title: High dose D-serine in the treatment of schizophrenia.
abstract: BACKGROUND
  D-serine is an allosteric modulator of the brain N-methyl-d-aspartate (NMDA) receptor and a potential novel treatment of schizophrenia. Double-blind studies have been performed at 30 mg/kg/day (approximately 2 g/day) with encouraging results, but no formal dose escalation studies have been performed. We describe the first evaluation of the efficacy and safety of d-serine at doses >30 mg/kg/day; a 4-week, open-label trial of adjunctive D-serine (30, 60 or 120 mg/kg/day).
  
  
  METHODS
  42 antipsychotic-stabilized patients with schizophrenia or schizoaffective disorder participated. PANSS was obtained bi-weekly and neuropsychological (MATRICS) was obtained pre- and post medication phase. The pharmacokinetics/pharmacodynamics (PK/PD), and safety of doses> or =30 mg/kg was also evaluated.
  
  
  RESULTS
  Significant improvement in symptoms and neuropsychological measures was noted across doses. On the PANSS, improvement was observed for positive (p=0.006;d=0.46), negative (p<0.001;d=0.68), general (p=0.001;d=0.53), and total (p<0.0001;d=0.74) symptoms. On MATRICS, while only non-significant improvement was noted at 30 mg/kg, highly significant, large effect size improvement was noted on the composite score (p<0.01;d=1.0) for doses> or =60 mg/kg, leading to a significant dose-by-time interaction (p<0.01). In PK analyses, significant dose-dependent increases in plasma D-serine levels were seen during the study, predictive of significantly increased brain levels. Furthermore, increases in plasma levels correlated with improved symptomatic and neuropsychological function.
  
  
  CONCLUSIONS
  These findings support double-blind investigation of D-serine at doses> or =60 mg/kg/d, and suggest effectiveness in treatment of both persistent symptoms and neurocognitive dysfunction.
authors.affiliation: Schizophrenia Research Center, Nathan Kline Institute for Psychiatric Research/New York University Langone School of Medicine, Orangeburg, NY, United States.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Kantrowitz
authors.forename: Anil K
authors.initials: AK
authors.lastname: Malhotra
authors.forename: Barbara
authors.initials: B
authors.lastname: Cornblatt
authors.forename: Gail
authors.initials: G
authors.lastname: Silipo
authors.forename: Andrea
authors.initials: A
authors.lastname: Balla
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Suckow
authors.forename: Cyril
authors.initials: C
authors.lastname: D'Souza
authors.forename: John
authors.initials: J
authors.lastname: Saksa
authors.forename: Scott W
authors.initials: SW
authors.lastname: Woods
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Javitt
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D003072:Cognition Disorders / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D012044:Regression Analysis; D012559:Schizophrenia / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D012694:Serine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D012694:Serine