHD in children & adolescents with epilepsy: A review and decision tree to guide clinicians[J]. Epilepsy & Behavior, 2022, 135: 108872.
- 4. 王麗君, 張心怡, 劉曌. 兒童及青少年癲癇共患注意缺陷多動障礙的研究進展[J]. 兒科藥學雜志, 2025, 31(8): 53-57.Wang LJ, Zhang XY, Liu Z. Research progress on epilepsy comorbid with attention deficit hyperactivity disorder in children and adolescents[J]. Journal of Pediatric Pharmacy, 2025, 31(8): 53-57.
- 5. Yadav SK, Bhat AA, Hashem S, et al. Genetic variations influence brain changes in patients with attention-deficit hyperactivity disorder[J]. Translational Psychiatry, 2021, 11(1): 349.
- 6. 李娟, 姚寶珍. 癲癇共患注意缺陷多動障礙發病機制與治療的研究進展[J]. 山東醫藥, 2023, 63(3): 96-100.Li J, Yao BZ. Research progress on pathogenesis and treatment of epilepsy complicated with attention deficit hyperactivity disorder[J]. Shandong Medical Journal, 2023, 63(3): 96-100.
- 7. Fan HC, Chiang KL, Chang KH, et al. Epilepsy and attention deficit hyperactivity disorder: connection, chance, and challenges[J]. International Journal of Molecular Sciences, 2023, 24(6): 5270.
- 8. Ahlqvist VH, Dardani C, Madley-Dowd P, et al. Psychiatric comorbidities in epilepsy: population co-occurrence, genetic correlations and causal effects[J]. General Psychiatry, 2024, 37(1): e101201.
- 9. Uliel-Sibony S, Chernuha V, Tokatly Latzer I, et al. Epilepsy and attention-deficit/hyperactivity disorder in children and adolescents: an overview of etiology, prevalence, and treatment[J]. Frontiers in Human Neuroscience, 2023, 17: 1021605.
- 10. Park KJ, Kim MJ, Yum MS, et al. Clinical and neuropsychological characteristics of children with epilepsy and attention-deficit/hyperactivity disorder[J]. Seizure - European Journal of Epilepsy, 2021, 91: 325-331.
- 11. Dela pe?a I, Shen G, Shi WX. Droxidopa alters dopamine neuron and prefrontal cortex activity and improves attention-deficit/hyperactivity disorder-like behaviors in rats[J]. European Journal of Pharmacology, 2021, 892: 173826.
- 12. Carboni E. Adolescent stress differentially modifies dopamine and norepinephrine release in the medial prefrontal cortex of adult rats[J]. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2024, 134: 111055.
- 13. Inagaki R, Kita S, Niwa N, et al. Aberrant extracellular dopamine clearance in the prefrontal cortex exhibits ADHD‐like behavior in NCX3 heterozygous mice[J]. The Febs Journal, 2025, 292(2): 426-444.
- 14. Islam KUS, Meli N, Blaess S. The development of the mesoprefrontal dopaminergic system in health and disease[J]. Frontiers in Neural Circuits, 2021, 15: 746582.
- 15. Brodovskaya A, Kapur J. Anticonvulsant dopamine type 2 receptor agonist activates inhibitory parvalbumin interneurons[J]. Epilepsia, 2021, 62(9): e147-e152.
- 16. Li B, Sun Q, Ding F, et al. Anti-seizure effects of norepinephrine-induced free fatty acid release[J]. Cell Metabolism, 2025, 37(1): 223-238. e5.
- 17. Holmes GL. Drug treatment of epilepsy neuropsychiatric comorbidities in children[J]. Paediatric drugs, 2021, 23(1): 55-73.
- 18. Tomasi D, Manza P, Demiral ?B, et al. Methylphenidate reorganizes cortical hierarchy through dopaminergic modulation[J]. Nature Communications, 2025, 17: 791.
- 19. Nugiel T, Fogleman ND, Lyons MG, et al. Methylphenidate stabilizes dynamic brain network organization during tasks probing attention and reward processing in stimulant-na?ve children with ADHD[J]. Translational Psychiatry, 2025, 15: 488.
- 20. Salpekar JA, Ertenu DD. Common ground: we can comprehensively treat pediatric epilepsy and psychiatric comorbidities[J]. Epilepsy Currents, 2024, 24(6): 381-386.
- 21. Eaton C, Yong K, Walter V, et al. Stimulant and non‐stimulant drug therapy for people with attention deficit hyperactivity disorder and epilepsy[J]. The Cochrane Database of Systematic Reviews, 2022, 2022(7): CD013136.
- 22. Perucca E, Bialer M, White HS. New GABA-targeting therapies for the treatment of seizures and epilepsy: I[J]. Role of GABA as a modulator of seizure activity and recently approved medications acting on the GABA system[J]. CNS Drugs, 2023, 37(9): 755-779.
- 23. Wen Y, Dong Z, Liu J, et al. Glutamate and GABAA receptor crosstalk mediates homeostatic regulation of neuronal excitation in the mammalian brain[J]. Signal Transduction and Targeted Therapy, 2022, 7(1): 340.
- 24. Ferranti AS, Luessen DJ, Niswender CM. Novel pharmacological targets for GABAergic dysfunction in ADHD[J]. Neuropharmacology, 2024, 249: 109897.
- 25. Cediel ML, Stawarski M, Blanc X, et al. GABBR1 monoallelic de novo variants linked to neurodevelopmental delay and epilepsy[J]. American Journal of Human Genetics, 2022, 109(10): 1885-1893.
- 26. Aroniadou-Anderjaska V, Figueiredo TH, De Araujo Furtado M, et al. Alterations in GABAA receptor-mediated inhibition triggered by status epilepticus and their role in epileptogenesis and increased anxiety[J]. Neurobiology of Disease, 2024, 200: 106633.
