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Objective: To assess the possibility of achieving physiological ketosis with oral administration of beta-hydroxybutyrate salts and, if ketosis is achieved, to assess its effect on cognitive functioning in patients with brain dysfunction during the recovery period after a somatic disease., Material and Methods: The study included 86 patients with complaints of asthenic manifestations (ICD-10 diagnoses F06; F07; R53). Half of the patients were included in the study group taking beta-hydroxybutyrate salts, and the other half were included in the control group taking placebo. The duration of administration was 15 days. The content of ketones in the blood was assessed immediately before and after taking the drug on the first and last days of the study. Subjective severity of asthenia manifestations was assessed using a visual-analog scale (VAS). The Montreal Cognitive Assessment and the Trial Making Test (TMT) were used to assess cognitive functions., Results: The control and study groups did not differ significantly in subjective and objective indicators of mental performance before taking the drug. At the end of the study, the blood ketone content in the experimental group was statistically significantly higher than in the control group. Physiological ketosis was achieved in 29 patients of the experimental group (67%). By the end of the study, the experimental group showed a significant improvement in all cognitive tests. At the same time, by the end of the study, only an improvement in TMT-A performance was noted in the control group. Also, in the experimental group, statistically significantly more patients achieved a significant improvement in mental performance on VAS tasks., Conclusion: The results confirm the hypothesis that oral administration of beta-hydroxybutyrate can stimulate physiological ketosis. A significant positive dynamics of cognitive functioning of patients and a decrease in the severity of asthenia during beta-hydroxybutyrate intake are noted.

Objective: To study the relationship of the parameters of immunity and systemic inflammation with the structural magnetic resonance imaging (MRI) parameters in patients with mild cognitive impairment (MCI) and pre-MCI undergoing neurocognitive rehabilitation to search for candidate markers of its effectiveness., Material and Methods: The main group included 49 patients, aged ≥60 years, with MCI and pre-MCI with memory impairment, who underwent a course of neurorehabilitation for 5 weeks. The control group included 19 volunteers of similar age with a total MoCA score of ≥25, who did not have cognitive impairment and immuno-inflammatory disorders. The parameters of cellular and humoral immunity and markers of inflammation were studied, and structural MRI was performed., Results: The content of activated natural killer cells (NK-cells) was increased in MCI and pre-MCI (0.63±0.12% vs. 0.22±0.07% in the control group, p =2.2·10 -7 ). The level of immunoglobulin G (IgG) <12.5 g/l in patients with MCI and pre-MCI with the Montreal Cognitive Assessment Scale (MoCA) score <22 was associated with a decrease in the volume of the right nucleus accumbens (376±35 mm 3 in patients with IgG <12.5 g/l ( p =0.0013) and 480±44 mm 3 at IgG <12.5 g/l, 480±44 mm 3 in the control group), as well as with a decrease of the thickness and volume of a number of other cortical zones. A logistic regression model including the level of immunoglobulin G, NK cells, CD8+ NK cells and right amygdala volume was constructed to predict the number of MoCA scores 6 months after the course of rehabilitation (R 2 =0.57; p <1·10 -5 ; standard error of estimate: 2.93)., Conclusion: As a result of this work, the perspectives of assessing the immunological parameters in combination with socio-demographic data and morphometric changes of the brain as potential prognostic markers of the dynamics of cognitive impairment in patients with MCI and pre-MCI after neurorehabilitation has been shown.

Objective: To compare the content of β-amyloid (Aβ) peptides Aβ40, Aβ42, total and threonine phosphorylated 181 tau-protein in cerebrospinal fluid (CSF) of patients with the clinical diagnosis of Alzheimer's disease (AD)., Material and Methods: The study was performed on 64 patients with a diagnosis of dementia and MMSE scores of 24 or lower. All patients underwent lumbar puncture. Aβ40, Aβ42, Aβ42/40 ratio, total tau, phosphorylated tau at threonine 181 were determined in the CSF using a multiplex assay according to the manufacturer's protocol, the concentration was determined in pkg/ml., Results: The preliminary diagnosis of AD was made in 3 patients (5%). As a result of the study of protein content in the CSF, signs of AD were detected in 48 (75%) people. The findings suggest that the diagnosis of AD is made 10-14 times less frequently than it should be according to the World Health Organization data. The discrepancy between clinical diagnosis and laboratory findings is confirmed by our study., Conclusion: Differences in the therapy of dementias and the development of new drugs targeting specific links in the pathogenesis of different types of dementias require accurate and complete diagnosis of dementias, especially AD, as the most common type of dementia.

Objective: To study the efficiency of the neuropsychological rehabilitation of patients with mild cognitive impairments., Material and Methods: The study included 103 elderly people, aged 59 to 88 years, including 90 women and 13 men with subjective complaints of memory loss (ICD-10: F06.70; F06.71; F06.78; F06.79). Participants were divided into experimental group ( n =43) and comparison group ( n =42). The estimated impact was the rehabilitation program «The psychosocial therapy and neurocognitive rehabilitation of elderly patients with cognitive impairments», within which the principle of complex stimulation of various parameters of the cognitive sphere was used in rehabilitation work with patients in the experimental group in accordance with the «Memory Clinic» program. The study was conducted using randomized, equalized comparison groups, and the principle of «triple-blind» research. Non-parametric statistics (SPSS) methods were used to assess differences., Results: A significant difference between the comparison and experimental groups has been identified, primarily in relation to high-level mental processes associated with the function of the third structural-functional block according to A.R. Luria. After the training, the number of correct answers significantly increased ( t (42)=-2.67, p <0.001) in the experimental group, while in the comparison group the indicator did not change ( t (41)=0.50, p =0.617). The number of false alarms in the experimental group decreased significantly ( t (42)=2.13, p =0.039)., Conclusion: The results confirm the leading role of these processes in the hierarchy of mental functions, which suggests that they should primarily be targets of rehabilitation interventions.

Objective: To develop a systematics of chronic delusional psychoses in schizophrenia and pathology of the schizophrenic spectrum that takes into account psychopathological structure (the mechanism of delusional formation) and the trajectories of the disease course (the ratio of negative/positive dimensions)., Material and Methods: The study sample was recruited from the large Moscow psychiatric hospital in 2019-2024 and included 126 patients (94 male, 32 female, mean age 36.5±12.1 years) hospitalized with ICD-10 diagnosis of paranoid schizophrenia (F20.00) or delusional disorder (F22). A clinical-psychopathological method was used., Results: The study identifies three variants of paranoid domains, the typology of which takes into account both the psychopathological structure and the trajectories of their development, which determine the dominance of predominantly negative or positive symptoms throughout the disease: 1) psychosis with delusional interpretations and predominant orientation of symptoms towards the negative pole of the schizophrenia psychopathology ( n =37, 29.4%); 2) psychosis with hallucinatory delusions and predominant direction of symptoms towards the positive pole of the schizophrenia psychopathology ( n =50, 39.7%); and 3) «combined» hallucinatory-delusional psychosis with a simultaneous orientation of symptoms to the negative/positive poles of the schizophrenia psychopathology ( n =39, 30.9%). Detailed phenomenological characteristics of each of the three presented variants are given., Conclusion: The developed three-component taxonomy confirms, on the model of chronic delusional psychoses appearing in schizophrenia and the pathology of the schizophrenia spectrum, the concept of simultaneous representation of two relatively independent domains determined by neurobiological processes in the schizophrenia psychopathology positive and negative disorders.

