Factors associated with Psychiatric and Behavioral Adverse Events After Levetiracetam initiation in Psychiatric-Naïve Adults with Epilepsy: A Nested Case–Control Study
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Abstract
Levetiracetam is a widely used first-line antiseizure medication. However, psychiatric and behavioral adverse events (PBAEs) have been reported, whereas evidence regarding risk factors in patients without prior psychiatric disorders remains limited. Objective: To evaluate factors associated with PBAEs following levetiracetam initiation in outpatient adults with epilepsy without a history of psychiatric disorders. Methods: A nested case–control study was conducted among outpatient adults (aged ≥18 years) with epilepsy who initiated levetiracetam for the first time and had no prior psychiatric history. Cases and controls were matched by sex and age at a ratio of 1:3. Cases were patients who developed PBAEs within 12 months of levetiracetam initiation, whereas controls were selected from those who did not. Baseline characteristics were collected at the time of levetiracetam initiation. Dose-related data, including daily dose and dose escalation, were collected before the event date for cases and before the corresponding index date for matched controls. Conditional logistic regression was used for data analysis. Results: Among 356 eligible patients, 34 patients developed PBAEs and were matched with 102 controls, comprising a total of 136 patients included in the analysis. Irritability was the most common PBAE. The median time to onset was 2.9 months (IQR 0.8-6.0). Levetiracetam dose escalation of at least 500 mg/day was significantly associated with an increased risk of PBAEs (adjusted OR 4.50; 95% CI 1.46–13.92; p = 0.009). Conclusion: Levetiracetam dose escalation was associated with PBAEs in patients with epilepsy without prior psychiatric disorders. Careful dose titration and close monitoring for psychiatric symptoms during the first 3 months after treatment initiation may improve treatment safety and continuity.
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References
Ben-Menachem E, Gilland E. Efficacy and tolerability of levetiracetam during 1-year follow-up in patients with refractory epilepsy. Seizure. 2003; 12(3): 131-5. doi:10.1016/s1059-1311(02)00251-0.
Bolin K, Patric B, Tomson T. Trends in antiseizure medication initiation, switch, or termination in patients with newly diagnosed epilepsy: a nationwide study. Neurology. 2024; 103(2): e209500. doi:10.1212/WNL.0000000000209500.
Chan AYL, Yuen ASC, Hsia Y, Lau WCY, Cross JH, Walker MC, et al. Antiseizure medications consumption in 73 countries and regions from 2012 to 2022: a longitudinal trend study. EClinicalMedicine. 2025; 89: 103558. doi:10.1016/j.eclinm.2025.103558.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40(5): 373-83. doi:10.1016/0021-9681(87)90171-8.
Chen B, Choi H, Hirsch LJ, Katz A, Legge A, Buchsbaum R, et al. Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy. Epilepsy Behav. 2017; 76: 24-31. doi:10.1016/j.yebeh.2017.08.039.
Cortes C, Manterola C. Behavioral alterations associated with levetiracetam in pediatric epilepsy. Epilepsy Behav. 2020; 112: 107472. doi:10.1016/j.yebeh.2020.107472.
Durairaj T, Porchezhian M, Kumar M, Britto JRJ, K M, Saravanan A. Beyond seizure control: a case series on levetiracetam associated psychiatric manifestations. Indian J Psychol Med. 2025: 02537176251363453. doi:10.1177/02537176251363453.
Frey N, Bodmer M, Bircher A, Ruegg S, Jick SS, Meier CR, et al. The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptic drugs. Epilepsia. 2017; 58(12): 2178-85. doi:10.1111/epi.13925.
Guo W, Li YX, Zhang Y, Lv XR, Wang SX, Zhang SY, et al. Risk analysis of depression among adult patients with epilepsy of different sex: a retrospective single-center study from China. Front Psychiatry. 2023; 14: 1283983. doi:10.3389/fpsyt.2023.1283983.
Hansen CC, Ljung H, Brodtkorb E, Reimers A. Mechanisms underlying aggressive behavior induced by antiepileptic drugs: focus on topiramate, levetiracetam, and perampanel. Behav Neurol. 2018; 2018: 2064027. doi:10.1155/2018/2064027.
