title: Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a double-blind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine.
abstract: BACKGROUND
  Glutamate deregulation may be involved in the neuropathology of schizophrenia, mainly through N-methyl-d-aspartate (NMDA) receptor dysfunction. Memantine, a drug approved by the FDA for the treatment of moderate to severe Alzheimer's disease, acts as a weak nonselective NMDA receptor antagonist. The aim of this study was to examine the efficacy of memantine as an adjunctive treatment to clozapine in patients with refractory schizophrenia.
  
  
  METHODS
  In this double-blind, placebo-controlled study, outpatients with refractory schizophrenia according to DSM-IV clinical criteria were randomly assigned, from March 2005 to February 2008, to receive either 20 mg/d memantine (n = 10) or placebo (n = 11), in addition to clozapine, for 12 weeks. The primary outcome measure was the total score on the 18-item Brief Psychiatry Rating Scale (BPRS) and BPRS subscales of positive and negative symptoms. Secondary outcomes were global severity of disease as measured by the Clinical Global Impressions scale (CGI), cognition as assessed by the Mini-Mental State Examination (MMSE), and extrapyramidal symptoms as assessed by the Simpson-Angus Scale (SAS).
  
  
  RESULTS
  Twenty-one participants completed the study and were used in the analysis. Significant improvement (P < .01) on the total BPRS score, its subscales of positive (effect size [ES] = -1.38) and negative (ES = -3.33) symptoms, the CGI score (ES = 1.56), and the MMSE score was observed with memantine as compared with placebo. No significant changes in extrapyramidal symptoms were observed.
  
  
  CONCLUSIONS
  Memantine add-on to clozapine therapy was associated with improvement in negative and positive symptoms in refractory schizophrenia patients.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00757978.
authors.affiliation: Programa de Pós-Graduação em Medicina: Psiquiatria, Universidade Federal do Rio Grande do Sul, Brazil.
authors.forename: David
authors.initials: D
authors.lastname: de Lucena
authors.forename: Brisa Simões
authors.initials: BS
authors.lastname: Fernandes
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.forename: Seetal
authors.initials: S
authors.lastname: Dodd
authors.forename: Dalton W
authors.initials: DW
authors.lastname: Medeiros
authors.forename: Mariana
authors.initials: M
authors.lastname: Pedrini
authors.forename: Mauricio
authors.initials: M
authors.lastname: Kunz
authors.forename: Fabiano Alves
authors.initials: FA
authors.lastname: Gomes
authors.forename: Larriany F
authors.initials: LF
authors.lastname: Giglio
authors.forename: Maria Inês
authors.initials: MI
authors.lastname: Lobato
authors.forename: Paulo Silva
authors.initials: PS
authors.lastname: Belmonte-de-Abreu
authors.forename: Clarissa Severino
authors.initials: CS
authors.lastname: Gama
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D010054:Brief Psychiatric Rating Scale / Q000706:statistics & numerical data; D003024:Clozapine / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008559:Memantine / Q000627:therapeutic use*; D008875:Middle Aged; D010919:Placebos; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D010919:Placebos; D003024:Clozapine; D008559:Memantine