Adding Sarcosine to Antipsychotic Treatment in Patients with Stable Schizophrenia Changes the Concentrations of Neuronal and Glial Metabolites in the Left Dorsolateral Prefrontal Cortex

Dominik Strzelecki, Michał Podgórski, Olga Kałużyńska, Ludomir Stefańczyk, Magdalena Kotlicka-Antczak, Agnieszka Gmitrowicz, Piotr Grzelak, Dominik Strzelecki, Michał Podgórski, Olga Kałużyńska, Ludomir Stefańczyk, Magdalena Kotlicka-Antczak, Agnieszka Gmitrowicz, Piotr Grzelak

Abstract

The glutamatergic system is a key point in pathogenesis of schizophrenia. Sarcosine (N-methylglycine) is an exogenous amino acid that acts as a glycine transporter inhibitor. It modulates glutamatergic transmission by increasing glycine concentration around NMDA (N-methyl-d-aspartate) receptors. In patients with schizophrenia, the function of the glutamatergic system in the prefrontal cortex is impaired, which may promote negative and cognitive symptoms. Proton nuclear magnetic resonance (¹H-NMR) spectroscopy is a non-invasive imaging method enabling the evaluation of brain metabolite concentration, which can be applied to assess pharmacologically induced changes. The aim of the study was to evaluate the influence of a six-month course of sarcosine therapy on the concentration of metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine and γ-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left dorso-lateral prefrontal cortex (DLPFC) in patients with stable schizophrenia. Fifty patients with schizophrenia, treated with constant antipsychotics doses, in stable clinical condition were randomly assigned to administration of sarcosine (25 patients) or placebo (25 patients) for six months. Metabolite concentrations in DLPFC were assessed with 1.5 Tesla ¹H-NMR spectroscopy. Clinical symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS). The first spectroscopy revealed no differences in metabolite concentrations between groups. After six months, NAA/Cho, mI/Cr and mI/Cho ratios in the left DLPFC were significantly higher in the sarcosine than the placebo group. In the sarcosine group, NAA/Cr, NAA/Cho, mI/Cr, mI/Cho ratios also significantly increased compared to baseline values. In the placebo group, only the NAA/Cr ratio increased. The addition of sarcosine to antipsychotic therapy for six months increased markers of neurons viability (NAA) and neurogilal activity (mI) with simultaneous improvement of clinical symptoms. Sarcosine, two grams administered daily, seems to be an effective adjuvant in the pharmacotherapy of schizophrenia.

Trial registration: ClinicalTrials.gov NCT01503359.

Keywords: 1H-NMR spectroscopy; NMDA receptor; dorso-lateral prefrontal cortex; glutamate; sarcosine; schizophrenia.

Figures

Figure 1
Figure 1
Correlation between the differences in metabolite ratios (A) NAA/Cho; (B) NAA/Cr; (C) mI/Cho; (D) mI/Cr and differences in negative PANSS subscale score.
Figure 2
Figure 2
Images showing voxel location in the left DLPFC (dorso-lateral prefrontal cortex) area and an example before (white line) and after (red line) fitting. Peak areas for N-acetylaspartate (NAA); creatine (Cr and Cr2); choline (Cho); and myo-inositol (Ins dd1) are labelled.

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