Background: Self-esteem and depressive symptoms contribute to a lower quality of life in people suffering from eating disorders. However, limited research has examined whether other factors may affect how these variables influence one another over time. Metacognition is a previously unexplored determinant that may impact the relationships between self-esteem, depressive symptoms, and quality of life in instances of eating disorders., Aim: This study sought to examine metacognitive self-reflectivity and mastery as moderators of the relationships between self-esteem, depressive symptoms, and quality of life and to determine if these relationships are different in people with anorexia compared with people with bulimia., Methods: Participants with anorexia ( n= 40) and bulimia ( n= 40) were recruited from outpatient clinics. The participants were assessed on their metacognitive ability and self-reported on measures to assess their depressive symptoms, self-esteem, and quality of life., Results: The results indicate that metacognitive self-reflectivity moderates the relationship between self-esteem, depressive symptoms, and quality of life in people with anorexia such that when self-reflectivity is high, lower self-esteem and higher depressive symptoms are associated with a lower quality of life. These relationships did not appear to be significant when self-reflectivity was low. In contrast, in the anorexia and bulimia groups, metacognitive mastery appeared to moderate the relationships between self-esteem, depressive symptoms, and quality of life such that when mastery was low, lower self-esteem and higher depressive symptoms were associated with a lower quality of life. These relationships did not appear significant when mastery was high., Conclusion: Metacognitive self-reflectivity and mastery seem to play paradoxical moderating roles in the relationships between self-esteem, depressive symptoms, and quality of life in people with anorexia and bulimia. These findings pave the way toward further research and have important clinical implications., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023, Springfield C.R., Bonfils K.A., Chernov N.V., Moiseeva T.V., Sozinova M.V., Dmitryeva N.G., Lysaker P.H., Karpenko O.A., Kostyuk G.P.)

Background: Transcriptomic studies of the brains of schizophrenia (SZ) patients have produced abundant but largely inconsistent findings about the disorders pathophysiology. These inconsistencies might stem not only from the heterogeneous nature of the disorder, but also from the unbalanced focus on particular cortical regions and protein-coding genes. Compared to protein-coding transcripts, long intergenic non-coding RNA (lincRNA) display substantially greater brain region and disease response specificity, positioning them as prospective indicators of SZ-associated alterations. Further, a growing understanding of the systemic character of the disorder calls for a more systematic screening involving multiple diverse brain regions., Aim: We aimed to identify and interpret alterations of the lincRNA expression profiles in SZ by examining the transcriptomes of 35 brain regions., Methods: We measured the transcriptome of 35 brain regions dissected from eight adult brain specimens, four SZ patients, and four healthy controls, using high-throughput RNA sequencing. Analysis of these data yielded 861 annotated human lincRNAs passing the detection threshold., Results: Of the 861 detected lincRNA, 135 showed significant region-dependent expression alterations in SZ (two-way ANOVA, BH-adjusted p 0.05) and 37 additionally showed significant differential expression between HC and SZ individuals in at least one region ( post hoc Tukey test, p 0.05). For these 37 differentially expressed lincRNAs (DELs), 88% of the differences occurred in a cluster of brain regions containing axon-rich brain regions and cerebellum. Functional annotation of the DEL targets further revealed stark enrichment in neurons and synaptic transmission terms and pathways., Conclusion: Our study highlights the utility of a systematic brain transcriptome analysis relying on the expression profiles measured across multiple brain regions and singles out white matter regions as a prospective target for further SZ research., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023, Nguyen T., Efimova O.I., Tokarchuk A.V., Morozova A.Y., Zorkina Y.A., Andreyuk D.S., Kostyuk G.P., Khaitovich P.E.)

Despite of multiple systematic studies of schizophrenia based on proteomics, metabolomics, and genome-wide significant loci, reconstruction of underlying mechanism is still a challenging task. Combination of the advanced data for quantitative proteomics, metabolomics, and genome-wide association study (GWAS) can enhance the current fundamental knowledge about molecular pathogenesis of schizophrenia. In this study, we utilized quantitative proteomic and metabolomic assay, and high throughput genotyping for the GWAS study. We identified 20 differently expressed proteins that were validated on an independent cohort of patients with schizophrenia, including ALS, A1AG1, PEDF, VTDB, CERU, APOB, APOH, FASN, GPX3, etc. and almost half of them are new for schizophrenia. The metabolomic survey revealed 18 group-specific compounds, most of which were the part of transformation of tyrosine and steroids with the prevalence to androgens (androsterone sulfate, thyroliberin, thyroxine, dihydrotestosterone, androstenedione, cholesterol sulfate, metanephrine, dopaquinone, etc.). The GWAS assay mostly failed to reveal significantly associated loci therefore 52 loci with the smoothened p < 10 -5 were fractionally integrated into proteome-metabolome data. We integrated three omics layers and powered them by the quantitative analysis to propose a map of molecular events associated with schizophrenia psychopathology. The resulting interplay between different molecular layers emphasizes a strict implication of lipids transport, oxidative stress, imbalance in steroidogenesis and associated impartments of thyroid hormones as key interconnected nodes essential for understanding of how the regulation of distinct metabolic axis is achieved and what happens in the conditioned proteome and metabolome to produce a schizophrenia-specific pattern., (© 2023. The Author(s).)

Oxidized in vitro genomic DNA (gDNA) is known to launch an adaptive response in human cell cultures. The cfDNA extracted from the plasma of schizophrenic patients (sz-cfDNA) and healthy controls (hc-cfDNA) contains increased amounts of 8-oxodG, a DNA-oxidation marker. The aim of the research was answering a question: can the human cfDNA isolated from blood plasma stimulate the adaptive response in human cells? In vitro responses of ten human skin fibroblasts (HSFs) and four peripheral blood mononuclear cell (PBMC) lines after 1-24 h of incubation with sz-cfDNA, gDNA and hc-cfDNA containing different amounts of 8-oxodG were examined. Expressions of RNA of eight genes ( NOX4, NFE2L2, SOD1, HIF1A, BRCA1, BRCA2, BAX and BCL2 ), six proteins (NOX4, NRF2, SOD1, HIF1A, γH2AX and BRCA1) and DNA-oxidation marker 8-oxodG were analyzed by RT-qPCR and flow cytometry (when analyzing the data, a subpopulation of lymphocytes (PBL) was identified). Adding hc-cfDNA or sz-cfDNA to HSFs or PBMC media in equal amounts (50 ng/mL, 1-3 h) stimulated transient synthesis of free radicals (ROS), which correlated with an increase in the expressions of NOX4 and SOD1 genes and with an increase in the levels of the markers of DNA damage γH2AX and 8-oxodG. ROS and DNA damage induced an antioxidant response (expression of NFE2L2 and HIF1A ), DNA damage response ( BRCA1 and BRCA2 gene expression) and anti-apoptotic response (changes in BAX and BCL2 genes expression). Heterogeneity of cells of the same HSFs or PBL population was found with respect to the type of response to (sz,hc)-cfDNA. Most cells responded to oxidative stress with an increase in the amount of NRF2 and BRCA1 proteins along with a moderate increase in the amount of NOX4 protein and a low amount of 8-oxodG oxidation marker. However, upon the exposure to (sz,hc)-cfDNA, the size of the subpopulation with apoptosis signs (high DNA damage degree, high NOX4 and low NRF2 and BRCA1 levels) also increased. No significant difference between the responses to sz-cfDNA and hc-cfDNA was observed. Sz-cfDNA and hc-cfDNA showed similarly high bioactivity towards fibroblasts and lymphocytes. Conclusion: In cultured human cells, hc-cfDNA and sz-cfDNA equally stimulated an adaptive response aimed at launching the antioxidant, repair, and anti-apoptotic processes. The mediator of the development of the adaptive response are ROS produced by, among others, NOX4 and SOD1 enzymes.

Introduction : Mild cognitive impairments (MCI) accompanying aging are associated with oxidative stress. The ability of cells to respond to stress is determined by the protein synthesis level, which depends on the ribosomes number. Ribosomal deficit was documented in MCI. The number of ribosomes depends, together with other factors, on the number of ribosomal genes copies. We hypothesized that MCI is associated with low rDNA CN in the elderly person genome. Materials and Methods: rDNA CN and the telomere repeat (TR) content were determined in the DNA of peripheral blood leukocytes of 93 elderly people (61-91 years old) with MCI and 365 healthy volunteers (16-91 years old). The method of non-radioactive quantitative hybridization of DNA with biotinylated DNA probes was used for the analysis. Results: In the MCI group, rDNA CN (mean 329 ± 60; median 314 copies, n = 93) was significantly reduced ( p < 10 -15 ) compared to controls of the same age with preserved cognitive functions (mean 412 ± 79; median 401 copies, n = 168) and younger (16-60 years) control group (mean 426 ± 109; median 416 copies, n = 197). MCI is also associated with a decrease in TR DNA content. There is no correlation between the content of rDNA and TR in DNA, however, in the group of DNA samples with rDNA CN > 540, TR content range was significantly narrowed compared to the rest of the sample. Conclusion: Mild cognitive impairment is associated with low ribosomal genes copies in the elderly people genomes. A low level of rDNA CN may be one of the causes of ribosomal deficit that was documented in MCI. The potential possibilities of using the rDNA CN indicator as a prognostic marker characterizing human life expectancy are discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Veiko, Ershova, Veiko, Umriukhin, Kurmyshev, Kostyuk, Kutsev and Kostyuk.)

