<b>OBJECTIVE:</b> To provide context for the boxed warning for serious psychiatric and behavioral reactions in the perampanel (PER) US prescribing information (PI), more detail on psychiatric and behavioral safety from PER clinical studies is reviewed. <b>BACKGROUND:</b> PER, a selective, noncompetitive AMPA receptor antagonist, has been approved as adjunctive treatment for partial-onset seizures (POS) in patients 蠅12 years. <b>DESIGN/METHODS:</b> The safety database consisted of data from POS and non-epilepsy populations. Serious and non-serious treatment-emergent adverse events (TEAEs) were evaluated using MedDRA dictionary search terms and Standard MedDRA Queries (SMQs). Narrow SMQ identifies cases highly likely to represent the condition of interest; broad SMQ identifies all possible “broadly-related” cases. <b>RESULTS: </b>When all hostility/aggression-related TEAEs from phase III double-blind (DB) POS trials were grouped using the “narrow and broad” SMQ, there was a dose-related increase (2mg:5%, 4mg:5%, 8mg:12%, 12mg:20%, total PER:12% vs placebo:6%); the most common TEAE was irritability (total PER 7.0% vs placebo 2.9%). Serious TEAEs occurred in 7(0.7%) of PER vs 1(0.2%) of placebo patients. These reactions have occurred in patients with and without prior psychiatric history, aggressive behavior, or concomitant use of medications associated with hostility/aggression. In the non-epilepsy DB population, psychiatric TEAEs occurring in PER more often than placebo included disorientation (0.3% vs 0.1%), delusion (0.3% vs 0.1%), and paranoia (0.2% vs 0.0%); 2 events were serious in PER patients and treatment discontinuation occurred in 9 PER patients and 1 placebo. In the all-treated population (POS and non-epilepsy), events associated with homicidal ideation and/or threat were exhibited in 6(0.1%) PER patients. <b>CONCLUSIONS:</b> The PER US PI includes a warning on serious psychiatric and behavioral reactions. Patients and caregivers should be counseled regarding potential for risk of psychiatric events with PER; patients should be monitored for these events during treatment, especially during titration and at higher doses. <b>Study Supported by:</b> Eisai Inc. <b>Disclosure:</b> Dr. Ettingerhas received personal compensation for activities with Ortho-McNeil Janssen as a member of the scientific advisory board. Dr. Ettinger has received research support from GlaxoSmithKline Inc. Dr. LoPresti has received personal compensation for activities with Eisai, Inc. as an employee. Dr. Yang has received personal compensation for activities with Eisai, Inc. Dr. Williams has received personal compensation for activities with Eisai Inc. as an employee. Dr. Zhou has received personal compensation for activities with Eisai, Inc. Dr. Fain has received personal compensation for activities with Eisai Inc., as an employee. Dr. Laurenza has received personal compensation for activities with Eisai Inc. as an employee.