Neuropsychiatric Adverse Effects Associated with the Use of Levetiracetam in Adults: A Systematic Review and Meta-Analysis

Objective Levetiracetam is a broad-spectrum anti-seizure medication (ASM) with a good safety profile; however, the occurrence of neuropsychiatric manifestations has been described in relation to its use. The aim of this study was to provide an updated assessment of the neuropsychiatric adverse effects related to levetiracetam in patients aged 16 and older with epilepsy, without psychiatric comorbidity, and perform a meta-analysis comparing the occurrence of neuropsychiatric adverse effects between levetiracetam, placebo, and other ASMs. Methods A systematic literature search was conducted in PubMed, Embase, and Web of Science. Studies published until March 14th, 2024, were included. Out of the 33 studies, 7 were randomized clinical trials comparing levetiracetam to placebo and 4 comparing levetiracetam to other ASM, all of which were selected for further quantitative analysis. Results Somnolence was the most frequently reported NPAE (15 articles), followed by depression (11 articles). Fatigue, aggression/agitation, cognitive and memory impairment, irritability, anxiety, and behavioral changes were also commonly described. Across pooled analyses, levetiracetam-treated patients demonstrated a significantly higher risk of somnolence/drowsiness (OR 1.61, 95% CI: 1.20–2.17) and asthenia/fatigue (OR 1.48, 95% CI: 1.04–2.11) compared with placebo. In contrast, a separate meta-analysis comparing levetiracetam to other ASMs showed no significant difference for depression (OR 1.41, 95% CI: 0.80–2.51). Conclusion Patients treated with levetiracetam have a greater risk of developing neuropsychiatric effects, such as somnolence and fatigue, compared to placebo.