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Effect of Levetiracetam on Cognition: A Systematic Review and Meta-analysis of Double-Blind Randomized Placebo-Controlled Trials

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Abstract

Background

Studies have suggested that levetiracetam may help improve cognitive function in patients with epilepsy. Recently, its efficacy in improving cognitive function was reported in patients with amnestic mild cognitive impairment, schizophrenia, and Alzheimer’s disease. However, the specific cognitive domains affected and the degree of evidence supporting these effects remain unclear. This systematic review and meta-analysis aimed to explore the effects of levetiracetam on different cognitive domains.

Methods

This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. We defined our inclusion criteria for the systematic review as: (1) randomized placebo-controlled trials (RCTs) involving human subjects, (2) double-blinded RCTs, and (3) RCTs evaluating the quantitative differences in cognitive function between levetiracetam and placebo. We excluded: (1) non-RCT studies, (2) open-label studies, and (3) RCTs lacking cognitive assessments for either intervention. Two authors independently searched electronic databases, including PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov, from inception until 2 July 2023. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. Meta-analytic techniques were applied to examine the impact of levetiracetam on cognitive domain tests, with Hedges’ g facilitating the comparison with placebo. The domains analyzed comprised multi-domain, executive function, processing speed, working memory, verbal memory/learning (verbal ML), visuospatial memory/learning (visuospatial ML), and language. We used odds ratios to compare the incidence of treatment-emergent adverse events between the groups, including somnolence, fatigue, dizziness, headache, irritability, and cognitive adverse events.

Results

A random-effects model was utilized to perform a meta-analysis of 16 RCTs including 545 participants. Compared with a placebo, levetiracetam was associated with improved executive function [Hedges’g = − 0.390, 95% confidence interval (CI) = − 0.609 to − 0.172, p < 0.001, I2 = 24.0%]. Subgroup analysis showed that levetiracetam outperformed placebo in patients without epilepsy (Hedges’ g = − 0.419, 95% CI = − 0.647 to − 0.191, p < 0.001, I2 = 26.2%). Meanwhile, low-dose levetiracetam showed a moderate favorable effect over placebo (Hedges’ g = −0.544, 95% CI = − 1.085 to − 0.003, p = 0.049, I2 = 65.3%). In patients without epilepsy, low-dose levetiracetam was associated with improved executive function (Hedges’g = − 0.544, 95% CI = − 1.085 to − 0.003, p = 0.049, I2 = 65.3%). Concurrently, levetiracetam was associated with more frequent somnolence than a placebo (odds ratio = 4.654, 95% CI = 1.533 to 14.124, p = 0.007, I2 = 32.9%). Potential publication bias was observed in the executive function domain.

Conclusions

This exploratory study suggests that levetiracetam might improve executive function in specific populations. However, the diversity in study populations and potential publication bias warrant caution.

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References

  1. Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA. 2004;101(26):9861–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sanz-Blasco S, Piña-Crespo JC, Zhang X, McKercher SR, Lipton SA. Levetiracetam inhibits oligomeric Aβ-induced glutamate release from human astrocytes. NeuroReport. 2016;27(9):705–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci. 2012;109(42):E2895–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Romoli M, Sen A, Parnetti L, Calabresi P, Costa C. Amyloid-β: a potential link between epilepsy and cognitive decline. Nat Rev Neurol. 2021;17(8):469–85.

    Article  CAS  PubMed  Google Scholar 

  5. Liu J, Wang LN. Treatment of epilepsy for people with Alzheimer's disease. Cochrane Database Syst Rev. 2021;5(5):CD011922.

  6. Zhou B, Zhang Q, Tian L, Xiao J, Stefan H, Zhou D. Effects of levetiracetam as an add-on therapy on cognitive function and quality of life in patients with refractory partial seizures. Epilepsy Behav. 2008;12(2):305–10.

    Article  PubMed  Google Scholar 

  7. Schoenberg MR, Rum RS, Osborn KE, Werz MA. A randomized, double-blind, placebo-controlled crossover study of the effects of levetiracetam on cognition, mood, and balance in healthy older adults. Epilepsia. 2017;58(9):1566–74.

