Background: the normal brain functioning is provided by a brain system maintaining pools and balance of concentrations of the main high-energy compounds, such as ATP and creatine phosphate (CrP), with its main components — creatine (Cr), creatine phosphate (CrP) and creatine phosphokinase (or creatine kinase, CK), the last is catalyzing the reaction of high-energy phosphate residue transfer between ATP, Cr and CrP. The purpose of this review is to analyze the results of studies on the elements of the Cr — CrP system: Cr, CrP and CK in healthy persons and in patients with mental and neurodegenerative disorders and to consider the possibilities of using Cr — CrP-targeted therapy for mental and neurodegenerative disorders. Methods: using combinations of keywords “creatine”, “creatine phosphate”, “creatine kinase”, “schizophrenia”, “bipolar affective disorder”, “Alzheimer’s disease” and “pharmacotherapy”, a search was conducted for sources in the Medline/PubMed, Scopus and RSCI databases. Conclusion: a critical examination of the original articles, both clinical and experimental, including studies performed on animal models, provides a good reason to believe that the involvement of the Cr — CrP system in the pathogenesis of mental illnesses has been confirmed and opens up further prospectives for Cr — CrP-oriented therapy of mental and neurodegenerative disorders, however, further clinical studies of the Cr — CrP system in psychiatry are necessary.

The involvement of inflammation, disturbances of glutamate metabolism and oxidative stress in the pathogenesis of schizophrenia and affective disorders has been proven by numerous studies. It seems relevant to assess the role of these systems in the development of prodromal stages of schizophrenia in juvenile patients with depression. The aim of this study was to investigate the connection between markers of inflammation, energy and glutamate metabolism, and antioxidant defense with the clinical features of patients with adolescent depression. 74 males aged 16–25 years with a first depressive episode (F32.1–2, F32.38, F32.8) were observed: 32 subjects with attenuated positive symptoms, 22 persons with attenuated negative symptoms, 20 individuals without attenuated schizophrenia symptoms. The control group included 57 mentally healthy adults aged 16–25 years. The activity of leukocyte elastase and α1-proteinase inhibitor, the level of autoantibodies to S100B and myelin basic protein in plasma and the activity of cytochrome c-oxidase, glutamate dehydrogenase, glutathione reductase and glutathione-S-transferase in platelets were determined. Within each clinical group, differences in the profiles of immunological and biochemical parameters were identified. Division of patients into clusters according to all biological parameters showed different level of inflammation and changes of glutamate metabolism and antioxidant defense related to the features of psychopathological symptoms. The results confirm the connection of the studied metabolic systems and their different involvement to the development of adolescent depression with different psychopathological structure, which is important to assess the role of these systems in the trajectory of the disease and early therapeutic correction.