Helmstaedter C, Fritz NE, Kockelmann E, Kosanetzky N, Elger CE. Positive and negative psychotropic effects of levetiracetam. Epilepsy Behav. 2008; 13(3): 535-41. doi:10.1016/j.yebeh.2008.05.012.
Josephson CB, Engbers JDT, Jette N, Patten SB, Singh S, Sajobi TT, et al. Prediction tools for psychiatric adverse effects after levetiracetam prescription. JAMA Neurol. 2019; 76(4): 440-6. doi:10.1001/jamaneurol.2018.4561.
Kang BS, Moon HJ, Kim YS, Lee ST, Jung KH, Chu K, et al. The long-term efficacy and safety of levetiracetam in a tertiary epilepsy centre. Epileptic Disord. 2013; 15(3): 302-10. doi:10.1684/epd.2013.0599.
Kaufman KR, Bisen V, Zimmerman A, Tobia A, Mani R, Wong S. Apparent dose-dependent levetiracetam-induced de novo major depression with suicidal behavior. Epilepsy Behav Case Rep. 2013; 1: 110-2. doi:10.1016/j.ebcr.2013.07.002.
Lyndon S, Dworetzky BA, Baslet G. Psychiatric and behavioural side effects of antiseizure medications in epilepsy. J Neurol. 2025; 273(1): 45. doi:10.1007/s00415-025-13591-2.
Mula M, Trimble MR, Yuen A, Liu RS, Sander JW. Psychiatric adverse events during levetiracetam therapy. Neurology. 2003; 61(5): 704-6. doi:10.1212/01.wnl.0000078031.32904.0d.
Mula M, Trimble MR, Sander JW. Psychiatric adverse events in patients with epilepsy and learning disabilities taking levetiracetam. Seizure. 2004; 13(1): 55-7. doi:10.1016/s1059-1311(03)00111-0.
Pinckaers FME, Boon ME, Majoie M. Risk factors predisposing to psychotic symptoms during levetiracetam therapy: a retrospective study. Epilepsy Behav. 2019; 100(Pt A): 106344. doi:10.1016/j.yebeh.2019.05.039.
Sribanphai M, Chusiri S. Incidence and risk factors of neurological adverse events in patients with focal epilepsy treated with levetiracetam. Thai Bull Pharm Sci [Internet]. 2024 [cited 2026 Apr 13]; 19(1): 1-14. Available from: https://li01.tci-thaijo.org/index.php/TBPS/article/view/260925
Steinhoff BJ, Klein P, Klitgaard H, Laloyaux C, Moseley BD, Ricchetti-Masterson K, et al. Behavioral adverse events with brivaracetam, levetiracetam, perampanel, and topiramate: a systematic review. Epilepsy Behav. 2021; 118: 107939. doi:10.1016/j.yebeh.2021.107939.
Tao K, Chen H, Chen Y, Gu Y, Wang X. Levetiracetam induces severe psychiatric symptoms in people with epilepsy. Seizure. 2024; 116: 147-50. doi:10.1016/j.seizure.2022.12.002.
Veroniki AA, Cogo E, Rios P, Straus SE, Finkelstein Y, Kealey R, et al. Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Med. 2017; 15(1): 95. doi:10.1186/s12916-017-0845-1.
Weintraub D, Buchsbaum R, Resor SR Jr, Hirsch LJ. Psychiatric and behavioral side effects of the newer antiepileptic drugs in adults with epilepsy. Epilepsy Behav. 2007; 10(1): 105-10. doi:10.1016/j.yebeh.2006.08.008.
White JR, Walczak TS, Leppik IE, Rarick J, Tran T, Beniak TE, et al. Discontinuation of levetiracetam because of behavioral side effects: a case-control study. Neurology. 2003; 61(9): 1218-21. doi:10.1212/01.wnl.0000091865.46063.67.
Wright C, Downing J, Mungall D, Khan O, Williams A, Fonkem E, et al. Clinical pharmacology and pharmacokinetics of levetiracetam. Front Neurol. 2013; 4: 192. doi:10.3389/fneur.2013.00192.
