Volume : 13, Issue : 06, June – 2026
Title:
THE DEVELOPMENT OF THIRD-GENERATION ANTISEIZURE DRUGS AND SYNAPTIC VESICLE PROTEIN 2A (SV2A) LIGANDS: AN EXTENSIVE ANALYSIS OF CLINICAL EFFECTIVENESS, SAFETY, AND PRACTICAL RESULTS
Authors :
Kadeejathul Hana KP, Fathimath Safa, Honey Mariya Babu, Rincy K Geevarghese,Mrs. Vineetha S, Dr. T. Tamilselvan
Abstract :
The advent of tailored, third-generation antiseizure drugs (ASMs) has significantly enlarged the treatment landscape for epilepsy. Targeting the synaptic vesicle protein 2A (SV2A), a crucial regulator of neurotransmitter exocytosis, has been essential to this advancement. Along with other modern ASMs like perampanel, this review examines the preclinical discovery, clinical efficacy, and practical results of well-known SV2A ligands, mainly levetiracetam and its high-affinity counterpart, brivaracetam. By combining data from clinical trials, systematic reviews, we assess how variations in molecular affinity and pharmacokinetic profiles translate into unique therapeutic advantages, specific administration methods, and neuropsychiatric tolerance margins across various patient populations using meta-analyses and real-world observational data.
KEYWORDS: Brivaracetam (BRV), Levetiracetam (LEV) Antiseizure Medications (ASMs) / Antiepileptic Drugs (AEDs), Behavioral Adverse Events (BAEs), COMPARE study (the prominent real-world comparative study of third-generation ASMs) (Roberti, 2023), SV2A Ligands
Cite This Article:
Please cite this article in press Kadeejathul Hana KP et al., The Development Of Third-Generation Antiseizure Drugs And Synaptic Vesicle Protein 2a (Sv2a) Ligands: An Extensive Analysis Of Clinical Effectiveness, Safety, And Practical Results, Indo Am. J. P. Sci, 2026; 13(06).
REFERENCES:
1. Zhang L, Li S, Li H, Zou X. Levetiracetam vs. brivaracetam for adults with refractory focal seizures: A meta-analysis and indirect comparison. Seizure. 2016 Jul;39:28-33. doi: 10.1016/j.seizure.2016.05.004.
2. Liguori C, Manfredi N, Renna R, Izzi F, Pagliuca M, Pagliuca F, Mercuri NB, Fabio P. Comparison of the effectiveness and tolerability of perampanel and brivaracetam: a real-world, observational, retrospective study.
3. Matagne A, Margineanu DG, Kenda B, Michel P, Klitgaard H. Anti-convulsive and anti-epileptic properties of brivaracetam (ucb 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A. Br J Pharmacol. 2008 Aug;154(8):1662-71. doi: 10.1038/bjp.2008.198.
4. Russo E, Citraro R, Mula M. The preclinical discovery and development of brivaracetam for the treatment of focal epilepsy. Expert Opin Drug Discov. 2017 Nov;12(11):1169-1178. doi: 10.1080/17460441.2017.1366985.
5. Nicolas JM, Hannestad J, Holden D, Kervyn S, Nabulsi N, Tytgat D, Huang Y, Chanteux H, Staelens L, Matagne A, Mathy FX, Mercier J, Stockis A, Carson RE, Klitgaard H. Brivaracetam, a selective high-affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action. Epilepsia. 2016 Feb;57(2):201-9. doi: 10.1111/epi.13267.
6. Hamann M, Sander SE, Richter A. Brivaracetam and seletracetam, two new SV2A ligands, improve paroxysmal dystonia in the dt sz mutant hamster. Eur J Pharmacol. 2008 Dec 28;601(1-3):99-102. doi: 10.1016/j.ejphar.2008.10.048.
7. Trinka E, Tsong W, Toupin S, Patten A, Wilson K, Isojarvi J, James D. A systematic review and indirect treatment comparison of perampanel versus brivaracetam as adjunctive therapy in patients with focal-onset seizures with or without secondary generalization. Epilepsy Res. 2020 Oct;166:106403. doi: 10.1016/j.eplepsyres.2020.106403.
8. Roberti R, Di Gennaro G, Anzellotti F, Arnaldi D, Belcastro V, Beretta S, Boero G, Bonanni P, Canafoglia L, D’Aniello A, Dainese F, De Caro C, Di Gennaro G, Di Giacomo R, DiFrancesco JC, Dono F, Falcicchio G, Ferlazzo E, Foschi N, Franciotta S, Gambardella A, Giordano A, Iannone LF, Labate A, La Neve A, Lattanzi S, Leggio U, Liguori C, Maschio M, Nilo A, Operto FF, Pascarella A, Pauletto G, Renna R, Strigaro G; COMPARE Study Group; Russo E. A real-world comparison among third-generation antiseizure medications: Results from the COMPARE study. Epilepsia. 2024 Feb;65(2):456-472. doi: 10.1111/epi.17843.
9. Xie K, Korzun J, Zhou DJ, Chang E, Ghosn NJ, Lavelle S, Oganisian A, Acton EK, Gelfand MA, Roth D, Litt B, Ellis CA. Comparative effectiveness of anti-seizure medications in emulated trials using medical informatics. Brain. 2025 Dec 4;148(12):4288-4298. doi: 10.1093/brain/awaf238.