Major depressive disorder (MDD) is among the most prevalent mental disorders worldwide. Factors causing the pathogenesis of MDD include gut microbiota (GM), which interacts with the host through the gut-brain axis. In previous studies of GM in MDD patients, 16S rRNA sequencing was used, which provided information about composition but not about function. In our study, we analyzed whole metagenome sequencing data to assess changes in both the composition and functional profile of GM. We looked at the GM of 36 MDD patients, compared with that of 38 healthy volunteers. Comparative taxonomic analysis showed decreased abundances of Faecalibacterium prausnitzii , Roseburia hominis , and Roseburia intestinalis , and elevated abundances of Escherichia coli and Ruthenibacterium lactatiformans in the GM of MDD patients. We observed decreased levels of bacterial genes encoding key enzymes involved in the production of arginine, asparagine, glutamate, glutamine, melatonin, acetic, butyric and conjugated linoleic acids, and spermidine in MDD patients. These genes produced signature pairs with Faecalibacterium prausntizii and correlated with decreased levels of this species in the GM of MDD patients. These results show the potential impact of the identified biomarker bacteria and their metabolites on the pathogenesis of MDD, and should be confirmed in future metabolomic studies.

Introduction: Increased systemic oxidative stress is common in schizophrenia (SZ) patients. NADPH-oxidase 4 (NOX4) is the cell oxidoreductase, catalyzing the hydrogen peroxide formation. Presumably, NOX4 is the main oxidative stress factor in a number of diseases such as cardiovascular diseases and cancer. We hypothesized that NOX4 may be involved in the oxidative stress development caused by the disease in the schizophrenic patients' peripheral blood lymphocytes (PBL)., Materials and Methods: The SZ group included 100 patients (68 men and 32 women aged 28 ± 11 years). The control group included 60 volunteers (35 men and 25 women aged 25 ± 12 years). Flow cytometry analysis (FCA) was used for DNA damage markers (8-oxodG, ɣH2AX), pro- and antiapoptotic proteins (BAX1 and BCL2) and the master-regulator of anti-oxidant response NRF2 detection in the lymphocytes of the untreated SZ patients (N = 100) and the healthy control (HC, N = 60). FCA and RT-qPCR were used for NOX4 and RNANOX4 detection in the lymphocytes. RT-qPCR was used for mtDNA quantitation in peripheral blood mononuclear cells. Cell-free DNA concentration was determined in blood plasma fluorimetrically., Results: 8-oxodG, NOX4, and BCL2 levels in the PBL in the SZ group were higher than those in the HC group (p < 0.001). ɣH2AX protein level was increased in the subgroup with high 8-oxodG (p<0.02) levels and decreased in the subgroup with low 8-oxodG (p <0.0001) levels. A positive correlation was found between 8-oxodG, ɣH2AX and BAX1 levels in the SZ group (p <10-6). NOX4 level in lymphocytes did not depend on the DNA damage markers values and BAX1 and BCL2 proteins levels. In 15% of PBL of the HC group a small cellular subfraction was found (5-12% of the total lymphocyte pool) with high DNA damage level and elevated BAX1 protein level. The number of such cells was maximal in PBL samples with low NOX4 protein levels., Conclusion: Significant NOX4 gene expression was found a in SZ patients' lymphocytes, but the corresponding protein is probably not a cause of the DNA damage., Competing Interests: The authors have declared that no competing interests exist.

Schizophrenia is associated with low-grade systemic inflammation. Circulating cell-free DNA (c-cfDNA) belongs to the DAMP class. The major research question was: can the c-cfDNA of schizophrenic patients (sz-cfDNA) stimulate the DNA sensor genes, which control the innate immunity? We investigated the in vitro response of ten human skin fibroblast (HSF) lines to five DNA probes containing different amounts of a GC-rich marker (the ribosomal repeat) and a DNA oxidation marker (8-oxodG) including sz-cfDNA and healthy control c-cfDNA (hc-cfDNA) probes. After 1 h, 3 h, and 24 h of incubation, the expression of 6 protein genes responsible for cfDNA transport into the cell (EEA1 and HMGB1) and the recognition of cytosolic DNA (TLR9, AIM2, STING and RIG-I) was analyzed at the transcriptional (RT-qPCR) and protein level (flow cytometry and fluorescence microscopy). Additionally, we analyzed changes in the RNA amount of 32 genes (RT-qPCR), which had been previously associated with different cellular responses to cell-free DNA with different characteristics. Adding sz-cfDNA and hc-cfDNA to the HSF medium in equal amounts (50 ng/mL) blocked endocytosis and stimulated TLR9 and STING gene expression while blocking RIG-I and AIM2 expression. Sz-cfDNA and hc-cfDNA, compared to gDNA, demonstrated much stronger stimulated transcription of genes that control cell proliferation, cytokine synthesis, apoptosis, autophagy, and mitochondrial biogenesis. No significant difference was observed in the response of the cells to sz-cfDNA and hc-cfDNA. Sz-cfDNA and hc-cfDNA showed similarly high biological activity towards HSFs, stimulating the gene activity of TLR9 and STING DNA sensor proteins and blocking the activity of the AIM2 protein gene. Since the sz-cfDNA content in the patients' blood is several times higher than the hc-cfDNA content, sz-cfDNA may upregulate pro-inflammatory cytokines in schizophrenia.

Background: COVID-19 treatment remains a challenge for medicine because of the extremely short time for clinical studies of drug candidates, so the drug repurposing strategy, which implies the use of well-known and safe substances, is a promising approach. Objective: We present the results of an observational clinical study that focused on the influence of riboflavin (vitamin B2) supplementation on the immune markers of COVID-19 severity in patients with mental health disorders. Results: We have found that 10 mg of flavin mononucleotide (a soluble form of riboflavin) intramuscularly twice a day within 7 days correlated with the normalization of clinically relevant immune markers (neutrophils and lymphocytes counts, as well as their ratio) in COVID-19 patients. Additionally, we demonstrated that total leucocytes, neutrophils, and lymphocytes counts, as well as the neutrophils to leucocytes ratio (NLR), correlated with the severity of the disease. We also found that patients with organic disorders (F0 in ICD-10) demonstrated higher inflammation then patients with schizophrenia (F2 in ICD-10). Conclusion: We suggest that riboflavin supplementation could be promising for decreasing inflammation in COVID-19, and further evaluation is required. This observational clinical trial has been registered by the Sverzhevsky Research Institute of Clinical Otorhinolaryngology (Moscow, Russia), Protocol No. 4 dated 05/27/2020., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Akasov, Khaydukov, Andreyuk, Sholina, Sheremeta, Romanov, Kostyuk, Panchenko and Kovalchuk.)

Introduction: As shown earlier, copy number variations (CNV) in the human satellite III (1q12) fragment (f-SatIII) and the telomere repeat (TR) reflects the cell's response to oxidative stress. The contents of f-SatIII and TR in schizophrenic (SZ) patients were found to be lower than in healthy controls (HC) in previous studies. The major question of this study was: 'What are the f-SatIII and TR CNV dynamic changes in human leukocytes, depending on psychoemotional stress?', Materials and Methods: We chose a model of psychoemotional stress experienced by second-year medical students during their exams. Blood samples were taken in stressful conditions (exams) and in a control non-stressful period. Biotinylated probes were used for f-SatIII, rDNA, and TR quantitation in leukocyte DNA by non-radioactive quantitative hybridization in SZ patients ( n = 97), HC ( n = 97), and medical students ( n = 17, n = 42). A flow cytometry analysis was used for the oxidative stress marker (NOX4, 8-oxodG, and γH2AX) detection in the lymphocytes of the three groups., Results: Oxidative stress markers increased significantly in the students' lymphocytes during psychoemotional stress. The TR and f-SatIII, but not the rDNA, contents significantly changed in the DNA isolated from human blood leukocytes. After a restoration period (post-examinational vacations), the f-SatIII content decreased, and the TR content increased. Changes in the blood cells of students during examinational stress were similar to those in SZ patients during an exacerbation of the disease., Conclusions: Psychoemotional stress in students during exams triggers a universal mechanism of oxidative stress. The oxidative stress causes significant changes in the f-SatIII and TR contents, while the ribosomal repeat content remains stable. A hypothesis is proposed to explain the quantitative polymorphisms of f-SatIII and TR contents under transient (e.g., students' exams) or chronic (in SZ patients) stress. The changes in the f-SatIII and TR copy numbers are non-specific events, irrespective of the source of stress. Thus, our findings suggest that the psychoemotional stress, common in SZ patients and healthy students during exams, but not in a schizophrenia-specific event, was responsible for the changes in the repeat contents that we observed earlier in SZ patients.

