Abstract
We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating the efficacy of levetiracetam (LEV) compared to placebo in improving cognitive performance in people with cognitive decline. The protocol was pre-registered with PROSPERO (CRD420250656389) and reporting followed PRISMA guidelines. We searched RCTs that enrolled adult patients with cognitive decline, of any stage, comparing LEV to placebo or other active substance, and which reported at least one of the following primary or secondary outcomes: clinical dementia rating scale (CDR) or its sub-items; language, verbal memory/memory, executive, visuo-spatial and multi-domain cognitive test results. Studies were assessed for bias against the Cochrane Risk of Bias 2.0 tool. A meta-analysis was conducted using mean difference (MD) or standardized MD (SMD) according to the available scales. Meta-analysis of binary outcomes was used to compare adverse events. Overall, 6 RCTs provided data for 283 participants. LEV was not associated with a significant improvement in cognitive function measured by CDR-SB compared to placebo (MD = 0.04, 95% CI = -0.23 to 0.31, I(2) = 0%, n studies = 2). LEV significantly improved visuospatial function (SMD = -0.25, 95% CI = -0.49 to -0.01, I(2) = 0%, n studies = 2) and marginally improved executive function (SMD = -0.29, 95% CI = -0.63 to +0.05, I(2) = 0%, n studies = 3). Importantly, no differences between LEV and placebo emerged in terms of adverse events. LEV was well tolerated in people with cognitive impairment. Although LEV did not improve global cognitive function, there were improvements in visuospatial function and, more marginally, executive function. Further studies are needed to assess LEV in larger cohorts of people with cognitive impairment, with application of standardized testing paradigms. PLAIN LANGUAGE SUMMARY: Levetiracetam (LEV) is a medication commonly used to treat epilepsy. As has emerged from clinical and neuroimaging studies, some people with neurocognitive disorders have abnormal brain activity, especially in the temporal lobes, which may worsen cognitive decline. We reviewed clinical trials testing whether LEV could help improve cognitive function in people with cognitive decline. Overall, LEV was well tolerated and did not lead to more side effects than placebo. While LEV did not improve general cognitive function, some studies reported small improvements in visuospatial and executive domains. More research in larger studies is needed to understand if LEV can benefit cognition in these individuals.