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Glutathione Levels and Glutathione-Glutamate Correlation in Patients With Treatment-Resistant Schizophrenia.

ABSTRACT: Treatment-resistant schizophrenia (TRS) has been suggested to involve glutamatergic dysfunction. Glutathione (GSH), a dominant antioxidant, is known to be involved in glutamatergic neurotransmission. To date, no study has examined GSH levels in patients with TRS. The aim of this study was to examine GSH levels in the dorsal anterior cingulate cortex (dACC) of patients with TRS. Patients with schizophrenia were categorized into 3 groups with respect to their antipsychotic response: (1) clozapine (CLZ) nonresponders, (2) CLZ responders, and (3) first-line responders (FLR). GSH and glutamine + glutamate (Glx) levels were measured using 3T proton magnetic resonance spectroscopy. Firstly, dACC GSH levels were compared among the patient groups and healthy controls (HCs). Further, relationships between GSH and Glx levels were compared between the groups and GSH levels were explored stratifying the patient groups based on the glutamate-cysteine ligase catalytic (GCLC) subunit polymorphism. There was no difference in GSH levels between the groups. FLR showed a more negative relationship between GSH and Glx levels in the dACC compared to HCs. There were no effects of GCLC genotype on the GSH levels. However, CLZ responders had a higher ratio of high-risk GCLC genotype compared to CLZ nonresponders. This study demonstrated different relationships between GSH and Glx in the dACC between groups. In addition, the results suggest a potential link between CLZ response and GCLC genotype. However, it still remains unclear how these differences are related to the underlying pathophysiology of schizophrenia subtypes or the mechanisms of action of CLZ.

SUBMITTER: Iwata Y

PROVIDER: S-EPMC8086698 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Treatment-resistant schizophrenia (TRS) or suboptimal response to antipsychotics affects almost 30% of schizophrenia (SCZ) patients, and it is a relevant clinical issue with significant impact on the functional outcome and on the global burden of disease. Among putative novel treatments, glycine-centered therapeutics (i.e. sarcosine, glycine itself, D-Serine, and bitopertin) have been proposed, based on a strong preclinical rationale with, however, mixed clinical results. Therefore, a better appraisal of glycine interaction with the other major players of SCZ pathophysiology and specifically in the framework of dopamine - glutamate interactions is warranted. New methodological approaches at cutting edge of technology and drug discovery have been applied to study the role of glycine in glutamate signaling, both at presynaptic and post-synaptic level and have been instrumental for unveiling the role of glycine in dopamine-glutamate interaction. Glycine is a non-essential amino acid that plays a critical role in both inhibitory and excitatory neurotransmission. In caudal areas of central nervous system (CNS), such as spinal cord and brainstem, glycine acts as a powerful inhibitory neurotransmitter through binding to its receptor, i.e. the Glycine Receptor (GlyR). However, glycine also works as a co-agonist of the N-Methyl-D-Aspartate receptor (NMDAR) in excitatory glutamatergic neurotransmission. Glycine concentration in the synaptic cleft is finely tuned by glycine transporters, i.e. GlyT1 and GlyT2, that regulate the neurotransmitter's reuptake, with the first considered a highly potential target for psychosis therapy. Reciprocal regulation of dopamine and glycine in forebrain, glycine modulation of glutamate, glycine signaling interaction with postsynaptic density proteins at glutamatergic synapse, and human genetics of glycinergic pathways in SCZ are tackled in order to highlight the exploitation of this neurotransmitters and related molecules in SCZ and TRS.

Project description:The association of antipsychotic medication with abnormal brain morphometry in schizophrenia remains uncertain. This study investigated subcortical morphometric changes 6 months after switching treatment to clozapine in patients with treatment-resistant schizophrenia compared with healthy volunteers, and the relationships between longitudinal volume changes and clinical variables. In total, 1.5T MRI images were acquired at baseline before commencing clozapine and again after 6 months of treatment for 33 patients with treatment-resistant schizophrenia and 31 controls, and processed using the longitudinal pipeline of Freesurfer v.5.3.0. Two-way repeated MANCOVA was used to assess group differences in subcortical volumes over time and partial correlations to determine association with clinical variables. Whereas no significant subcortical volume differences were found between patients and controls at baseline (F(8,52) = 1.79; p = 0.101), there was a significant interaction between time, group and structure (F(7,143) = 52.54; p < 0.001). Corrected post-hoc analyses demonstrated that patients had significant enlargement of lateral ventricles (F(1,59) = 48.89; p < 0.001) and reduction of thalamus (F(1,59) = 34.85; p < 0.001), caudate (F(1,59) = 59.35; p < 0.001), putamen (F(1,59) = 87.20; p < 0.001) and hippocampus (F(1,59) = 14.49; p < 0.001) volumes. Thalamus and putamen volume reduction was associated with improvement in PANSS (r = 0.42; p = 0.021, r = 0.39; p = 0.033), SANS (r = 0.36; p = 0.049, r = 0.40; p = 0.027) and GAF (r = -0.39; p = 0.038, r = -0.42; p = 0.024) scores. Reduced thalamic volume over time was associated with increased serum clozapine level at follow-up (r = -0.44; p = 0.010). Patients with treatment-resistant schizophrenia display progressive subcortical volume deficits after switching to clozapine despite experiencing symptomatic improvement. Thalamo-striatal progressive volumetric deficit associated with symptomatic improvement after clozapine exposure may reflect an adaptive response related to improved outcome rather than a harmful process.

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Glutathione Levels and Glutathione-Glutamate Correlation in Patients With Treatment-Resistant Schizophrenia.

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