    Article  CAS  PubMed  Google Scholar 

  8. Behdani F, Hassanzadeh B, Eslamzadeh M, Moradi M, Hebrani P, Dadgarmoghaddam M, et al. Can levetiracetam improve clinical symptoms in schizophrenic patients? A randomized placebo-controlled clinical trial. Int Clin Psychopharmacol. 2022;37(4):159–65.

    Article  PubMed  Google Scholar 

  9. Feltner DE, Haig G. Evaluation of the subjective and reinforcing effects of diphenhydramine, levetiracetam, and valproic acid. J Psychopharmacol. 2011;25(6):763–73.

    Article  CAS  PubMed  Google Scholar 

  10. Mecarelli O, Vicenzini E, Pulitano P, Vanacore N, Romolo FS, Di Piero V, et al. Clinical, cognitive, and neurophysiologic correlates of short-term treatment with carbamazepine, oxcarbazepine, and levetiracetam in healthy volunteers. Ann Pharmacother. 2004;38(11):1816–22.

    Article  CAS  PubMed  Google Scholar 

  11. Levisohn PM, Mintz M, Hunter SJ, Yang H, Jones J. Neurocognitive effects of adjunctive levetiracetam in children with partial-onset seizures: a randomized, double-blind, placebo-controlled, noninferiority trial. Epilepsia. 2009;50(11):2377–89.

    Article  CAS  PubMed  Google Scholar 

  12. Brown ES, Frol AB, Khan DA, Larkin GL, Bret ME. Impact of levetiracetam on mood and cognition during prednisone therapy. Eur Psychiatry. 2007;22(7):448–52.

    Article  PubMed  Google Scholar 

  13. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372: n71.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Tsai IC, Hsu CW, Chang CH, Tseng PT, Chang KV. Effectiveness of coenzyme Q10 supplementation for reducing fatigue: a systematic review and meta-analysis of randomized controlled trials. Front Pharmacol. 2022;13: 883251.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Pieper D, Rombey T. Where to prospectively register a systematic review. Syst Rev. 2022;11(1):8.

    Article  PubMed  PubMed Central  Google Scholar 

  16. HJ LCCMJ. The effect of levetiracetam on cognition, a systemic review and meta-analysis of the double-blinded randomized placebo-controlled trials. 2023.

  17. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366: l4898.

    Article  PubMed  Google Scholar 

  18. Deeks JJ HJ, Altman DG. Chapter 10: Analysing data and undertaking meta-analyses. Cochrane Handbook for Systematic Reviews of Interventions version 63. 2022.

  19. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Research Methodol. 2005;5(1):13.

    Article  Google Scholar 

  20. Higgins JPT ES, Li T Chapter 23: Including variants on randomized trials. Cochrane Handbook for Systematic Reviews of Interventions version 63. 2022.

  21. Higgins JPT LT, Deeks JJ. Chapter 6: Choosing effect measures and computing estimates of effect. Cochrane Handbook for Systematic Reviews of Interventions version 63. 2022.

  22. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Fixed-effect versus random-effects models. Introduction to meta‐analysis; 2009. p. 77–86.

  23. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin. 2015;7:688–98.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, et al. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012;74(3):467–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bjørnæs H, Bakke KA, Larsson PG, Heminghyt E, Rytter E, Brager-Larsen LM, et al. Subclinical epileptiform activity in children with electrical status epilepticus during sleep: effects on cognition and behavior before and after treatment with levetiracetam. Epilepsy Behav. 2013;27(1):40–8.

    Article  PubMed  Google Scholar 

  27. Meador KJ, Gevins A, Leese PT, Otoul C, Loring DW. Neurocognitive effects of brivaracetam, levetiracetam, and lorazepam. Epilepsia. 2011;52(2):264–72.

    Article  CAS  PubMed  Google Scholar 

  28. Magalhães JC, Gongora M, Vicente R, Bittencourt J, Tanaka G, Velasques B, et al. The influence of levetiracetam in cognitive performance in healthy individuals: neuropsychological, behavioral and electrophysiological approach. Clin Psychopharmacol Neurosci. 2015;13(1):83–93.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Knapp CM, Ciraulo DA, Sarid-Segal O, Richardson MA, Devine E, Streeter CC, et al. Zonisamide, topiramate, and levetiracetam: efficacy and neuropsychological effects in alcohol use disorders. J Clin Psychopharmacol. 2015;35(1):34–42.