Introduction Basing on our previous findings of significant additional gain obtained from usage of adjunctive antioxidant medicine added to antipsychotic+antidepressant therapy in late-onset schizophrenia-like psychoses (LOP), the group often suffering of comorbid pathologies and experiencing substantial side-effects of drugs, we spred our approach to try “metabolic” medicines as adjunctives in LOP. Objectives To reveal biochemical parameters of the blood cells which might be used for distinguishing subgroups of patients suffering with LOP for whom various adjunctive therapy (antioxidant, metabolic) would be advantageous. Methods The study included 59 patients 50-89 years old, with LOP (onset after 40 years), and 38 healthy peoples 51 – 84 years old. The activities of glutamate dehydrogenase (GDH), glutathione reductase (GR), and glutathione S-transferase (GST) were determined spectrophotometrically in erythrocytes and platelets. Scores by PANSS were evaluated twice: before and on the 28-th day of antipsychotic treatment. Results Samples from control group were used for determination of the control ranges for levels of studied enzymatic activities. Enzymatic activity levels were analyzed in three groups of patients: group Gr1 (n=16) treated without adjunctive therapy, and two other groups (Gr2 and Gr3) treated with adjunctive medicines: antioxidant 2-ethyl-6-methyl-3-hydroxypyridine succinate (Gr2, n=20), or “metabolic” medicines citicoline/cerebrolysin/cortexin/actovegin/gliatilin (Gr3, n=23). As compared with controls, activity of erythrocyte GR was decreased at baseline and after the treatment course in all patients’ groups (p<0.01); in Gr2 significant decreases in baseline platelet GDH and GST activities were observed (p=0.005). Different significant links between biochemical parameters and scores by clinical scales before treatment were observed: in Gr1, erythrocyte GST activity positively correlated with scores by PANSS-Neg (R=0.61, p=0.012), by PANSS-Psy (R=0.54, p=0.032), and by PANSS (R=0.62, p=0.010), in Gr2, erythrocyte GST activity positively correlated with scores by PANSS-Pos (R=0.53, p=0.016), by PANSS-Psy (R=0.52, p=0.015), and by PANSS (R=0.60, p=0.005), in Gr3, platelet GR activity positively correlated with PANSS-Pos (R=0.50, p=0.014). Conclusions We have confirmed the additional favor (decrease in side-effect severity) obtained by distinct patient groups when treated with adjunctive antioxidant or “metabolic” therapy. Moreover, correlations revealed in the patient subgroups between enzymatic activities and scores by psychometric scales enable revealing those biochemical markers measurement of which facilitate differentiating the patients for whom the adjunctive medicines to antipsychotic+antioxidant treatment can positively influence the treatment outcome. Disclosure of Interest None Declared

Coordinated regulation of energy conversion processes in the brain maintains its highly productive work and efficient mental activity. Impairments of the brain energy metabolism are considered among pathogenetic factors in the schizophrenia origin, but presently it is difficult to say whether these impairments are primary and causative the development of the disease or represent consequences of certain changes in the functioning of neurotransmitter and other neurochemical systems. This review discusses the main results of the energy metabolism research in schizophrenia – at various levels and using different approaches, as well as regards some attempts of influencing the energy processes in the brain as an adjunctive therapy in schizophrenia. To date, the efficacy of these therapeutic approaches has not been proven, this may be due to the paucity of studies and the lack of preliminary identification/stratification of patient subgroups to whom the energy metabolism-targeted therapy would be the most useful. Based on the data presented, one can conclude that an analysis is necessary of relationships between the psychopathological manifestations of schizophrenia and energy metabolism deviations for further identification of those patients to whom the use of mitochondrial modulators, mitoprotection, and other approaches may represent a promising method of adjunctive therapy.

OBJECTIVE:To assess clinical and psychopathological characteristics of late-aged female patients with late-onset psychoses in clusters formed on the basis of biochemical and immunological blood parameters.MATERIAL AND METHODS:We examined 59 women with schizophrenia and schizophrenia-like psychoses with onset after 40 years (ICD-10 F20, F22.8, F25, F23, F06.2), including 34 women with late-onset (40-60 years) and 25 with very late onset psychoses (after 60 years). At the time of hospitalization, a clinical/ psychopathological study was carried out using CGI-S, PANSS, CDSS, and HAMD-17, as well as the activities of glutathione reductase (GR) and glutathione-S-transferase (GT) have been determined in erythrocyte hemolysates, and the activities of leukocyte elastase (LE) and α1-proteinase inhibitor (α1-PI) have been assessed in blood plasma. Biochemical and immunological parameters have been also determined in 34 age-matched mentally healthy women.RESULTS:Clustering by signs such as GR, GT, LE and α1-PI has yielded two clusters of objects (patients) significantly different in GT (p<0.0001), LE (p<0.0001), and α1-PI (p<0.001) activities. Relatively to the controls, in the cluster 1 patients, the activities of GST and α1-PI are increased, the activity of LE is decreased, whereas, in the cluster 2 patients, the activity of GR is decreased, and the activities of LE and α1-PI are increased. Cluster 1 patients differ from cluster 2 patients in greater severity of the condition (CGI-S, p=0.04) and higher total scores on PANSS subscales' items. Cluster 1 includes 76% of patients with very late onset. Different correlations between clinical and biological signs are found in two clusters.CONCLUSION:The identified clusters have different clinical and psychopathological characteristics. Dividing patients into subgroups according to biochemical and immunological parameters is promising for the search for differentiated therapeutic approaches.

