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

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.