Supplementation of antipsychotic treatment with sarcosine – GlyT1 inhibitor – causes changes of glutamatergic (1)NMR spectroscopy parameters in the left hippocampus in patients with stable schizophrenia

Neurosci Lett. 2015 Oct 8;606:7-12. doi: 10.1016/j.neulet.2015.08.039. Epub 2015 Aug 22.

Abstract

Glutamatergic system, the main stimulating system of the brain, plays an important role in the pathogenesis of schizophrenia. Hippocampus, a structure crucial for memory and cognitive functions and rich in glutamatergic neurons, is a natural object of interest in studies on psychoses. Sarcosine, a glycine transporter (GlyT-1) inhibitor influences the function of NMDA receptor and glutamate-dependent transmission. The aim of the study was to assess the effects of sarcosine on metabolism parameters in the left hippocampus in patients with schizophrenia. Assessments were performed using proton nuclear magnetic resonance ((1)H NMR) spectroscopy (1.5T). Fifty patients diagnosed with schizophrenia (DSM-IV-TR), with dominant negative symptoms, in stable clinical condition and stable antipsychotics doses were treated either with sarcosine (n=25) or placebo (n=25). Spectroscopic parameters were evaluated within groups and between two groups before and after 6-month intervention. All patients were also assessed with the Positive and Negative Syndrome Scale (PANSS). In the sarcosine group, after 6-month treatment, we found significant decrease in hippocampal Glx/Cr (Glx-complex of glutamate, glutamine and GABA, Cr-creatine) and Glx/Cho (Cho-choline), while N-acetylaspartate (NAA), myo-inositol (mI), Cr and Cho parameters remained stable along the study and also did not differ significantly between both groups. This is the first study showing that a pharmacological intervention in schizophrenia, particularly augmentation of the antypsychotic treatment with sarcosine, may reverse the pathological increase in glutamatergic transmission in the hippocampus. The results confirm involvement of glutamatergic system in the pathogenesis of schizophrenia and demonstrate beneficial effects of GlyT-1 inhibitor on the metabolism in the hippocampus and symptoms of schizophrenia.

Trial registration: ClinicalTrials.gov NCT01503359.

Keywords: (1)H NMR spectroscopy; Glutamate; Hippocampus; NMDA receptor; Sarcosine; Schizophrenia.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antipsychotic Agents / therapeutic use*
  • Aspartic Acid / analogs & derivatives
  • Aspartic Acid / metabolism
  • Choline / metabolism
  • Creatine / metabolism
  • Double-Blind Method
  • Female
  • Glutamic Acid / metabolism
  • Glutamine / metabolism
  • Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • Inositol / metabolism
  • Male
  • Middle Aged
  • Sarcosine / therapeutic use*
  • Schizophrenia / drug therapy*
  • Schizophrenia / metabolism
  • Young Adult
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Antipsychotic Agents
  • Glycine Plasma Membrane Transport Proteins
  • SLC6A9 protein, human
  • Glutamine
  • Aspartic Acid
  • Glutamic Acid
  • Inositol
  • gamma-Aminobutyric Acid
  • N-acetylaspartate
  • Creatine
  • Choline
  • Sarcosine

Associated data

  • ClinicalTrials.gov/NCT01503359