Background: heterogeneity of schizophrenia is reflected in the variety of clinical manifestations and biological disorders, on the basis of which several neurochemical hypotheses are formulated for schizophrenia pathogenesis. Review of the current hypotheses of schizophrenia pathogenesis shows that oxidative stress is not the main cause of the disease development, but affects its course and contributes to the deterioration of the patient’s condition. Objective: analysis of the relationships between redox imbalance and oxidative stress and the development of pathological processes in schizophrenia within the framework of neurochemical hypotheses of the disease pathogenesis. Material and methods: a search was made for sources in the Medline/PubMed databases, Scopus and RSCI using keyword combinations “oxidative stress”, “oxidation-reduction imbalance”, “schizophrenia”, “hypotheses of schizophrenia pathogenesis”, “antioxidants”, “neurotransmitters”, “glutathione”, “neuroinflammation”. Conclusion: data from numerous studies of the brain of patients with schizophrenia, their blood plasma, serum, and blood cells as well as the study of animal models of schizophrenia indicate the presence of redox imbalance and oxidative stress in this disease. Taken together, these data indicate that genetic and environmental factors that affect the manifestation of various pathological mechanisms in schizophrenia (disturbances in neurotransmitter systems, hypofunction of N-methyl-D-aspartate receptors, neuroinflammation, impaired signaling protein phosphorylation pathways) lead to the oxidative stress, enhancing the initial pathological changes, as a result of which synchronization processes and intercellular communications in the brain become disrupted. Medicines with antioxidant and anti-inflammatory properties, compounds for correcting mitochondrial dysfunction, and NMDAR-mediated signaling modulators can be used as drugs to reduce the harmful effects of oxidative stress. The efficacy of these medicines may vary in different patients, so the development of biomarker systems aimed at identifying individuals who are more likely to respond to a particular drug is of great importance.

Introduction While chronic inflammation and enhanced imbalance of pro- and antioxidant, including glutathione-dependent, systems contribute substantially to pathogenesis of mental disorders in old age, extent of oxidative stress and degree of inflammatory processes severity are varying among patients with late onset schizophrenia. Objectives Revealing various phenotypes in patients with late onset schizophrenia basing on measurement of activity levels for blood glutathione-dependent enzymes and inflammation markers and analysis of their links with clinical features of the patients. Methods Of 59 studied women patients 34 were with late onset (after 40 years) and 25 with very late onset (after 60 years) schizophrenia or schizophrenia-like psychoses (F20; F22.8; F25; F23; F06.2 by ICD-10). 34 mentally healthy women elder than 50 years comprised controls. Glutathione reductase (GR), glutathione-S-transferase (GST), neutrophil elastase (NE), and α1-roteinase inhibitor (α1-PI) activities were measured in blood. PANSS, CDSS and CGI-S were used to assess the severity of psychotic symptoms, depression and treatment effectiveness. Results In the whole group of patients, GR was lower (p<0.05), and α1-PI was higher (p<0.0001) than in control group. Clustering the patients by their biochemical and immunological signs revealed two clusters (C1, n=34, and C2, n=25) significantly differing by GST (p<0.0001), NE (p<0.0001), and α1-PI (p<0.001) activities. As compared with controls, GST and α1-PI were higher (p<0.05 and p<0.0001), and NE was lower (p<0.05) in C1. As compared with controls, GR activity was lower (p<0.05), NE activity was higher (p<0.001), and α1-PI activity was much higher (p<0.001) in C2. Patients of C1 and C2 did not differ in age, diagnosis, severity of the disease, but differed in clinical features of the course of the disease: significantly more patients with very late onset schizophrenia (76%) were met in C1 (χ2=13.41, p<0.001). Also, different clinical-biological correlations were found in these clusters. Particularly, negative correlations of baseline NE activity with PANSS general psychopathology subscale scores (R=-0.39, p<0.05) and with total PANSS scores (R=-0.39, p<0.05) were found in C1. Positive correlation of GST activity with PANSS positive subscale score was found in C2 (R=0.43, p<0.05). Conclusions The revealed clusters differ in the extent of the glutathione antioxidant system impairment and in levels of the immune response markers. The revealing of the patient subgroups on the basis of biological markers reflecting impairments in metabolic and immune systems can represent interest in the search for individual treatment approaches. Disclosure of Interest None Declared