Genotype - phenotype relationships are considered in view of recent advances in our understanding of genome structure. Different DNA elements can contribute to phenotype formation. Genotype - phenotype relationships are mediated by epigenetic effects that can have various origins - from the most studied to date methylation of certain sites in the genome to only developing ideas about the role of remote regulatory genomic elements in the development of schizophrenia. The transition to a more in-depth study of genotype - phenotype relationships is relevant for the current period of molecular-genetic studies of schizophrenia. Obviously, the concept of phenotype as applied to schizophrenia is not limited to a causal reflection of changes in the structure of a particular gene, but is the product of the combined effect of environmental factors and epigenetic changes that affect gene expression, taking into account tissue specificity and the degree of cell stimulation.

Objective: An analysis of clinical and social characteristics of patients aged 40 years and older with primary diagnosis of schizophrenia (F 20-21) in a psychiatric hospital., Material and Methods: We studied 114 medical records of patients aged 40 and over who were admitted to a psychiatric hospital for a two-year period (2018-2019) with a first-time diagnosis of schizophrenia (F 20-21) based on the results of inpatient examination and treatment., Results: The analysis shows that 90% of patients were aged 40-59 years, 59.6% of them were women. In every third patient (33.3%), clinical signs of psychosis were observed for five or more years before hospitalization and diagnosis, and in 14.9% for more than 10 years, the average duration of psychosis before diagnosis was 5.1 years. Markers of psychosis were non-specific factors of family adaptation, working capacity, and substance use, which revealed relationships with gender characteristics and age of diagnosis of psychosis. Better adaptation parameters correlated with the female sex and later diagnosis of schizophrenia, lower indicators were more typical for the male sex and earlier diagnosis., Conclusion: Signs of increasing social maladjustment should be alarming to the patient's relatives, as well as social and medical services. In addition, the timely diagnosis of psychosis requires psychoeducation of the population, training of social workers and primary health care professionals.

Objective: To investigate the effects of diet on the gut microbiota and to assess the relationship of these factors with depression., Material and Methods: Microorganisms that predominate in depressed patients were identified and associations of the identified organisms with the patients' diet were performed. Fourteen depressed patients and 14 healthy volunteers with the same socio-demographic parameters were included in the study. The Hamilton Depression Scale, Generalized Anxiety Disorder Questionnaire, and the Center for Epidemiologic Studies Questionnaire were used., Results: Erysipelatoclostridium and Clostridium innocuum species were 11.3 and 14.4 times higher in depressed patients compared with healthy controls. Fusicatenibacter saccharivorans, Faecalibacterium prausnitzii and Roseburia faecis species , as well as members of the genus Roseburia were statistically significantly more abundant in the healthy volunteers group (6.5, 2.14, 8.75 and 5.2 times more frequently compared to patients). The presence of these microorganisms was correlated with dietary components., Conclusion: Our study revealed groups of microorganisms that differ in healthy volunteers and depressed patients. The association of these microorganisms with the diet was shown, which partially confirmed the influence of a «healthy diet» on the development of depressive disorders.

Introduction: Schizophrenia, although a debilitating mental illness, greatly affects individuals' physical health as well. One of the leading somatic comorbidities associated with schizophrenia is cardiovascular disease, which has been estimated to be one of the leading causes of excess mortality in patients diagnosed with schizophrenia. Although the shared susceptibility to schizophrenia and cardiovascular disease is well established, the mechanisms linking these two disorders are not well understood. Genetic studies have hinted toward shared lipid metabolism abnormalities co-occurring in the two disorders, while lipid compounds have emerged as prognostic markers for cardiovascular disease. In particular, three ceramide species in the blood plasma, Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1), have been robustly linked to the latter disorder., Aim: We aimed to assess the differences in abundances of Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) in the blood plasma of schizophrenia patients compared to healthy controls., Methods: We measured the abundances of Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) in a cohort of 82 patients with schizophrenia and 138 controls without a psychiatric diagnosis and validated the results using an independent cohort of 26 patients with schizophrenia, 55 control individuals, and 19 patients experiencing a first psychotic episode., Results: We found significant alterations for all three ceramide species Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) and a particularly strong difference in concentrations between psychiatric patients and controls for the ceramide species Cer(d18:1/18:0)., Conclusions: The alteration of Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) levels in the blood plasma might be a manifestation of metabolic abnormalities common to both schizophrenia and cardiovascular disease., Competing Interests: Conflict of interests: The authors declare no conflict of interest., (© Authors, 2021.)

The association between cancer risk and schizophrenia is widely debated. Despite many epidemiological studies, there is still no strong evidence regarding the molecular basis for the comorbidity between these two pathological conditions. The vast majority of assays have been performed using clinical records of schizophrenic patients or those undergoing cancer treatment and monitored for sufficient time to find shared features between the considered conditions. We performed mass spectrometry-based proteomic and metabolomic investigations of patients with different cancer phenotypes (breast, ovarian, renal, and prostate) and patients with schizophrenia. The resulting vast quantity of proteomic and metabolomic data were then processed using systems biology and one-dimensional (1D) convolutional neural network (1DCNN) machine learning approaches. Traditional systematic approaches permit the segregation of schizophrenia and cancer phenotypes on the level of biological processes, while 1DCNN recognized "signatures" that could segregate distinct cancer phenotypes and schizophrenia at the comorbidity level. The designed network efficiently discriminated unrelated pathologies with a model accuracy of 0.90 and different subtypes of oncophenotypes with an accuracy of 0.94. The proposed strategy integrates systematic analysis of identified compounds and application of 1DCNN model for unidentified ones to reveal the similarity between distinct phenotypes., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: ICD-11 implementation will start in early 2022 in WHO member countries, including Russia. This process should be preceded not only by the official translation and wide distribution of ICD-11 statistical classification and diagnostic guidelines but also by clinicians' training. For recent years ICD-11 development and innovations in the diagnosis of mental disorders were in the focus of attention of mental health professionals in all over the world., Objectives: This online survey aimed to identify the current views of the Russian psychiatric community on the upcoming implementation of ICD-11., Methods: A survey was composed in a Google form and circulated through the website of the Russian Society of Psychiatrists and other professional networks. Statistical and narrative analysis was provided. The sample was represented by 148 psychiatrists working in inpatient or outpatient clinical settings., Results: Expectations for the classification of mental disorders reported by the respondents were wider than the current purpose of ICD-10. In general, the Russian psychiatrists expressed their interests to forthcoming ICD-11 implementation. Positive attitudes to ICD-11 innovations were associated with the familiarity with the ICD-11 draft. Conservative or negative views were related to longer years of clinical experience. Early carrier psychiatrists were more practically oriented than 'old school' clinicians., Conclusion: This survey may help to promote the ICD-11 by focusing on its advantages for clinical practice and develop targeted training programs., Competing Interests: Conflict of Interest: The authors report no conflicts of interest., (© Authors, 2021.)

