High dose D-serine in the treatment of schizophrenia

Schizophr Res. 2010 Aug;121(1-3):125-30. doi: 10.1016/j.schres.2010.05.012. Epub 2010 Jun 11.


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.

Discussion: 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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Analysis of Variance
  • Antipsychotic Agents / blood
  • Antipsychotic Agents / pharmacokinetics
  • Antipsychotic Agents / therapeutic use*
  • Chi-Square Distribution
  • Cognition Disorders / blood
  • Cognition Disorders / drug therapy
  • Cognition Disorders / etiology
  • Dose-Response Relationship, Drug
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Neuropsychological Tests
  • Psychiatric Status Rating Scales
  • Regression Analysis
  • Schizophrenia / blood
  • Schizophrenia / complications
  • Schizophrenia / drug therapy*
  • Serine / blood
  • Serine / pharmacokinetics
  • Serine / therapeutic use*
  • Treatment Outcome
  • Young Adult


  • Antipsychotic Agents
  • Serine