Critical reassessment of manic and psychotic episodes related to levetiracetam: a systematic review of published case reports

Levetiracetam (LEV) is a widely used antiepileptic but associated with psychiatric side effects. While mild reactions are common, manic and psychotic episodes are less frequent, though clinically significant. This review critically assesses published cases of (hypo)manic and psychotic episodes related to LEV. A systematic review was conducted using MEDLINE (PubMed), Cochrane Library, and Web of Science (up to 1 June 2025), restricted to studies with primary clinical data on (hypo)manic or psychotic episodes associated with LEV. The quality of each case was assessed using a critical appraisal checklist, and the Naranjo Adverse Drug Reaction Probability Scale was applied to evaluate causality. A total of 50 cases met the inclusion criteria: Eight (hypo)manic and 42 psychotic episodes. The most frequent psychiatric manifestations were delusions (48%), aggressiveness (44%), and manic symptoms (38%). Temporal lobe epilepsy was present in 26% of patients, and 66% had uncontrolled seizures. Although case reports describe an association between LEV and (hypo)manic and psychotic episodes, causality assessment based on the methodological approach applied indicated a low probability that LEV alone was responsible. Alternative explanations, including epilepsy-related factors and comorbid medical conditions, were frequently cited. In some cases, an alternative diagnosis might be manic episode with psychotic features.