- 27. Mamiya p C, Richards TL, Edden RAE, et al. Reduced glx and GABA inductions in the anterior cingulate cortex and caudate nucleus are related to impaired control of attention in attention-deficit/hyperactivity disorder[J]. International Journal of Molecular Sciences, 2022, 23(9): 22.
- 28. Savonlehto T, Nevalainen E, Kukko-Lukjanov TK, et al. Lgi2-deficient mice manifest epileptiform activity in the developing hippocampal network and ADHD-like behavioural comorbidity in adulthood[J]. Experimental Neurology, 2026, 396: 115541.
- 29. Stefanski A, Pérez-Palma E, Brünger T, et al. SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis[J]. Brain, 2023, 146(12): 5198-5208.
- 30. Mermer F, Poliquin S, Zhou S, et al. Astrocytic GABA transporter 1 deficit in novel SLC6A1 variants mediated epilepsy: Connected from protein destabilization to seizures in mice and humans[J]. Neurobiology of disease, 2022, 172: 105810.
- 31. Akyüz E, K?klü B, Ozenen C, et al. Elucidating the potential side effects of current anti-seizure drugs for epilepsy[J]. Current Neuropharmacology, 2021, 19(11): 1865-1883.
- 32. Faraone SV, Ward CL, Boucher M, et al. Role of serotonin in psychiatric and somatic comorbidities of attention-deficit/hyperactivity disorder: a systematic literature review[J]. Neuroscience & Biobehavioral Reviews, 2025, 176: 106275.
- 33. Patodia S, Somani A, Liu J, et al. Serotonin transporter in the temporal lobe, hippocampus and amygdala in SUDEP[J]. Brain Pathology, 2022, 32(5): e13074.
- 34. Zhou BY, Li ZX, Li YW, et al. Central Med23 deficiency leads to malformation of dentate gyrus and ADHD-like behaviors in mice[J]. Neuropsychopharmacology, 2025, 50(8): 1224-1236.
- 35. Stevelink R, Campbell C, Chen S, et al. GWAS meta-analysis of over 29, 000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture[J]. Nature Genetics, 2023, 55(9): 1471-1482.
- 36. Poliquin S, Hughes I, Shen W, et al. Genetic mosaicism, intrafamilial phenotypic heterogeneity, and molecular defects of a novel missense SLC6A1 mutation associated with epilepsy and ADHD[J]. Experimental neurology, 2021, 342: 113723.
- 37. Brant B, Stern T, Shekhidem HA, et al. IQSEC2 mutation associated with epilepsy, intellectual disability, and autism results in hyperexcitability of patient-derived neurons and deficient synaptic transmission[J]. Molecular Psychiatry, 2021, 26(12): 7498-7508.
- 38. Wu Y, Li Y, Zhu J, et al. Shared genetics and causality underlying epilepsy and attention-deficit hyperactivity disorder[J]. Psychiatry Research, 2022, 316: 114794.
- 39. Li D, Sham PC, Owen MJ, et al. Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD)[J]. Human Molecular Genetics, 2006, 15(14): 2276-2284.
- 40. Wang S, Yao B, Zhang H, et al. Comorbidity of epilepsy and attention-deficit/hyperactivity disorder: A systematic review and meta-analysis[J]. Journal of Neurology, 2023, 270(9): 4201-4213.
- 41. Hongyao H, Chun J, Xiaoyan G, et al. Associative gene networks reveal novel candidates important for ADHD and dyslexia comorbidity[J]. BMC Medical Genomics, 2023, 16: 208.
- 42. Bonvicini C, Cortese S, Maj C, et al. DRD4 48 bp multiallelic variants as age-population-specific biomarkers in attention-deficit/hyperactivity disorder[J]. Translational Psychiatry, 2020, 10: 70.
- 43. Anderson PJ, De Miranda DM, Albuquerque MR, et al. Psychiatric disorders in individuals born very preterm / very low-birth weight: An individual participant data (IPD) meta-analysis[J]. EClinicalMedicine, 2021, 42: 101216.
- 44. Pedersen MV, Lindhard MS, Moster D, et al. Umbilical cord blood pH level, apgar score, and attention-deficit/hyperactivity disorder[J]. JAMA Network Open, 2026, 9(1): e2554672.
- 45. Asarnow RF, Newman N, Weiss RE, et al. Association of attention-deficit/hyperactivity disorder diagnoses with pediatric traumatic brain injury: a meta-analysis[J]. JAMA Pediatrics, 2021, 175(10): 1009-1016.
- 46. Larivière S, Schaper FLWVJ, Royer J, et al. Brain networks for cortical atrophy and responsive neurostimulation in temporal lobe epilepsy[J]. JAMA Neurology, 2024, 81(11): 1199-1209.
- 47. Jiang Y, Li W, Li J, et al. Identification of four biotypes in temporal lobe epilepsy via machine learning on brain images[J]. Nature Communications, 2024, 15(1): 2221.
- 48. ShoU Q, Yamashita M, Hirano Y, et al. Brain structure characteristics in children with attention-deficit/hyperactivity disorder elucidated using traveling-subject harmonization[J]. Molecular Psychiatry, 2025, 30(12): 5873-5879.
- 49. Pan N, Long Y, Qin K, et al. Mapping ADHD heterogeneity and biotypes by topological deviations in morphometric similarity networks[J]. JAMA Psychiatry, 2026, 3: 25.
- 50. Norman LJ, Sudre G, Price J, et al. Evidence from “big data” for the default-mode hypothesis of ADHD: A mega-analysis of multiple large samples[J]. Neuropsychopharmacology, 2023, 48(2): 281-289.
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