OBJECTIVE:To search for possible connections between the anti-inflammatory activity of monocytes (PAM) and the activity of glutathione metabolic enzymes: glutathione reductase (GR) and glutathione-S-transferase (GT) in patients with depressive states (DS) within various mental pathologies, as well as between the studied biological parameters and clinical condition of patients. MATERIAL AND METHODS:Sixty-one women, aged 18-56 years, with DC were examined before and after treatment. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Depressive Symptom Rating Scale (HDRS-21). The control group included 23 women of the corresponding age without mental pathology. Biological parameters were assessed in the peripheral blood of patients and healthy people. RESULTS:Patients with a high level of PAM compared to the control (p<0.001) (subgroup 1, n=31) and with a low (at the control level) level (subgroup 2, n=30) were identified. In the subgroup 1, the values of GR and GT were significantly lower than in patients of subgroup 2 (p<0.05 and p<0.01, respectively). Negative correlations between the level of PAM before treatment and GR before and after treatment were revealed in patients who responded to treatment (r=-0.67; p=0.0041; r=-0.76; p=0.0001). CONCLUSION:The results may indicate the inverse relationship between the level of PAM and the activity of GR and GT, which are involved in the pathogenesis of DC, and can also serve as criteria for assessing the response of patients to treatment.

Introduction Impairments in energy metabolism, glutamate neurotransmitter and antioxidant systems contribute substantially in development of schizophrenia spectrum disorders, especially in late-onset psychosis (LOP). Objectives Revealing subgroups of patients with LOP by determining activity of platelet enzymes of energy, glutamate, and glutathione metabolism. Methods 62 women of 52-89 years old were studied, with late onset schizophrenia spectrum disorders (F20.0, F25, F22.0, F06.2 by ICD-10). PANSS with its subscales was used to assess the severity of psychotic symptoms. Scores by PANSS and activity levels of platelet cytochrome c-oxidase (COX), glutamate dehydrogenase (GDH), glutathione reductase (GR) and glutathione-S-transferase (GST) were evaluated twice: before and on the 28-th day of antipsychotic treatment. Activities of COX, GDH, GR, and GST were measured in 37 women of 50-84 years old comprising the control group. Results Clustering of patients by the enzymatic activities resulted in 2 clusters (C1 and C2) significantly different by COX and GST (p<0.001). In C1 (n=40), as compared with control, reduced level of GDH activity before and after treatment (p=0.049 and p=0.032, respectively) and a reduced level of GR activity before treatment (p=0.026) were revealed. In C2 (n=22), as compared with the control, COX activity was increased before and after treatment (p=0.0001), GDH activity was decreased before and after treatment (p=0.0002 and p=0.0001, respectively), and GST activity was decreased before and after treatment (p=0.029 and p=0.0029, respectively). GR activity was not significantly changed in both clusters. Significant correlations were found between enzymatic activities and scores by psychometric scales: in C1, GR activity positively correlated with the score reduction (delta) by PANSS-Pos (R=0.45, p=0.004), by PANSS-Psy (R=0.44, p=0.005), and by PANSS (R=0.47, p=0.002), and GST activity – with the score reduction by PANSS-Psy (R=0.315, p=0.048). In C2 (n=22), GDH activity negatively correlated with the score reduction by PANSS-Pos (R=-0.41, p=0.050) and by PANSS (R=-0.49, p=0.021). Conclusions The different correlations revealed in two separated clusters between enzymatic activity levels and clinical measures characterizing the antipsychotic treatment efficacy will allow us to approach differentiated predicting the effectiveness of pharmacotherapy using the biochemical parameters. Disclosure of Interest None Declared