10. Comparison Table: Some oral antiseizure medications. Med Lett Drugs Ther. 2024 Aug 5;66(1708):e133-e140. doi: 10.58347/tml.2024.1708b.
11. Klitgaard H. Antiepileptic drug discovery: lessons from the past and future challenges. Acta Neurol Scand Suppl. 2005;181:68-72. doi: 10.1111/j.1600-0404.2005.00513.x.
12. Vrielynck P. Current and emerging treatments for absence seizures in young patients. Neuropsychiatr Dis Treat. 2013;9:963-75. doi: 10.2147/NDT.S30991.
13. Kuntz T, Martin AS, Kleinebudde P. Increased compactibility of acetames after roll compaction. Eur J Pharm Biopharm. 2011 Jan;77(1):164-9. doi: 10.1016/j.ejpb.2010.09.013.
14. Konstantinos F, Tsolaki V, Georgakopoulou VE, Aravantinou A, Fotakopoulos G. Value of Combination Therapy With Antiepileptic Drugs (AEDs) for Migraine to Prevent Ischemic Stroke in Young Women.
15. Howard P, Remi J, Remi C, Charlesworth S, Whalley H, Bhatia R, Hitchens M, Mihalyo M, Wilcock A. Levetiracetam. J Pain Symptom Manage. 2018 Oct;56(4):645-649. doi: 10.1016/j.jpainsymman.2018.07.012.
16. Fang T, Valdes E, Frontera JA. Levetiracetam for Seizure Prophylaxis in Neurocritical Care: A Systematic Review and Meta-analysis. Neurocrit Care. 2022 Feb;36(1):248-258. doi: 10.1007/s12028-021-01296-z.
17. Nash EM, Sangha KS. Levetiracetam. Am J Health Syst Pharm. 2001 Jul 1;58(13):1195-9. doi: 10.1093/ajhp/58.13.1195.
18. Kaplan YC, Demir O. Use of Phenytoin, Phenobarbital Carbamazepine, Levetiracetam Lamotrigine and Valproate in Pregnancy and Breastfeeding: Risk of Major Malformations, Dose-dependency, Monotherapy vs Polytherapy, Pharmacokinetics and Clinical Implications. Curr Neuropharmacol. 2021;19(11):1805-1824. doi: 10.2174/1570159X19666210211150856.
19. Unkun R, Kochan Kizilkilic E, Delil S, Kemerdere R, Ozkara C. Levetiracetam-associated pancytopenia. Acta Neurol Belg. 2023 Aug;123(4):1625-1626. doi: 10.1007/s13760-022-02138-1.
20. Vigevano F. Levetiracetam in pediatrics. J Child Neurol. 2005 Feb;20(2):87-93. doi: 10.1177/08830738050200020101.
21. Klein P, Bourikas D. Narrative Review of Brivaracetam: Preclinical Profile and Clinical Benefits in the Treatment of Patients with Epilepsy. Adv Ther. 2024 Jul;41(7):2682-2699. doi: 10.1007/s12325-024-02876-z.
22. Hwang H, Kim WJ. Brivaracetam: Pharmacology, Clinical Efficacy, and Safety in Epilepsy.
23. Kuo JR, Su BY. Neuropsychological Impairments in Patients With Post-traumatic Epilepsy: A Scoping Review. World Neurosurg. 2023 Aug;176:85-97. doi: 10.1016/j.wneu.2023.04.101.
24. Kuramochi I, Horikawa N, Shimotsu S, Hiwatashi T, Watanabe M, Okazaki M, Yoshimasu H. The self-stigma of patients with epilepsy in Japan: A qualitative approach. Epilepsy Behav. 2020 Aug;109:106994. doi: 10.1016/j.yebeh.2020.106994.
25. Conde Blanco E, Manzanares I, Centeno M, Khawaja M, Betrán O, Donaire A, Carreño M. Epilepsy and lockdown: A survey of patients normally attending a Spanish centre. Acta Neurol Scand. 2021 Feb;143(2):206-209. doi: 10.1111/ane.13354.
26. Bertran F. [Epilepsy today]. Rev Infirm. 2018 Aug-Sep;67(243):14-16. doi: 10.1016/j.revinf.2018.07.003.
27. Maschio M, Sperati F, Dinapoli L, Vidiri A, Fabi A, Pace A, Pompili A, Carapella CM, Cantelmi T. Weight of epilepsy in brain tumor patients. J Neurooncol. 2014 Jun;118(2):385-393. doi: 10.1007/s11060-014-1449-7.
28. Glauser TA. Following catastrophic epilepsy patients from childhood to adulthood. Epilepsia. 2004;45 Suppl 5:23-6. doi: 10.1111/j.0013-9580.2004.05005.x.
29. Hagemann A, Lahr D, May TW, Speicher P, Hausfeld H, Coban I, Müffelmann B, Bien CG, Specht U. Efficacy of a specialized inpatient rehabilitation program in patients with early versus chronic epilepsy. Epilepsy Behav. 2023 May;142:108999. doi: 10.1016/j.yebeh.2022.108999.
30. Zhou S, Zhang D, Chang J, Xia Z, Li J, Ni M, Li H. Effect of SARS-CoV-2 infection on seizure, anxiety, and depression in 107 patients with epilepsy. Epilepsy Behav. 2023 Aug;145:109290. doi: 10.1016/j.yebeh.2023.109290.