title: Glutamatergic medication in the treatment of obsessive compulsive disorder (OCD) and autism spectrum disorder (ASD) - study protocol for a randomised controlled trial.
abstract: BACKGROUND
  Compulsivity is a cross-disorder trait underlying phenotypically distinct psychiatric disorders that emerge in childhood or adolescence. Despite the effectiveness of serotonergic compounds in the treatment of obsessive-compulsive disorder, treatment-resistant symptoms remaining in 40 to 60 % of patients present a pressing clinical problem. There are currently no medications that effectively treat the core impairments of autism spectrum disorder. There is an urgent need for the development of conceptually novel pharmacological strategies. Agents targeting glutamate neurotransmission, such as memantine, represent promising candidates. This proof-of-concept clinical study will allow pilot-testing of memantine for both clinical effectiveness and tolerability/safety. Memantine is an N-methyl-D-aspartate receptor antagonist, approved for the treatment of Alzheimer's dementia in a number of countries.
  
  
  METHODS
  This 12-week study has an add-on, randomised, double-blind, placebo-controlled design of treatment with memantine, including an up-titration phase (forced flexible dose design, 5-15 mg/day), in patients aged 6-17 years and 9 months with obsessive-compulsive disorder or autism spectrum disorder. It is planned to include patients with obsessive-compulsive disorder (N = 50) or autism spectrum disorder (N = 50) across four centres in three European countries. Patients will be randomly assigned to memantine or placebo in a 1:1 ratio. Primary objectives are the investigation of the effectiveness of memantine in paediatric patients for improving symptoms of compulsivity (primary outcome measure: total score on the Children's Yale-Brown Obsessive-Compulsive Scale) and to explore its tolerability and safety. Secondary objectives are to explore the effects of memantine at the level of structure, function and biochemistry of the fronto-striatal circuits, and to collect blood for genetic analyses and biomarkers. Tertiary objectives are to explore the role of new candidate genes and pathways for compulsivity by linking genes to clinical phenotypes, response to treatment, neurocognitive test performance, and key structural and functional neuroimaging measures of the fronto-striatal circuits and to explore biomarkers/proteomics for compulsivity traits.
  
  
  CONCLUSIONS
  This study is part of the large, translational project TACTICS ( http://www.tactics-project.eu/ ) that is funded by the European Union and investigates the neural, genetic and molecular factors involved in the pathogenesis of compulsivity. Its results will provide clinically relevant solid information on potential new mechanisms and medication treatment in obsessive-compulsive and autism spectrum disorders.
  
  
  BACKGROUND
  EudraCT Number: 2014-003080-38 , date of registration: 14 July 2014.
authors.affiliation: Paediatric Psychopharmacology, Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, PO Box 12 21 20, 68072, Mannheim, Germany. alexander.haege@zi-mannheim.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Häge
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Banaschewski
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.affiliation: Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Dijkhuizen
authors.affiliation: Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Department of Neuroimaging, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lythgoe
authors.affiliation: Paediatric Psychopharmacology, Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, PO Box 12 21 20, 68072, Mannheim, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mechler
authors.affiliation: Department of Neuroimaging, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Steven C R
authors.initials: SC
authors.lastname: Williams
authors.affiliation: Paediatric Psychopharmacology, Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, PO Box 12 21 20, 68072, Mannheim, Germany.
authors.forename: Ralf W
authors.initials: RW
authors.lastname: Dittmann
mesh_terms: D000293:Adolescent; D000294:Adolescent Behavior / Q000187:drug effects*; D000067877:Autism Spectrum Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002648:Child; D002652:Child Behavior / Q000187:drug effects*; D002985:Clinical Protocols; D004311:Double-Blind Method; D005060:Europe; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D008559:Memantine / Q000009:adverse effects / Q000627:therapeutic use*; D059906:Neuroimaging; D009771:Obsessive-Compulsive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D011569:Psychiatric Status Rating Scales; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D008559:Memantine
keywords: Autism; Child and adolescent psychiatry; Glutamate; Memantine; Obsessive-compulsive disorder; Pilot trial; Psychopharmacology