title: Psychiatric and behavioral adverse events in randomized clinical studies of the noncompetitive AMPA receptor antagonist perampanel.
abstract: OBJECTIVE
  Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is indicated for adjunctive treatment of partial seizures in patients ≥12 years based on three phase III clinical studies. The perampanel U.S. Prescribing Information includes a boxed warning for serious psychiatric and behavioral adverse reactions. To provide context for this warning, detail on psychiatric and behavioral safety data from perampanel clinical studies is presented.
  
  
  METHODS
  An analysis of pooled safety data from three phase III studies in patients with partial seizures is presented. Data from phase I and phase II studies in patients with and without epilepsy were also analyzed. Psychiatric and behavioral treatment-emergent adverse events (TEAEs) were evaluated according to Medical Dictionary for Regulatory Activities (MedDRA) terms, using "narrow" and "narrow-and-broad" standardized MedDRA queries (SMQs) for TEAEs suggestive of hostility/aggression.
  
  
  RESULTS
  From the three phase III partial-seizure studies, the overall rate of psychiatric TEAEs was higher in the 8 mg (17.2%) and 12 mg (22.4%) perampanel groups versus placebo (12.4%). In the "narrow" SMQ, hostility/aggression TEAEs were observed in 2.8% for 8 mg and 6.3% for 12 mg perampanel groups, versus 0.7% of placebo patients. "Narrow-and-broad" SMQs for hostility/aggression TEAE rates were 12.3% for 8 mg and 20.4% for 12 mg perampanel groups, versus 5.7% for placebo; rates for events resulting in discontinuation were perampanel = 1.6% versus placebo = 0.7%. For events reported as serious AEs (SAEs), rates were perampanel = 0.7% versus placebo = 0.2%. In nonepilepsy patients, psychiatric TEAEs were similar between patients receiving perampanel and placebo. In phase I subjects/volunteers, all psychiatric TEAEs were mild or moderate. These analyses suggest that psychiatric adverse effects are associated with use of perampanel.
  
  
  CONCLUSIONS
  Patients and caregivers should be counseled regarding the potential risk of psychiatric and behavioral events with perampanel in patients with partial seizures; patients should be monitored for these events during treatment, especially during titration and at higher doses.
authors.affiliation: Department of Clinical Neurology, Albert Einstein College of Medicine, Bronx, New York, U.S.A.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Ettinger
authors.affiliation: Eisai Medical and Scientific Affairs, Eisai Inc., Woodcliff Lake, New Jersey, U.S.A.
authors.forename: Antonia
authors.initials: A
authors.lastname: LoPresti
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Eisai Inc., Woodcliff Lake, New Jersey, U.S.A.
authors.forename: Haichen
authors.initials: H
authors.lastname: Yang
authors.affiliation: Eisai Medical and Scientific Affairs, Eisai Inc., Woodcliff Lake, New Jersey, U.S.A.
authors.forename: Betsy
authors.initials: B
authors.lastname: Williams
authors.affiliation: Eisai Medical and Scientific Affairs, Eisai Inc., Woodcliff Lake, New Jersey, U.S.A.
authors.forename: Sharon
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Eisai Medical and Scientific Affairs, Eisai Inc., Woodcliff Lake, New Jersey, U.S.A.
authors.forename: Randi
authors.initials: R
authors.lastname: Fain
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Eisai Inc., Woodcliff Lake, New Jersey, U.S.A.
authors.forename: Antonio
authors.initials: A
authors.lastname: Laurenza
mesh_terms: D000293:Adolescent; D000328:Adult; D000374:Aggression; D000927:Anticonvulsants / Q000009:adverse effects*; D002648:Child; D004305:Dose-Response Relationship, Drug; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D006791:Hostility; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000139:chemically induced*; D008875:Middle Aged; D009570:Nitriles; D011728:Pyridones / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel
keywords: Antiepileptic drugs; Behavioral symptoms; Epilepsy; Partial seizures; Perampanel; Psychiatric adverse events; Safety