Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms

Schizophr Res. 2018 Jan:191:70-79. doi: 10.1016/j.schres.2017.02.027. Epub 2017 Mar 18.

Abstract

Background: Deficits in N-methyl-d-aspartate-type (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia. The efficacy of NMDAR agonists in the treatment of persistent symptoms of schizophrenia has been variable, potentially reflecting limitations in functional target engagement. We recently demonstrated significant improvement in auditory mismatch negativity (MMN) with once-weekly treatment with d-serine, a naturally occurring NMDAR glycine-site agonist. This study investigates effects of continuous (daily) NMDAR agonists in schizophrenia/schizoaffective disorder.

Methods: Primary analysis was on MMN after double-blind crossover (60mg/kg/d, n=16, 6weeks) treatment with d-serine/placebo. Secondary measures included clinical symptoms, neurocognition, and the effects of open-label (30-120mg/kg/d, n=21) d-serine and bitopertin/placebo (10mg, n=29), a glycine transport inhibitor.

Results: Double-blind d-serine treatment led to significant improvement in MMN frequency (p=0.001, d=2.3) generation and clinical symptoms (p=0.023, d=0.80). MMN frequency correlated significantly with change in symptoms (r=-0.63, p=0.002) following co-variation for treatment type. d-Serine treatment led to a significant, large effect size increase vs. placebo in evoked α-power in response to standards (p=0.036, d=0.81), appearing to normalize evoked α power relative to previous findings with controls. While similar results were seen with open-label d-serine, no significant effects of bitopertin were observed for symptoms or MMN.

Conclusions: These findings represent the first randomized double-blind placebo-controlled study with 60mg/kg d-serine in schizophrenia, and are consistent with meta-analyses showing significant effects of d-serine in schizophrenia. Results overall support suggest that MMN may have negative, as well as positive, predictive value in predicting efficacy of novel compounds.

Clinical trials registration: Clinicaltrials.gov: NCT00322023/NCT00817336 (d-serine); NCT01116830 (bitopertin).

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation
  • Adolescent
  • Adult
  • Antipsychotic Agents / therapeutic use*
  • Cognition Disorders / etiology
  • Contingent Negative Variation / drug effects*
  • Cross-Over Studies
  • Double-Blind Method
  • Evoked Potentials, Auditory / drug effects
  • Evoked Potentials, Auditory / physiology*
  • Female
  • Humans
  • Male
  • Meta-Analysis as Topic
  • Middle Aged
  • Piperazines / therapeutic use
  • Schizophrenia / drug therapy*
  • Schizophrenia / physiopathology
  • Serine / therapeutic use*
  • Sulfones / therapeutic use
  • Time Factors
  • Young Adult

Substances

  • (4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone
  • Antipsychotic Agents
  • Piperazines
  • Sulfones
  • Serine

Associated data

  • ClinicalTrials.gov/NCT00817336
  • ClinicalTrials.gov/NCT01116830
  • ClinicalTrials.gov/NCT00322023