    Article  CAS  PubMed  Google Scholar 

  30. Musaeus CS, Shafi MM, Santarnecchi E, Herman ST, Press DZ. Levetiracetam alters oscillatory connectivity in Alzheimer’s disease. J Alzheimers Dis. 2017;58(4):1065–76.

    Article  CAS  PubMed  Google Scholar 

  31. Vossel K, Ranasinghe KG, Beagle AJ, La A, Ah Pook K, Castro M, et al. Effect of levetiracetam on cognition in patients with alzheimer disease with and without epileptiform activity: a randomized clinical trial. JAMA Neurol. 2021;78(11):1345–54.

    Article  PubMed  Google Scholar 

  32. Keshavarzi A, Sharifi A, Jahangard L, Soltanian A, Brühl AB, Ahmadpanah M, et al. Levetiracetam as an adjunctive treatment for mania: a double-blind, randomized, placebo-controlled trial. Neuropsychobiology. 2022;81(3):192–203.

    Article  CAS  PubMed  Google Scholar 

  33. Diamond A. Executive functions. Annu Rev Psychol. 2013;64:135–68.

    Article  PubMed  Google Scholar 

  34. Harada CN, Natelson Love MC, Triebel KL. Normal cognitive aging. Clin Geriatr Med. 2013;29(4):737–52.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Brown ES, Frol A, Bobadilla L, Nejtek VA, Perantie DC, Dhillon H. Effect of lamotrigine on mood and cognition in patients receiving chronic exogenous corticosteroids. Psychosomatics. 2003;44(3):204–8.

    Article  CAS  PubMed  Google Scholar 

  36. Houston RJ, Derrick JL, Leonard KE, Testa M, Quigley BM, Kubiak A. Effects of heavy drinking on executive cognitive functioning in a community sample. Addict Behav. 2014;39(1):345–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Harvey PD. Domains of cognition and their assessment. Dialog Clin Neurosci. 2019;21(3):227–37.

    Article  Google Scholar 

  38. Bubb EJ, Metzler-Baddeley C, Aggleton JP. The cingulum bundle: anatomy, function, and dysfunction. Neurosci Biobehav Rev. 2018;92:104–27.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Stam CJ, van der Made Y, Pijnenburg YA, Scheltens P. EEG synchronization in mild cognitive impairment and Alzheimer’s disease. Acta Neurol Scand. 2003;108(2):90–6.

    Article  CAS  PubMed  Google Scholar 

  40. Contreras-García IJ, Cárdenas-Rodríguez N, Romo-Mancillas A, Bandala C, Zamudio SR, Gómez-Manzo S, et al. Levetiracetam mechanisms of action: from molecules to systems. Pharmaceuticals (Basel). 2022;15(4):475.

    Article  PubMed  Google Scholar 

  41. Park SP, Kwon OY. Increased EEG current-source density in the high Beta frequency band induced by levetiracetam adjunctive therapy in refractory partial epilepsy. J Clin Neurol. 2009;5(4):178–85.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Lyseng-Williamson KA. Levetiracetam: a review of its use in epilepsy. Drugs. 2011;71(4):489–514.

    CAS  PubMed  Google Scholar 

  43. Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA, Johannessen SI, et al. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE commission on therapeutic strategies. Epilepsia. 2008;49(7):1239–76.

    Article  CAS  PubMed  Google Scholar 

  44. Koh MT, Haberman RP, Foti S, McCown TJ, Gallagher M. Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology. 2010;35(4):1016–25.

    Article  PubMed  Google Scholar 

  45. Diaz-Orueta U, Rogers BM, Blanco-Campal A, Burke T. The challenge of neuropsychological assessment of visual/visuo-spatial memory: a critical, historical review, and lessons for the present and future. Front Psychol. 2022;13.

  46. Yassa MA, Stark SM, Bakker A, Albert MS, Gallagher M, Stark CE. High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic mild cognitive impairment. Neuroimage. 2010;51(3):1242–52.

    Article  PubMed  Google Scholar 

  47. Stark SM, Yassa MA, Stark CE. Individual differences in spatial pattern separation performance associated with healthy aging in humans. Learn Mem. 2010;17(6):284–8.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Budson AE, Price BH. Memory dysfunction. N Engl J Med. 2005;352(7):692–9.

    Article  CAS  PubMed  Google Scholar 

  49. Maguire EA, Valentine ER, Wilding JM, Kapur N. Routes to remembering: the brains behind superior memory. Nat Neuro. 2003;6(1):90–5.