Introduction: Associations of disturbances in innate and adaptive immunity during the clinical course of schizophrenia have been found in a number of studies. Yet, the relationship of immune parameters and systemic inflammation in relation to the clinical course of the disease and its prognosis, remains poorly understood, which highlights an interesting topic for further research. The goal of this study was to research the immuno-inflammatory changes in patients with clinical continuous and episodic paranoid schizophrenia, to assess the pathogenetic significance of these changes., Methods: Thirty-six patients with paranoid schizophrenia, of which 20 had episodic symptoms and 16 had continuous symptoms, consented to participate in the study, together with 30 healthy volunteers. In the study we assessed the parameters of innate immune response (serum levels of key pro-inflammatory and anti-inflammatory cytokines, C-reactive protein) and the adaptive immune response, including humoral-mediated immunity (serum immunoglobulins IgA, IgM, IgG, circulating immune complexes), as well as the cell link of adaptive immunity (key lymphocyte subpopulations). Positive and negative symptoms were assessed with the positive and negative symptoms scale; frontal dysfunction was assessed by Frontal Assessment Battery (FAB)., Results: Both patient groups had higher than normal levels of C-reactive protein and IL-8. There was a significant elevation of circulating immune complexes among patients with continuous symptoms of schizophrenia, compared to patients with episodic symptoms and healthy controls. Levels of CD45+CD3+ lymphocytes (T-cells) differed between clinical groups, with higher values identified among patients with episodic symptoms and lower values among those with continuous symptoms. In addition, patients with episodic symptoms had significantly increased levels of CD45+CD3+CD4+CD25+CD127- regulatory T-cells. Finally, the level of CD45+CD3-CD19+ B-cells was significantly higher among patients with continuous symptoms vs. patients with episodic symptoms and the control groups. Markers of activation of humoral immunity were associated with the severity of frontal disorders in these patients., Discussion: Comprehensive data on the serum level of cytokines and the parameters of adaptive immunity among individuals with continuous schizophrenia, by comparison with patients with episodic schizophrenia, are practically absent in the literature. We have shown that among those with continuous schizophrenia, there are signs of systemic inflammation and chronic activation of the adaptive humoral immune response, while among patients with episodic symptoms of the disease, there are signs of systemic inflammation and certain activation of cell-mediated immunity, without significant changes in the humoral link of adaptive immunity., Conclusion: More studies are needed, but the data obtained in this study are important for subsequent clinical studies of new treatment methods, based on various immunophenotypes of schizophrenia., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021, Malashenkova I.K., Krynskiy S.A., Ogurtsov D.P., Hailov N.A., Zakharova N.V., Bravve L.V., Kaydan M.A., Chekulaeva E.I., Andreyuk D.S., Ushakov V.L., Didkovsky N.A., Kostyuk G.P.)

Objective: To compare the cognitive functioning of patients with paranoid schizophrenia with alcohol dependence syndrome and patients with this disease without comorbid alcohol pathology., Material and Methods: The study included 34 patients with a diagnosis of schizophrenia, paranoid form, aged 24 to 39 years (22 men and 12 women). The experimental group included 17 patients with paranoid schizophrenia combined with alcohol dependence syndrome with diagnosed symptomatic alcoholism. The comparison group included 17 patients with a similar diagnosis without a comorbid disorder. The duration of the disease in both groups was 5-10 years. The main research tool was a neuropsychological examination, which included the Benton test, the pathway test, the Mini-Mental State Examination (MMSE), and the constructive praxis test., Results: Moderate cognitive impairments were found in patients with schizophrenia in combination with comorbid pathology, combined with disorders of intellectual flexibility and cognitive control. Also, in the experimental group, marked disorders of constructive praxis and visual memory were noted, which indicates a lesion of the occipital-parietal parts of the brain. Thus, in the course of the study, cognitive disorders were identified in patients with schizophrenia in combination with alcohol addiction: disturbances of perceptual organization, cognitive flexibility and attention switching, visual memory., Conclusion: Concomitant alcohol dependence is a significant factor for changing cognitive functions in patients with schizophrenia: control functions suffer, visual memory is disturbed and constructive apraxia is noted.

This paper explores the potential of recent research on metacognition to offer new avenues to assess and address the phenomenon of fragmentation in schizophrenia, which was described by E.Bleuler as «splitting». The concepts of metacognition characterize and quantify alterations or decrements in the processes by which fragments or pieces of information are integrated into a coherent sense of self and others. A method for assessing metacognition is presented along with research examining the presence and importance of metacognitive deficits in schizophrenia. Greater levels of metacognitive deficits have been detected in different phases of schizophrenia and linked to poorer psychosocial outcomes. These data were obtained both in foreign and preliminary Russian studies. The authors suggest that treatments, which successfully target metacognitive capacity, may uniquely promote wellness and recovery in schizophrenia.

The aim of the study was to analyze the immune-inflammatory profile of patients with paranoid schizophrenia and relate it to the severity of negative symptoms and the MRI data in order to identify biomarkers of schizophrenia severity, search for new approaches to therapy, and control its effectiveness., Materials and Methods: The main group included 51 patients with paranoid schizophrenia, the control group - 30 healthy subjects. Patients underwent MRI scans and immunological studies, which included an assessment of natural and adaptive immunity, the systemic level of key pro-inflammatory and anti-inflammatory cytokines, and other markers of inflammation., Results: Disorders of immunity and immunoinflammatory profile in patients with paranoid schizophrenia with severe negative symptoms were revealed for the first time: in the presence of severe negative symptoms (>15 points according to the NSA-4 scale), the levels of humoral immunity factors, cytokines IL-10 and IL-12p40 and neurotrophin NGF were increased as well as the markers of systemic inflammation. Morphometric changes in the brain, typical for patients with schizophrenia, and also specific for patients with severe negative symptoms, were determined. The data analysis revealed correlations between the immune changes with structural changes in some of the brain areas, including the frontal cortex and hippocampus. Associations were found between the levels of anti-inflammatory IL-10, IL-12p40 cytokines and morphometric parameters of the brain, specific only for schizophrenic patients with severe negative symptoms., Conclusion: The interdisciplinary approach, combining brain morphometry with in-depth immunological and clinical studies, made it possible to determine neurobiological, immune, and neurocognitive markers of paranoid schizophrenia with severe negative symptoms. The results are important for further deciphering the pathogenesis of schizophrenia and its subtypes, as well as for the search for new approaches to the treatment of severe forms of the disease., Competing Interests: Conflicts of interest. There are no conflicts of interest associated with this study.

Objective: To study the correlation between the blood plasma antioxidant profile and the transcriptional activity of the Nrf2 gene in acute psychosis in patients with schizophrenia and alcoholism., Material and Methods: The study included 40 patients with the first episode of the paranoid form of schizophrenia, 33 patients with schizophrenic psychosis who had previously received therapy, 22 patients with first-time acute alcohol psychosis, and 25 healthy volunteers. The level of Nrf2 in peripheral blood mononuclear cells was estimated by flow cytometry, and the antioxidant profile of blood plasma was estimated with chemiluminometry., Results: The total and «thiol» antioxidant capacity were reduced in patients with initially diagnosed schizophrenic psychosis and alcoholic psychosis. In patients after treatment, the total antioxidant capacity was higher compared to previously untreated patients. The level of Nrf2 protein in mononuclear cells in patients with the first psychotic episode was significantly lower than in patients with alcoholism and lower than in the control group. In patients with alcoholic psychosis, Nrf2 level was correlated with both the total antioxidant capacity due to uric acid and the «thiol» antioxidant capacity; in patients with psychosis in schizophrenia, Nrf2 level was correlated only with the «thiol» antioxidant capacity., Conclusions: The correlation between the total and «thiol» antioxidant capacity and the level of Nrf2 in mononuclear cells of patients with alcohol delirium indicates the undamaged state of the regulation. The absence of a correlation between the total antioxidant capacity and the level of Nrf2 in patients with schizophrenia indicates a disturbance of the activation of the Nrf2 pathway due to, possibly, a part associated with the participation of uric acid.

Objective: To study the prevalence of somatic diseases in patients with mental disorders based on the results of medical examination in Moscow mental health clinics in 2018., Material and Methods: A retrospective analysis of the results of the clinical examinations of 6492 outpatients, which accounted for 79.5% of patients who underwent medical examination in this time period., Results: Comorbid somatic diseases were found in 4883 (75%) patients. Hypertension and non-insulin-dependent diabetes mellitus were most frequent with the prevalence higher than in the general population of the Russian Federation. Patients with diagnosed schizophrenia, along with hypertension and diabetes mellitus, have found to be at increased risk of diseases of the endocrine system and metabolic disorders. The incidence of the mentioned diseases is not higher than that reported in literature., Conclusion: The higher prevalence of socially relevant diseases (hypertension, diabetes mellitus) among patients with mental disorders demands the development of strategies for prevention, early detection and treatment of these diseases in psychiatric patients.