Introduction The data of current research indicate the participation of systemic inflammation in the pathogenesis of endogenous psychoses. Changes in the level of peripheral immune markers are associated with the development of neuroinflammation and correlate with the severity of psychopathological symptoms detected in patients. However, the association between individual components of the immune system involved in the development of endogenous psychosis remains poorly understood. Objectives To study the connection between molecular and cellular components of the immune system in women with endogenous psychoses with depressive-delusional symptoms. Methods 32 female patients aged 23 [17; 36] years with endogenous psychoses within different nosologies (F20, F21, F31, depressive-delusional conditions) and 17 women without clinical signs of psychiatric pathology were examined. The activity of leukocyte elastase (LE), α1-proteinase inhibitor (α1-PI), the proportion of four subpopulations of monocytes (classical CD14++CD16-, intermediate CD14++CD16+, nonclassical CD14+CD16+ and transitional CD14+CD16-) in plasma, activity of cytochrome-c oxidase (COX), glutamate dehydrogenase (GDH), glutathione s-transferase (GST) and glutathione reductase (GR) in platelets and functional activity of complement system (faCS) in serum were determined. The PANSS scale was used to assess the severity of psychopathological symptoms. Results Increased activity of the inflammatory markers LE (p=0.033) and α1-PI (p=0.02) was found in the plasma of the patients. Increased percentage of pro-inflammatory monocytes (intermediate and transient) in plasma (p=0.003) was confirmed by negative correlations between CD14++CD16- and CD14++CD16+ (R=-0.685, p=0.00002), CD14++CD16- and CD14+CD16- (R=-0.608, p=0.0002), CD14++CD16- and CD14+CD16+ (R=-0.424, p=0.002). A decrease in GDH activity (p=0.0079), GST activity (p=0.002) and GR activity (p=0.0006) was observed in patient platelets, which can reflect changes in the activity of intracellular metabolic pathways. A positive correlation was found between COX activity and α1-PI (R=0.51, p=0.025). A significant decrease in faCS compared to control (p=0.0003) and a negative correlation between faCS and GST activity (R=-0.496, p=0.011) were observed. faCS was positively correlated with the degree of reduction in the PANSS score (R=0.416, p=0.038). Conclusions The revealed connection between molecular and cellular components of the immune system in patients with endogenous psychoses reflect activation of the systemic inflammatory response accompanied by changes in the ratio of monocyte subpopulations and impaired regulation of the complement system. The data obtained can be used to develop methods of monitoring patients taking into account their immunological features. Disclosure of Interest None Declared