    Article  CAS  Google Scholar 

  50. Li SJ, Bakker A, Ward BD, Wang Y, Schold S, Antuono P, et al. LilyPADD trial: targeting hippocampal hyperconnectivity in cognitively normal older adults at risk for Alzheimer’s disease with AGB101. J Prev Alzheimer’s Dis. 2022;9:S87–8.

    Google Scholar 

  51. Sen A, Akinola M, Tai XY, Symmonds M, Davis Jones G, Mura S, et al. An Investigation of Levetiracetam in Alzheimer’s Disease (ILiAD): a double-blind, placebo-controlled, randomised crossover proof of concept study. Trials. 2021;22(1):508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rosenzweig-Lipson S, Barton R, Gallagher M, Mohs R. HOPE4MCI trial: first trial targeting reduction of hippocampal overactivity to treat mild cognitive impairment due to Alzheimer’s disease with AGB101. Alzheimers Dement. 2021;17(S9).

  53. Timothy R, Malone M. Levetiracetam for Alzheimer’s disease neuropsychiatric symptoms related to epilepsy trial (LAPSE)—a phase II exploratory study. 2019.

  54. Zaccara G, Gangemi PF, Cincotta M. Central nervous system adverse effects of new antiepileptic drugs. A meta-analysis of placebo-controlled studies. Seizure. 2008;17(5):405–21.

    Article  CAS  PubMed  Google Scholar 

  55. Hirsch M, Hintz M, Specht A, Schulze-Bonhage A. Tolerability, efficacy and retention rate of Brivaracetam in patients previously treated with Levetiracetam: a monocenter retrospective outcome analysis. Seizure. 2018;61:98–103.

    Article  PubMed  Google Scholar 

  56. Mula M, Trimble MR, Sander JW. Psychiatric adverse events in patients with epilepsy and learning disabilities taking levetiracetam. Seizure. 2004;13(1):55–7.

    Article  PubMed  Google Scholar 

  57. Dinkelacker V, Dietl T, Widman G, Lengler U, Elger CE. Aggressive behavior of epilepsy patients in the course of levetiracetam add-on therapy: report of 33 mild to severe cases. Epilepsy Behav. 2003;4(5):537–47.

    Article  PubMed  Google Scholar 

  58. Cramer JA, De Rue K, Devinsky O, Edrich P, Trimble MR. A systematic review of the behavioral effects of levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials. Epilepsy Behav. 2003;4(2):124–32.

    Article  PubMed  Google Scholar 

  59. Larsson PG, Bakke KA, Bjørnæs H, Heminghyt E, Rytter E, Brager-Larsen L, et al. The effect of levetiracetam on focal nocturnal epileptiform activity during sleep—a placebo-controlled double-blind cross-over study. Epilepsy Behav. 2012;24(1):44–8.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank InnovaRad, Inc. for providing PRISMA flow chart template and their valuable consultation.

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Authors and Affiliations

  1. Department of Neurology, Neurological Institute, Taichung Veterans General Hospital, No. 1650, Taiwan Boulevard, Sect. 4, Taichung, 40705, Taiwan

    Chia-Yen Lin & Meng-Chia Chang

  2. Department of Neurology, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 50006, Taiwan

    Hong-Jie Jhou

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Correspondence to Hong-Jie Jhou.

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The authors declare no financial or non-financial conflicts of interest related to this manuscript.

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As a secondary analysis of publicly available data, this study did not require approval from an ethics review board.

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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Author’s contributions

Chia-Yen Lin conceptualized the article, curated the data, developed the methodology, performed the formal analysis, managed the project, validated findings, and authored the initial draft. Meng-Chia Chang engaged in methodology development discussions and reviewed the manuscript. Hong-Jie Jhou collected data, contributed to the investigation, assisted in methodology formulation, validated results, and participated in manuscript review and editing. All authors have approved the manuscript and accept responsibility for its contents.

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Lin, CY., Chang, MC. & Jhou, HJ. Effect of Levetiracetam on Cognition: A Systematic Review and Meta-analysis of Double-Blind Randomized Placebo-Controlled Trials. CNS Drugs 38, 1–14 (2024). https://doi.org/10.1007/s40263-023-01058-9

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