Depression is a global threat to mental health that affects around 264 million people worldwide. Despite the considerable evolution in our understanding of the pathophysiology of depression, no reliable biomarkers that have contributed to objective diagnoses and clinical therapy currently exist. The discovery of the microbiota-gut-brain axis induced scientists to study the role of gut microbiota (GM) in the pathogenesis of depression. Over the last decade, many of studies were conducted in this field. The productions of metabolites and compounds with neuroactive and immunomodulatory properties among mechanisms such as the mediating effects of the GM on the brain, have been identified. This comprehensive review was focused on low molecular weight compounds implicated in depression as potential products of the GM. The other possible mechanisms of GM involvement in depression were presented, as well as changes in the composition of the microbiota of patients with depression. In conclusion, the therapeutic potential of functional foods and psychobiotics in relieving depression were considered. The described biomarkers associated with GM could potentially enhance the diagnostic criteria for depressive disorders in clinical practice and represent a potential future diagnostic tool based on metagenomic technologies for assessing the development of depressive disorders.

Introduction: The association between schizophrenia and toxoplasmosis has been demonstrated in a number of studies: the prevalence of schizophrenia is significantly higher in toxoplasmosis positive subjects than in those with T. gondii negative status. However, the clinical significance of this association remains poorly understood., Objectives: To identify clinical phenomena that are typical for toxoplasmosis-associated ( T. gondii seropositive) schizophrenia compared to Toxoplasma-seronegative schizophrenia., Methods: A retrospective database analysis of serum samples from 105 inpatients with schizophrenia (ICD-10code: F20; including 55 male patients; mean age of 27.4 6.4 years) was carried out. The clinical examination involved a structured interview including ICD-10 and E. Bleulers criteria for schizophrenia and psychometric tests(Positive and Negative Scales of PANSS). Serum antibodies (IgG) to T. gondii were identified using ELISA. The statistical significance of any differences were evaluated using the non-parametric Mann-Whitney (U) and X 2 tests., Results: The proportion of seropositive patients in the sample was 16.2%. Comparing schizophrenia patients, who were seropositive or seronegative for toxoplasmosis, there were no statistically significant differences for the mean total PANSS score, mean PANSS-P, PANSS-N or PANSS-G scores. For the majority of PANSS items, differences were also statistically insignificant, except for G5 and G6mannerism and posturing. Seropositive patients had a higher score for this item than seronegative patients: 3.5 versus 2.1 points (U=389.5; р=0.001). Depression, on the contrary,was less pronounced in seropositive than seronegative patients: 1.4 versus 2.4 points (U=509.5; р=0.023). In addition,in seropositive patients, the frequency of symptoms such as mutism according to ICD-10 criteria for schizophrenia was significantly higher (23.5% versus 3.4%, X 2 =9.27, р=0.013), and the whole group of catatonic symptoms according to the E. Bleulers criteria for schizophrenia was higher (52.9% versus 28.4%, X 2 =3.916, p = 0.048)., Conclusion: The association between a positive toxoplasmosis status in patients with schizophrenia and catatonic symptoms has been revealed for the first time and should be verified in larger studies., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020, Romanov D.V., Brazhnikov A.I., Andreyuk D.S., Zakharova N.V., Bravve L.V., Kovaleva V.A., Abbazova E.V., Goncharov D.B., Titova I.V., Domonova E.A., Kostyuk G.P.)

Objective: Earlier we studied the copy number variations (CNVs) of ribosomal repeat (rDNA) and the satellite III fragment (1q12) (f-SatIII) in the cells of schizophrenia patients (SZ) and healthy controls (HC). In the present study we pursued two main objectives: (1) to confirm the increased rDNA and decreased f-SatIII content in the genomes of enlarged SZ and HC samples and (2) to compare the rDNA and f-SatIII content in the same DNA samples of SZ and HC individuals., Methods: We determined the rDNA CN and f-SatIII content in the genomes of leukocytes of 1770 subjects [HC (N = 814) and SZ (N = 956)]. Non-radioactive quantitative hybridization method (NQH) was applied for analysis of the various combinations of the two repeats sizes in SZ and HC groups., Results: f-SatIII in human leukocytes (N = 1556) varies between 5.7 and 44.7 pg/ng DNA. RDNA CN varies between 200 and 896 (N = 1770). SZ group significantly differ from the HC group by lower f-SatIII content and by rDNA abundance. The f-SatIII and rDNA CN are not randomly combined in the genome. Higher rDNA CN values are associated with higher f-SatIII index values in SZ and HC. The f-SatIII variation interval in SZ group increases significantly in the subgroup with the high rDNA CN index values (>300 copies)., Conclusion: Schizophrenia patients' genomes contain low number of f-SatIII copies corresponding with a large ribosomal repeats CN. A scheme is proposed to explain the low f-SatIII content in SZ group against the background of high rDNA CN., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Depression is a serious mental disorder that affects more than 300 million people worldwide. Due to the lack of effective treatment methods, the pathogenesis of depression is necessary to study in order to understand its development and find new therapies. The review describes the main mechanisms of depression, including the monoamine hypothesis, impairment of the hipotalamic-pituitary-adrenal axis, decreased production of neurotropic factors, and neuroinflammation. Genetic correlations, gene polymorphisms, and epigenetic mechanisms are also considered. Common and different features of the etiology are analyzed for depression and depressive conditions associated with other pathologies (schizophrenia, Parkinson disease, and Alzheimer's disease). Modern experimental methods used to investigate the molecular mechanisms of depressive conditions are described with a focus on gene knockouts in laboratory animals and the CRISPR/Cas technology. Consideration is given to optogenetic and chemogenetic methods and analyses of genetic polymorphisms and their combinations. The data may provide for a better integral understanding of the modern ideas about the pathogenesis of depression as an isolated or comorbid disorder and the prospects in studying the mechanisms of depressive conditions.

Introduction: Genome repeat cluster sizes can affect the chromatin spatial configuration and function. Low-dose ionizing radiation (IR) induces an adaptive response (AR) in human cells. AR includes the change in chromatin spatial configuration that is necessary to change the expression profile of the genome in response to stress. The 1q12 heterochromatin loci movement from the periphery to the center of the nucleus is a marker of the chromatin configuration change. We hypothesized that a large 1q12 domain could affect chromatin movement, thereby inhibiting the AR. Materials and Methods: 2D fluorescent in situ hybridization (FISH) method was used for the satellite III fragment from the 1q12 region (f-SatIII) localization analysis in the interphase nuclei of healthy control (HC) lymphocytes, schizophrenia (SZ) patients, and in cultured mesenchymal stem cells (MSCs). The localization of the nucleolus was analyzed by the nucleolus Ag staining. The non-radioactive quantitative hybridization (NQH) technique was used for the f-SatIII fragment content in DNA analysis. Satellite III fragments transcription was analyzed by reverse transcriptase quantitative PCR (RT-qPCR). Results: Low-dose IR induces the small-area 1q12 domains movement from the periphery to the central regions of the nucleus in HC lymphocytes and MSCs. Simultaneously, nucleolus moves from the nucleus center toward the nuclear envelope. The nucleolus in that period increases. The distance between the 1q12 domain and the nucleolus in irradiated cells is significantly reduced. The large-area 1q12 domains do not move in response to stress. During prolonged cultivation, the irradiated cells with a large f-SatIII amount die, and the population is enriched with the cells with low f-SatIII content. IR induces satellite III transcription in HC lymphocytes. Intact SZ patients' lymphocytes have the same signs of nuclei activation as irradiated HC cells. Conclusion: When a cell population responds to stress, cells are selected according to the size of the 1q12 domain (the f-SatIII content). The low content of the f-SatIII repeat in SZ patients may be a consequence of the chronic oxidative stress and of a large copies number of the ribosomal repeats., (Copyright © 2020 Konkova, Ershova, Savinova, Malinovskaya, Shmarina, Martynov, Veiko, Zakharova, Umriukhin, Kostyuk, Izhevskaya, Kutsev, Veiko and Kostyuk.)

