title: Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension.
abstract: OBJECTIVE
  Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension.
  
  
  METHODS
  A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day.
  
  
  RESULTS
  There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks.
  
  
  CONCLUSIONS
  This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.
authors.affiliation: 1 The Nisonger Center, Ohio State University , Columbus, Ohio.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Aman
authors.affiliation: 2 Kennedy Krieger Institute, Johns Hopkins University , Baltimore, Maryland.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Findling
authors.affiliation: 3 Department of Psychiatry and Behavioral Sciences, Stanford University , Stanford, California.
authors.forename: Antonio Y
authors.initials: AY
authors.lastname: Hardan
authors.affiliation: 4 Department of Psychiatry, University of California , San Francisco, California.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hendren
authors.affiliation: 5 Southwest Autism Research & Resource Center , Phoenix, Arizona.
authors.forename: Raun D
authors.initials: RD
authors.lastname: Melmed
authors.affiliation: 6 Forest Research Institute, (now Allergan) Jersey City, New Jersey.
authors.forename: Ola
authors.initials: O
authors.lastname: Kehinde-Nelson
authors.affiliation: 6 Forest Research Institute, (now Allergan) Jersey City, New Jersey.
authors.forename: Hai-An
authors.initials: HA
authors.lastname: Hsu
authors.affiliation: 6 Forest Research Institute, (now Allergan) Jersey City, New Jersey.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Trugman
authors.affiliation: 6 Forest Research Institute, (now Allergan) Jersey City, New Jersey.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Palmer
authors.affiliation: 6 Forest Research Institute, (now Allergan) Jersey City, New Jersey.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Graham
authors.affiliation: 6 Forest Research Institute, (now Allergan) Jersey City, New Jersey.
authors.forename: Allyson T
authors.initials: AT
authors.lastname: Gage
authors.affiliation: 6 Forest Research Institute, (now Allergan) Jersey City, New Jersey.
authors.forename: James L
authors.initials: JL
authors.lastname: Perhach
authors.affiliation: 6 Forest Research Institute, (now Allergan) Jersey City, New Jersey.
authors.forename: Ephraim
authors.initials: E
authors.lastname: Katz
mesh_terms: D001321:Autistic Disorder / Q000188:drug therapy* / Q000503:physiopathology; D002648:Child; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008559:Memantine / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D003692:Delayed-Action Preparations; D018691:Excitatory Amino Acid Antagonists; D008559:Memantine
keywords: Children's Communication Checklist-2; Social Responsiveness Scale; autistic disorder; core symptoms of autism; memantine extended release; tolerability, safety, and adverse events