Links of platelet glutamate and glutathione metabolism with attenuated positive and negative symptoms in depressed patients at clinical high risk for psychosis.

Aim of the study is to reveal clinical and biological correlations in patients with adolescent depression and attenuated psychotic symptoms. Activity of platelet enzymes involved in glutamate-, glutathione- and energy metabolism was evaluated in control group and in the patients, because these systems are suspected as related to pathogenesis of psychosis. Adolescents (78 men, 16-25 years old) hospitalized with the first acute depressive state composed two groups: with prevalence of attenuated psychotic positive or negative symptoms (Gr1 and Gr2, 48 and 30 patients, respectively). Control group comprised 20 mentally healthy men of 19-25 years old. Gr1 differed significantly from Gr2 in scores by the Scale of Prodromal Symptoms (SOPS) for positive symptoms, p < 0.001, for disorganization symptoms, p < 0.003, and for total SOPS score, p < 0.001, before the treatment started. When patients from either Gr1 or Gr2 were compared with the control group, significantly decreased baseline activities of platelet glutamate dehydrogenase (GDH), glutathione reductase (GR) and glutathione S-transferase (GST) were found (p < 0.0001). Different correlations were found between baseline enzymatic activities in Gr1 and Gr2: GDH activity correlated with GR activity in Gr1 (R = 0.37), and with GST activity in Gr2 (R = 0.70). Significant correlations were found only in Gr2 between the delta of scores by SOPS negative symptoms (SOPS-N) under treatment and baseline GDH, GST, and GR activities (R = - 0.36, R = - 0.60, and R = 0.38, respectively). The found correlations of the baseline enzymatic activity levels with the value of the decrease (delta) in SOPS-N scores under the treatment represent interest for the prediction of the pharmacotherapy efficiency.

Platelet glutamate dehydrogenase activity and efficacy of antipsychotic therapy in patients with schizophrenia.

BACKGROUND: Evaluation of possible relationship between platelet glutamate dehydrogenase (GDH) activity and mental state of schizophrenia patients after antipsychotic pharmacotherapy. METHODS: Patients (n = 50) with chronic paranoid schizophrenia (F20.0) initially in acute psychotic state were examined before and after a treatment course with antipsychotics. When assessing the patients' states using PANSS, the "responder" category was attributed to those patients who had not less than 30% reduction in the score for the corresponding PANSS "subscale". The control group (n = 48) was ageand gender-matched with the patient group. Platelet glutamate dehydrogenase (GDH) activity was measured in patients twice, before and after the treatment course, and once in controls. RESULTS: Significantly reduced GDH activity was found in patients compared with controls. The patient group was divided into two subgroups according to median GDH activity at baseline: above and below the median GDH, subgroup 1 and subgroup 2, respectively. GDH activity significantly increased from its level at baseline after antipsychotic treatment in subgroup 2. Distribution of non responders / responders to antipsychotic treatment (by PANSS scores) was significantly uneven among subgroups 1 and 2. In subgroup 1, GDH activity levels significantly correlated with PANSS scores after the treatment course. CONCLUSIONS: Baseline platelet GDH activity might serve as a predictor of antipsychotic therapy efficacy in schizophrenia patients.

Glutamine synthetase and glutamate dehydrogenase in the prefrontal cortex of patients with schizophrenia.

Basing primarily on the facts of altered levels of glutamate neurotransmitter, its receptors and transporters in schizophrenic brain, the "glutamatergic hypothesis" of schizophrenia has been broadened into the field of brain glutamate metabolism. Significantly changed levels of glutamine synthetase (GS) and glutamate dehydrogenase (GDH), the key enzymes involved in glutamine-glutamate cycling between neurons and glia, have been found in the prefrontal cortex (area 10) of patients with schizophrenia compared to controls (P<.01). The data were obtained by enzymatic activity determinations as well as immunoreactivity level evaluations for GS, glutamine synthetase-like protein (GSLP), and three GDH isoenzymes in brain extracts by immunoblotting using specific polyclonal and monoclonal antibodies. Inverse changes in amounts of proteins of GS and GSLP, as well as elevation in amounts of GDH isoenzymes have been observed in schizophrenia. The presented results provide evidence for the impairment of glutamate metabolism and, in turn, abnormalities in functioning of the glutamate-glutamine cycle in the frontal cortex of patients with schizophrenia.

Diversity of glutamate dehydrogenase in human brain.

Three forms of glutamate dehydrogenase (GDH, EC 1.4.1.3) are purified from human brain tissue. Two of them, named GDH I (consisting of 58+/-1-kDa subunit) and GDH II (consisting of 56+/-1 -kDa subunit), are readily solubilized and the third one, GDH III (consisting of 56+/-1-kDa subunit), is a membrane-associated (particulate bound) isoform. Kinetic constants were determined for GDH III. These GDH forms were found to differ in hydrophobicity as indicated by different affinity to Phenyl-Sepharose. All three GDH forms showed microheterogeneity on two-dimensional (2-D) gel electrophoresis. Specific polyclonal antibodies, which enable to determine the levels of immunoreactivities of all the GDH forms in human brain extracts by enzyme-chemiluminescent amplified (ECL)-Western immunoblotting, were obtained.