Schizophrenia is recognized to be a highly heterogeneous disease at various levels, from genetics to clinical manifestations and treatment sensitivity. This heterogeneity is also reflected in the variety of oxidative stress‐related mechanisms contributing to the phenotypic realization and manifestation of schizophrenia. At the molecular level, these mechanisms are supposed to include genetic causes that increase the susceptibility of individuals to oxidative stress and lead to gene expression dysregulation caused by abnormal regulation of redox‐sensitive transcriptional factors, noncoding RNAs, and epigenetic mechanisms favored by environmental insults. These changes form the basis of the prooxidant state and lead to altered redox signaling related to glutathione deficiency and impaired expression and function of redox‐sensitive transcriptional factors (Nrf2, NF‐κB, FoxO, etc.). At the cellular level, these changes lead to mitochondrial dysfunction and metabolic abnormalities that contribute to aberrant neuronal development, abnormal myelination, neurotransmitter anomalies, and dysfunction of parvalbumin‐positive interneurons. Immune dysfunction also contributes to redox imbalance. At the whole‐organism level, all these mechanisms ultimately contribute to the manifestation and development of schizophrenia. In this review, we consider oxidative stress‐related mechanisms and new treatment perspectives associated with the correction of redox imbalance in schizophrenia. We suggest that not only antioxidants but also redox‐regulated transcription factor‐targeting drugs (including Nrf2 and FoxO activators or NF‐κB inhibitors) have great promise in schizophrenia. But it is necessary to develop the stratification criteria of schizophrenia patients based on oxidative stress‐related markers for the administration of redox‐correcting treatment.

Purpose of study is revealing significant differences in serum proteomes in schizophrenia and bipolar disorder (BD). Quantitative mass-spectrometry based proteomic analysis was used to quantify proteins in the blood serum samples after the depletion of six major blood proteins. Comparison of proteome profiles of different groups revealed 27 proteins being specific for schizophrenia, and 18 – for BD. Protein set in schizophrenia was mostly associated with immune response, cell communication, cell growth and maintenance, protein metabolism and regulation of nucleic acid metabolism. Protein set in BD was mostly associated with immune response, regulating transport processes across cell membrane and cell communication, development of neurons and oligodendrocytes and cell growth. Concentrations of ankyrin repeat domain-containing protein 12 (ANKRD12) and cadherin 5 in serum samples were determined by ELISA. Significant difference between three groups was revealed in ANKRD12 concentration (p = 0.02), with maximum elevation of ANKRD12 concentration (median level) in schizophrenia followed by BD. Cadherin 5 concentration differed significantly (p = 0.035) between schizophrenic patients with prevailing positive symptoms (4.78 [2.71, 7.12] ng/ml) and those with prevailing negative symptoms (1.86 [0.001, 4.11] ng/ml). Our results are presumably useful for discovering the new pathways involved in endogenous psychotic disorders.

The objective: the involvement of glutamatergic neurotransmitter systems in the pathogenesis of schizophrenic spectrum disorders and BD has been repeatedly proven. But today, there are no methods available to evaluate the glutamate metabolism in patients with mental disorders. The paper presents differences in the level of glutamate in the blood serum of patients with a schizophrenic spectrum disorder, bipolar disorder, and healthy individuals.Patients and methods: the study included 224 people. 179 patients were presented with paranoid schizophrenia, simple schizophrenia, schizotypal disorder, acute polymorphic disorder, schizoaffective disorder and BD.Results: in this work shows that the level of glutamate in patients in all studied groups is statistically significantly higher than in healthy individuals, except for acute polymorphic psychotic disorder. Serum glutamate concentration in patients with schizotypal disorder is 1.6 times higher than in healthy individuals. The significant differences in glutamate levels were detected in patients with schizotypal disorder and OCD (p = 0.045), and patients with paranoid schizophrenia (p = 0.012). The concentration of glutamate is also increased in patients with simple schizophrenia compared to patients with paranoid schizophrenia (p = 0.039). In addition, it was observed a glutamate increase in healthy individuals compared in patients with a continuous course of schizophrenia (p = 0.001), in patients with an episodic course with progressive deficit (p = 0.0211) and in patients with a schizophrenia duration of more than 12 years.Conclusions: thus, the concentrations of glutamate in the blood serum of patients are depending on the severity of the course of schizophrenia and maybe an additional paraclinical criterion for the diagnosis of schizotypal disorder.