Schizophrenia is a complex chronic disease. The molecular determinants and neuropathology of schizophrenia are multifaceted; an important role in the pathogenesis is played by the dysregulation of molecular and epigenetic mechanisms. However, the molecular mechanisms of the development of the disease have not yet been studied. An important task is the accumulation and systematization of "OMICS"-knowledge of the molecular profiles (transcriptome, proteome, metabolome) of blood specific to pathology. Thereby the development and improvement of mass spectrometric methods for the detection of biological molecules has become increasingly important in biomedical research. In the field of applied problems in biomedical research, the most prevalent issue involves the identification of serological protein markers associated with the development of schizophrenia, which account for the diseases that cause the a life-shortening illness, disability, decreased of functioning and quality of life and wellbeing or health status. OMICS approaches are designed to detect genes (genomics), mRNA (transcriptomics), proteins (proteomics) and metabolites (metabolomics) in a specific biological sample. We report the proteomic datasets on the serum samples from patients with schizophrenia (series "SCZ") and healthy volunteers (series "CNT"). Data were acquired using shotgun ultra-high resolution mass spectrometry., (© 2020 The Authors.)

Recent advances in psychiatric genetics have led to the discovery of dozens of genomic loci associated with schizophrenia. However, a gap exists between the detection of genetic associations and understanding the underlying molecular mechanisms. This review describes the basic approaches used in the so-called post-GWAS studies to generate biological interpretation of the existing population genetic data, including both molecular (creation and analysis of knockout animals, exploration of the transcriptional effects of common variants in human brain cells) and computational (fine-mapping of causal variability, gene set enrichment analysis, partitioned heritability analysis) methods. The results of the crucial studies, in which these approaches were used to uncover the molecular and neurobiological basis of the disease, are also reported., Competing Interests: Owen, M.J.; Sawa, A.; Mortensen, P.B., Schizophrenia. Lancet 2016, 388, 86–97.

Objective: To search for the relationship between the results of functional imaging, immunological parameters and laboratory markers of inflammation in schizophrenia, taking into account cognitive impairment in patients, and to consider the possibility of using a multidisciplinary approach to diagnosis, treatment and prognosis of schizophrenia., Material and Methods: The study included 25 patients with schizophrenia and 13 healthy volunteers. Psychiatric scales were administered to evaluate the patient's condition. The main indicators of humoral immunity, the level of markers of inflammation, key pro-inflammatory and anti-inflammatory cytokines, and growth factor VEGF were determined by ELISA. Brain MRI was performed. All calculated tractographic data are included in the connection database to study the effect of immunological markers and the degree of severity of cognitive impairment., Results and Conclusion: Levels of markers of systemic inflammation and growth factor VEGF-A as well as the activation of humoral immunity are increased in patients with schizophrenia compared with controls. For the first time, the relationship of immunological parameters with the coefficient of quantitative anisotropy in the area of the corpus callosum in schizophrenia was revealed. The results indicate the possible value of indicators of the activation of the humoral immune response and systemic inflammation as markers of neurophysiological changes and cognitive dysfunction in schizophrenia.

The concepts of schizophrenia and other primary psychotic disorders have been changed a lot since their beginnings more than century ago due to many factors such as the dominance of a certain hypothesis during a particular period of time, the development of new clinical research and specific treatments as well as different understanding of the boundaries between mental disorders. It was appeared the diagnosis of schizophrenia spectrum disorders which still based only on clinical symptoms. Whether psychotic disorders can be better represented dimensionally or categorically remains a challenging question. Regarding schizophrenia and other primary psychotic disorders, there are some important changes in DSM-5 and ICD-11 concerning the use of quantitative assessment of psychopathological domains, course of psychosis and remission as well as giving more attention to cognitive issues. The main differences between these classifications are the structure of corresponding sections and different criteria of some disorders. Before the ICD-11 implementation in 2022 into clinical practice, it is highly recommended to conduct a set of trainings for clinicians along with the comments to Diagnostic guidelines for Schizophrenia and other primary psychotic disorders.

Introduction: It was shown that copy number variations (CNVs) of human satellite III (1q12) fragment (f-SatIII) reflects the human cells response to stress of different nature and intensity. Patients with schizophrenia (SZ) experience chronic stress. The major research question: What is the f-SatIII CNVs in human leukocyte as a function of SZ? Materials and Methods: Biotinylated pUC1.77 probe was used for f-SatIII quantitation in leukocyte DNA by the non-radioactive quantitative hybridization for SZ patients (N = 840) and healthy control (HC, N = 401). SZ-sample included four groups. Two groups: first-episode drug-naïve patients [SZ (M-)] and medicated patients [SZ (M+)]. The medical history of these patients did not contain reliable confirmed information about fetal hypoxia and obstetric complications (H/OCs). Two other groups: medicated patients with documented H/OCs [hypoxia group (H-SZ (M+)] and medicated patients with documented absence of H/OCs [non-hypoxia group (NH-SZ (M+)]. The content of f-SatIII was also determined in eight post-mortem brain tissues of one SZ patient. Results: f-SatIII in human leukocyte varies between 5.7 to 44 pg/ng DNA. f-SatIII CNVs in SZ patients depends on the patient's history of H/OCs. f-SatIII CN in NH-SZ (M+)-group was significantly reduced compared to H-SZ (M+)-group and HC-group (p < 10 -30 ). f-SatIII CN in SZ patients negatively correlated with the index reflecting the seriousness of the disease (Positive and Negative Syndrome Scale). Antipsychotic therapy increases f-SatIII CN in the untreated SZ patients with a low content of the repeat and reduces the f-SatIII CN in SZ patients with high content of the repeat. In general, the SZ (M+) and SZ (M-) groups do not differ in the content of f-SatIII, but significantly differ from the HC-group by lower values of the repeat content. f-SatIII CN in the eight regions of the brain of the SZ patient varies significantly. Conclusion: The content of f-SatIII repeat in leukocytes of the most patients with SZ is significantly reduced compared to the HC. Two hypotheses were put forward: (1) the low content of the repeat is a genetic feature of SZ; and/or (2) the genomes of the SZ patients respond to chronic oxidative stress reducing the repeats copies number., (Copyright © 2019 Ershova, Agafonova, Zakharova, Bravve, Jestkova, Golimbet, Lezheiko, Morozova, Martynov, Veiko, Umriukhin, Kostyuk, Kutsev, Veiko and Kostyuk.)

Introduction: Schizophrenia (SZ) increases the level of cell death, leading to an increase in the concentration of circulating cell-free DNA (cfDNA). Ribosomal DNA (rDNA) contains many unmethylated CpG motifs that stimulate TLR9-MyD88-NF- κ B signaling and the synthesis of proinflammatory cytokines. The number of rDNA copies in the genomes of SZ patients is increased; therefore, we expect that the concentration of cell-free rDNA in the plasma of the SZ patients also increases. This may be one of the explanations of the proinflammatory cytokine increase that is often observed in SZ. The major research question is what is the rDNA copy number in cfDNA (cf-rDNA CN) and its putative role in schizophrenia? Materials and Methods . We determined cfDNA concentration (RNase A/proteinase K/solvent extraction; fluorescent dye PicoGreen) and endonuclease activity (NA) of blood plasma (radial diffusion method) in the untreated male SZ group ( N = 100) and in the male healthy control group (HC) ( N = 96). Blood leukocyte DNA and cfDNA rDNA CN were determined with nonradioactive quantitative hybridization techniques. Plasma concentration of cf-rDNA was calculated., Results: In the subjects from the SZ group, the mean cfDNA plasma concentration was twofold higher and NA of the plasma was fourfold higher than those in the healthy controls. rDNA CN in the blood leukocyte genome and in the cfDNA samples in the SZ group was significantly higher than that in the HC group. cf-rDNA concentration was threefold higher in the SZ group., Conclusion: Despite the abnormally high endonuclease activity in the blood plasma of SZ patients, the circulating cfDNA concentration is increased. Fragments of cf-rDNA accumulate in the blood plasma of SZ patients. Potentially, SZ patients' cfDNA should be a strong stimulating factor for the TLR9-MyD88-NF- κ B signaling pathway., Competing Interests: The authors declare that they have no conflicts of interest.