Introduction The studies on various groups of patients with schizophrenia revealed impairments in immune system, glutamatergic, and antioxidant systems contributing substantially in schizophrenia pathogenesis. Objectives To search for links between the activities of platelet enzymes involved in glutamate and glutathione metabolism and monocytes’ subpopulation compositions in patients with schizophrenia and to identify possible correlations of the biomarkers with clinical data. Research objectives: determination of subpopulation ratio of monocytes; measurement of the activity levels of glutamate dehydrogenase (GDH), phosphate-activated glutaminase (PAG), glutathione reductase (GR) and glutathione S-transferase (GST) in blood platelets; search for correlations between these parameters and the scores by psychometric scales. Methods The study included 36 women aged 16-45 years with acute schizophrenia hospitalized in the Mental Health Research Centre with their current condition assessed as depressive-delusional. The control group consisted of 17 women 18-45 years old without somatic or mental pathology. GDH, PAG, GR and GST activities were measured by spectrophotometric methods, and numbers of monocyte subpopulations - “classical”, “intermediate”, “non-classical” - by flow cytometry. The Hamilton Depression Rating Scale (HAMD-17) was used to assess depression severity. The data was processed using the Statistica 8.0 software. Results The detected changes in monocyte subpopulations’ composition towards the increase in the proportion of cells having a pro-inflammatory phenotype (CD14++CD16+ “intermediate”) indicated the activation of inflammatory reactions. Also, the activities of platelet enzymes of glutathione metabolism (GR and GST) were significantly decreased (p<0.05). Moreover, GDH and GST activities significantly correlated with the scores by HAMD-17 (r=0.40, p=0.022 and r=0.45, p=0.030, respectively). The results indicate the presence of pathological inflammatory process, the decrease in activities of glutathione antioxidant metabolism enzymes and a link to glutamate metabolism involvement (GDH) in the studied patient group. Conclusions The identified redistribution in the monocyte subpopulations’ composition and decrease in the activity of enzymes involved in glutamate metabolism and antioxidant system indicate the involvement of the immune, glutamate and antioxidant systems in the pathogenesis of schizophrenia and may reflect a functional interaction between these systems. Disclosure of Interest None Declared

Introduction We have previously found significant alterations in activities of glutathione dependent enzymes in blood cells of patients with late-life depression (LLD) compared with age-matched controls. Objectives The revealing subgroups of LLD patients by glutathione-metabolism enzymes’ activities in blood cells using cluster analysis. Methods LLD patients (n=101) of 60-86 age (69 patients with recurrent depression (RD), 23 with bipolar disorder (BD) and 9 patients with a single depressive episode (DE)) were assessed by Hamilton depression rating scale (HAMD-17), and Hamilton Anxiety Rating Scale (HARS). Activity levels of glutathione reductase (GR) and glutathione S-transferase (GST) were determined in patients’ platelets (-pl) and erythrocytes (-er). The control group consisted of 51 peoples 55-84 years old without mental pathology. Cluster analysis module of the STATISTICA software was used for clustering the patients by baseline blood parameters. Results Three clusters of patients were obtained: C1, n=39, C2, n=31, C3, n=31, differing significantly in all biochemical parameters (Kruskal-Wallis test, p<0.001), except GST. When compared with control group by Mann-Whitney test, GST-pl, GST-er, and GR-er were significantly decreased in C1; GST-er was significantly increased in C2; GST-pl, GR-pl, and GR-er were significantly decreased in C3. Several significant correlations were found between the measured parameters and scores by HDRS or HAMD-17. In C1, baseline activity of GST-er correlated with total scores by HAMD-17 (R=0.335, p=0.043) after treatment. In C2, baseline activity of GR-er correlated with total scores by HARS (R=-0.376, p=0,037) after treatment and GR-pl correlated with delta scores by HAMD-17 under the treatment (R=0.484, p=0.006). No significant correlations were found in C3. Patients with BD distributed significantly unevenly between C1, C2, and C3, with significantly more BD patients clustering in C1 (61%) compared with C2 and C3 (Yetes-corrected Chi-square =7.73, p=0.0054), whereas patients with RD and DE distributed evenly. Conclusions Patterns of activity levels for glutathione-dependent enzymes in patients with BD differ from those in patients with RD and DE. Significant correlations of the measured biochemical parameters with scores by HDRS or HAMD-17 assessed after the treatment and evidenced for the treatment efficacy seem to be promising biomarkers for further evaluation of the treatment efficacy in heterogeneous group of LLD patients using the proposed approach to their stratification into subgroups. Disclosure of Interest None Declared

We aimed to screen children aged 18–48 months in the general population of nine Russian regions for risk of mental, behavioral and developmental disorders (MBDDs) including autism spectrum disorders (ASD) using an original screening tool. The prevalence of the risk for MBDDs is 1307:10,000 (13.07

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.