ЦЕЛЬ ИССЛЕДОВАНИЯ Определить сывороточные концентрации ряда белков, обнаруженных с помощью протеомного анализа в сыворотке крови больных биполярным аффективным расстройством (БАР), и оценить взаимосвязь их уровня с клиническими характеристиками заболевания. МАТЕРИАЛ И МЕТОДЫ Концентрации кадгерина 5, XIII фактора свертывания крови и белка-продукта гена ANKRD12 в сыворотке крови больных БАР и здоровых лиц определялись при помощи коммерческих наборов для твердофазного иммуноферментного анализа согласно протоколу производителя. Степень тяжести текущей депрессии и тяжести основных клинических проявлений БАР оценивалась по шкалам SIGH-SAD и CGI при поступлении в стационар, до назначения терапии. Статистический анализ проводился с применением критериев Краскела—Уоллиса и Манна—Уитни. РЕЗУЛЬТАТЫ Сравнение подгрупп больных БАР, выделенных в соответствии с текущим аффективным эпизодом (гипоманиакальным, маниакальным, депрессивным и смешанным), и контрольной группы показало статистически значимые различия концентрации белка-продукта гена ANKRD12 (p=0,0448). При парном сравнении каждой подгруппы с контрольной группой статистически значимое различие концентрации белка-продукта гена ANKRD12 обнаружено только в подгруппе больных БАР с текущим депрессивным эпизодом (критерий Манна—Уитни, p=0,006). Сравнение концентрации белка-продукта гена ANKRD12 у подгрупп больных БАР с разной длительностью заболевания (с длительностью 11 лет) и контрольной группы выявило статистически значимые различия (p=0,04, p=0,01, p=0,02 соответственно), максимальная концентрация белка обнаружена у больных с длительностью заболевания >11 лет. Выявлены достоверная отрицательная корреляция концентрации кадгерина 5 с выраженностью атипичных депрессивных симптомов по SIGH-SAD (r=–0,69, p=0,038) и снижение его концентрации у больных БАР с бо`льшей тяжестью текущего депрессивного эпизода. Также выявлена достоверная отрицательная корреляция средней силы между концентрацией XIII фактора свертывания крови и показателями по CGI (r=–0,62, p=0,032). ЗАКЛЮЧЕНИЕ Полученные результаты указывают на связь изученных белков с патогенезом БАР. Дальнейшее изучение выявленных белков может помочь при разработке новых терапевтических и диагностических методик.

The prevalence of bipolar disorder (BD) in modern society is growing rapidly, but due to the lack of paraclinical criteria, its differential diagnosis with other mental disorders is somewhat challenging. In this regard, the relevance of proteomic studies is increasing due to the development of methods for processing large data arrays; this contributes to the discovery of protein patterns of pathological processes and the creation of new methods of diagnosis and treatment. It seems promising to search for proteins involved in the pathogenesis of BD in an easily accessible material—blood serum. Sera from BD patients and healthy individuals were purified via affinity chromatography to isolate 14 major proteins and separated using 1D SDS-PAGE. After trypsinolysis, the proteins in the samples were identified via HPLC/mass spectrometry. Mass spectrometric data were processed using the OMSSA and X!Tandem search algorithms using the UniProtKB database, and the results were analyzed using PeptideShaker. Differences in proteomes were assessed via an unlabeled NSAF-based analysis using a two-tailed Bonferroni-adjusted t-test. When comparing the blood serum proteomes of BD patients and healthy individuals, 10 proteins showed significant differences in NSAF values. Of these, four proteins were predominantly present in BD patients with the maximum NSAF value: 14-3-3 protein zeta/delta; ectonucleoside triphosphate diphosphohydrolase 7; transforming growth factor-beta-induced protein ig-h3; and B-cell CLL/lymphoma 9 protein. Further exploration of the role of these proteins in BD is warranted; conducting such studies will help develop new paraclinical criteria and discover new targets for BD drug therapy.

Background: Schizophrenia (SCZ) and bipolar disorder (BD) share common clinical features, complicating the identification of specific peripheral biomarkers. The objective of this study was to identify biomarkers that specifically characterize different clinical forms of BD and SCZ. Methods: A comparative proteomic analysis of serum samples from patients with SCZ and BD, as well as healthy controls, was performed using untargeted mass spectrometry to identify differentially expressed proteins. In an expanded cohort, accounting for clinical heterogeneity, the levels of six minor proteins (N-methyl-D-aspartate receptor 1 (NMDAR1), ankyrin 3 (ANK3), ankyrin repeat domain-containing protein 12 (ANKRD12), low-density lipoprotein receptor-related protein 2 (LRP2), dermcidin (DCD), and anti-NMDAR antibodies) were quantified using enzyme-linked immunosorbent assay (ELISA) and targeted mass spectrometry (for NMDAR1). Results: Comparative serum proteomic analysis identified 440 unique proteins in healthy controls versus 221 in patients with SCZ, and 474 unique proteins in healthy controls versus 55 in patients with BD. Quantitative analysis revealed the following findings: (1) a significant increase in NMDAR1 protein levels in patients with BD experiencing a current depressive episode (BD-cDE); (2) decreased ANK3 levels in patients with BD-cDE and SCZ; (3) increased ANKRD12 protein levels in patients with SCZ characterized by predominant negative symptoms and in patients with BD-cDE; (4) decreased DCD levels in patients with SCZ in remission compared with those in the acute phase of the disease; and (5) significantly increased LRP2 levels in both BD and SCZ. Elevated anti-NMDAR antibody levels were more frequently observed in patients with BD, although absolute antibody levels were also increased in patients with acute-phase SCZ. Conclusions: These findings suggest a common mechanism of synaptopathy involving destabilization of the ANK3-NMDAR scaffold, accompanied by a compensatory neuroprotective response in both BD and SCZ. The identified alterations in the serum protein profile may serve as potential biomarkers for the differential diagnosis of these disorders as part of multimarker diagnostic panels.