Supplementation of Antipsychotic Treatment with the Amino Acid Sarcosine Influences Proton Magnetic Resonance Spectroscopy Parameters in Left Frontal White Matter in Patients with Schizophrenia

Abstract

Dysfunction of the glutamatergic system, the main stimulating system in the brain, has a major role in pathogenesis of schizophrenia. The frontal white matter (WM) is partially composed of axons from glutamatergic pyramidal neurons and glia with glutamatergic receptors. The natural amino acid sarcosine, a component of a normal diet, inhibits the glycine type 1 transporter, increasing the glycine level. Thus, it modulates glutamatergic transmission through the glutamatergic ionotropic NMDA (N-methyl-d-aspartate) receptor, which requires glycine as a co-agonist. To evaluate the concentrations of brain metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine, and γ-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left frontal WM, Proton Nuclear Magnetic Resonance (1H-NMR) spectroscopy was used. Twenty-five patients randomly chosen from a group of fifty with stable schizophrenia (DSM-IV-TR) and dominant negative symptoms, who were receiving antipsychotic therapy, were administered 2 g of sarcosine daily for six months. The remaining 25 patients received placebo. Assignment was double blinded. 1H-NMR spectroscopy (1.5 T) was performed twice: before and after the intervention. NAA, Glx and mI were evaluated as Cr and Cho ratios. All patients were also assessed twice with the Positive and Negative Syndrome Scale (PANSS). Results were compared between groups and in two time points in each group. The sarcosine group demonstrated a significant decrease in WM Glx/Cr and Glx/Cho ratios compared to controls after six months of therapy. In the experimental group, the final NAA/Cr ratio significantly increased and Glx/Cr ratio significantly decreased compared to baseline values. Improvement in the PANSS scores was significant only in the sarcosine group. In patients with schizophrenia, sarcosine augmentation can reverse the negative effect of glutamatergic system overstimulation, with a simultaneous beneficial increase of NAA/Cr ratio in the WM of the left frontal lobe. Our results further support the glutamatergic hypothesis of schizophrenia.

The GlyT1 Inhibitor Bitopertin Ameliorates Allodynia and Hyperalgesia in Animal Models of Neuropathic and Inflammatory Pain

“…Evidence that GlyT1 substrates like sarcosine and inhibitors of GlyT1 indeed have diverging effects on CNS function despite comparable effects of the extracellular glycine concentration come from studies in the context of psychosis. Here, add-on treatment of patients with a high dose of sarcosine resulted in a significant amelioration of especially negative symptoms ( Strzelecki et al, 2015 ), whereas bitopertin (at least in the Phase III clinical trials) was shown to be not effective ( Bugarski-Kirola et al, 2016a ). Whether these differences are a result of the different mechanism of action on GlyT1 or a result of the different substrate specificity – sarcosine, e.g., functions as a partial agonist on GlyRs, as well as NMDAR, but also possibly effects system A ( Javitt et al, 2005 ) and system N ( Hamdani et al, 2012 ) – is unclear at present, and requires further studies.…”

Glutamate modulators for treatment of schizophrenia

“…Approximately half of the drug-naïve participants (5/11) were considered responders but none of the non-naïve patients responded. Strzelecki et al (2015) [75] correlated clinical improvement associated with adjunct sarcosine 2 g/d for 6 months with neuroimaging findings. Their result indicated add-on sarcosine was associated with statistically significant improvement in PANSS negative and general psychopathology scores in comparison to placebo.…”

“…Their result indicated add-on sarcosine was associated with statistically significant improvement in PANSS negative and general psychopathology scores in comparison to placebo. Furthermore, using Proton nuclear magnetic resonance (H-NMR) spectroscopy, they demonstrated reversal of the pathological increase in glutamatergic transmission in the left frontal lobe [75] and hippocampus [70] as well as increased markers of neuron viability and neuroglial activity in the left dorsolateral prefrontal cortex (DLPFC) [76].…”

Serum levels of interleukin 6 in schizophrenic patients during treatment augmentation with sarcosine (results of the PULSAR study)

“…Higher concentrations of glycine lead to an increase of the N‐methyl‐D‐aspartate (NMDA) receptor activity (Millan, ). Pharmacological interventions concerning the NMDA receptor either based on NMDA co‐agonists, such as glycine, D‐serine or D‐cycloserine, or GlyT1 inhibitors, such as sarcosine or bitopertine, decrease negative symptoms in schizophrenia (Balu, ; Hirayasu et al, ; Strzelecki et al, ); those based on ketamine, an NMDA antagonist, decrease depressive symptoms in affective disorders (Iadarola et al, ; Zarate et al, ).…”