The review is devoted to the analysis of the current state of pharmacogenetic research and their use in psychiatric practice. The main genes responsible for the pharmacodynamics and pharmacokinetics of drugs used in psychiatry are listed. Foreign pharmacogenetic clinical recommendations and progress on their implementation in medical practice in various countries of Europe and the USA are analyzed. The need to create Russian clinical guidelines on pharmacogenomics to improve the effectiveness of patient care and to implement a personalized approach to therapy is discussed.

The olfactory epithelium (OE) is an accessible source of neural stem cells and progenitor cells. The objective of the study was to compare the effectiveness of various biopsy sites to isolate and propagate neural progenitor cells from the olfactory epithelium (OE). The authors assessed OE cell count in OE in different sites of the nasal cavity and showed the possibility of isolation neurospheres from nasal biopsies. In total, 45 inpatinets were included in the study. Biopsy specimens were obtained from 30 patients undergoing septoplasty and/or turbinate surgery. Three areas of OE were biopsied: lower third section of the nasal septum (A), anterior part of the middle turbinate (B), upper third of the nasal septum (C). Immunocytochemistry and fluorescence-activated cell sorting showed that OE cells were NCAM-positive. Mean percentage of NCAM+ cells was 7.8% for A, 42.7% for B and 18.2% for C. The difference was significant between A and B (p=0.0001) and B and C (p=0.01). Therefore, the anterior part of the middle turbinate was an easily accessible and safe site to obtain neural cells. To confirm this, neurospheres were obtained in 15 patients with schizophrenia who underwent in-office endoscopy.

Because of the high prevalence of nonpsychotic anxiety-depressive disorders, the authors discuss the necessity and possibility of their diagnosis and treatment by primary care physicians. Arguments supporting this suggestion are presented.

Background: Psychosocial (PS) risk factors (RF) make a substantial contribution in populational burden of cardio-vascular diseases (CVD) and their complications., Purpose: The KOMETA (Comet) study was directed to obtaining actual information on PSRF among ambulatory patients with arterial hypertension (AH) and / or ischemic heart disease (IHD) in 30 cities of Russian Federation., Materials and Methods: This multicenter cross-sectional study was conducted in 2016-2017. Doctors participating in the study (n=325) recruited in state polyclinics 2775 patients aged ≥55 years with AH and / or IHD. Information collected from these patients comprised social-demographic and clinical characteristics, data on RF, adherence to therapy. Assessment of PSRF was carried out with consideration of levels of anxiety, depression and stress, presence of personality type D., Results: Population of patients studied (72 % women) was characterized by considerable prevalence of PSRFs. Low levels of education and income were found in 24.5 and 44.2 % of patients, respectively; 25.2 % of patients reported living alone, 6.3 % - felt social isolation. Elevated, extremely high levels of stress, type D personality were detected in 67.8, 10, and 37.6 % of patients, respectively; clinically significant symptoms of anxiety and depression were found in 25.5 and 16.3 %, respectively. Most RFs were significantly more often detected in women, and older people. One third of patients (33.1 %) during a year preceding inclusion took some psychotropic drugs mainly herbal or barbiturate-containing (27.1 %). Moreover, 30 % of patients had lowering of cognitive functioning., Conclusion: In this large-scale study we revealed high prevalence of PSRFs among ambulatory patients with AH and / or IHD in Russia. Despite positive dynamics of prevalence of states of anxiety and depression relative to earlier studies in this country their negative impact on prognosis of CVD and quality of life of affected patients requires optimization of efforts for organization of adequate care and directed to timely diagnosis and correction of these states.

Background: More than 10 years passed since conduction of the first clinical-epidemiological study of prevalence of psychosocial risk factors (PSRF) in patients with arterial hypertension (AH) an/or ischemic heart disease in Russian Federation., Purpose: to assess current prevalence of PSRF in patients with AH/CHD and their relationship with traditional risk factors., Materials and Methods: Patients with verified AH and/or CHD aged ≥55 years were included into this cross-sectional study in 30 cities of Russia representing 7 federal districts according to the following procedure. In each city we selected 2-5 federal clinics - providers of primary medical care; in each of these clinics we at random invited 2-5 physicians to take part in this study. Each of these physicians for 1-2 days included 10 consecutive patients with AH and/or CHD. Information collected from patients comprised social demographic and clinical characteristics, risk factors, adherence to therapy; Hospital Anxiety and Depression Scale (HADS) was applied for detection of symptoms of anxiety and depression. Obtained information was used for analysis of prevalence of cardiovascular risk factors and their association with symptoms of depression and anxiety in a framework of Pearson linear and Kendall rank correlation analysis., Results: Symptoms of anxiety of various severity (HADS-A≥7) were detected in 42.2% of patients with AH and/or CHD, in 25.5% they were clinically significant (HADS-A≥11). Symptoms of depression of various severity (HADS-D ≥7) were detected in 42.5% of patients with AH and/or CHD, in 16.3% they were clinically significant (HADS-D≥11). We also observed several significant associations of symptoms of depression and anxiety with traditional cardiovascular risk factors: low level of physical activity, elevated systolic and diastolic arterial pressure, level of total cholesterol, abdominal obesity; some unhealthy nutritional habits., Conclusions: Prevalence of symptoms of anxiety and depression was found to be high among ambulatory patients with AH and/or CHD. However, in this study it was lower compared with that reported by previous studies in Russia.

Objective: The aim of this study was (1) to examine the leukocyte mtDNA copy number ( CN ) in unmedicated (SZ (m-)) and medicated (SZ (m+)) male patients with paranoid schizophrenia (SZ) in comparison with the healthy male controls (HC) and (2) to compare the leukocyte mtDNA CN with the content of an oxidation marker 8-oxodG in lymphocytes of the SZ (m-) patients., Methods: We evaluated leukocyte mtDNA CN of 110 subjects with SZ in comparison with 60 male HC by the method qPCR (ratio mtDNA/nDNA (gene B2M) was detected). SZ patients were divided into two subgroups. The patients of the subgroups SZ (m+) ( N = 55) were treated with standard antipsychotic medications in the hospital. The patients of the subgroup SZ (m-) ( N = 55) were not treated before venous blood was sampled. To evaluate oxidative DNA damage, we quantified the levels of 8-oxodG in lymphocytes (flow cytometry) of SZ (m-) patients ( N = 55) and HC ( N = 30)., Results: The leukocyte mtDNA CN showed no significant difference in SZ (m+) patients and HC. The mtDNA CN in the unmedicated subgroup SZ (m-) was significantly higher than that in the SZ (m+) subgroup or in HC group. The level of 8-oxodG in the subgroup SZ (m-) was significantly higher than that in HC group., Conclusion: The leukocytes of the unmedicated SZ male patients with acute psychosis contain more mtDNA than the leukocytes of the male SZ patients treated with antipsychotic medications or the healthy controls. MtDNA content positively correlates with the level of 8-oxodG in the unmedicated SZ patients.

Olfactory neuroepithelium (OE) is shown to be a suitable experimental model to study neuronal biomarkers of psychiatric diseases including schizophrenia. Olfactory neuronal precursors can be useful for studying neurodevelopmental stages, neuronal markers, pharmacological screening. However, a limited number of research groups have used this cell model in a small number of patients and healthy people that can be explained by several factors. Based on literature reports and own research, the authors analyze the advantages and limitations of OE-derived cell/tissue models. The main limitations of these models are decreased rate of harvesting and culturing OE-derived cell and low percentage of patients who agreed to participate in the study. Our results showed that only 10% of patients with schizophrenia signed informed consent for nasal biopsy, 80% of them underwent biopsy.

Schizophrenia is a disease with a complex non-Mendelian inheritance mechanism in most cases involving the combined action of a large number of genes. Identifying of genomic variations associated with schizophrenia endophenotypes has a great potential. This review describes genetic markers of the disease, current methods of their analysis, including genome-wide association study (GWAS). Certain genes with mutations that increase the risk of schizophrenia are described. Functional polymorphisms with phenotypic expression, which are significantly associated with clinical manifestation of schizophrenia, can serve as useful genetic markers. The authors highlight that currently there are no certain susceptibility genes. Further global research and search for markers in different population groups are needed.