Сellular and Molecular Mechanisms of Proinflammatory Monocytes Participation in the Pathogenesis of Mental Disorders. Part 3

Background: at present, the important role of the monocyte-macrophage link of immunity in the pathogenesis of mental diseases has been determined. In the first and second parts of our review, the cellular and molecular mechanisms of activation of monocytes/macrophages, which secreting proinflammatory CD16 receptors, cytokines, chemokines and receptors to them, in the development of systemic immune inflammation in the pathogenesis of somatic diseases and mental disorders, including schizophrenia, bipolar affective disorder (BAD) and depression were analyzed. The association of high levels of proinflammatory activity of monocytes/macrophages in patients with mental disorders with somatic comorbidity, including immune system diseases, is shown. It is known that proinflammatory monocytes of peripheral blood, as a result of violation of the integrity of the hematoencephalic barrier can migrate to the central nervous system and activate the resident brain cells — microglia, causing its activation. Activation of microglia can lead to the development of neuroinammation and neurodegenerative processes in the brain and, as a result, to cognitive disorders. The aim of review: to analyze the results of the main scientific studies concerning the role of cellular and molecular mechanisms of peripheral blood monocytes interaction with microglial cells and platelets in the development of neuroinflammation in the pathogenesis of mental disorders, including Alzheimer’s disease (AD). Material and methods: keywords “mental disorders, AD, proinflammatory monocytes, microglia, neuroinflammation, cytokines, chemokines, cell adhesion molecules, platelets, microvesicles” were used to search for articles of domestic and foreign authors published over the past 30 years in the databases PubMed, eLibrary, Science Direct and EMBASE. Conclusion: this review analyzes the results of studies which show that monocytes/macrophages and microglia have similar gene expression profiles in schizophrenia, BAD, depression, and AD and also perform similar functions: phagocytosis and inflammatory responses. Monocytes recruited to the central nervous system stimulate the increased production of proinflammatory cytokines IL-1, IL-6, tumor necrosis factor alpha (TNF-α), chemokines, for example, MCP-1 (Monocyte chemotactic protein-1) by microglial cells. This promotes the recruitment of microglial cells to the sites of neuronal damage, and also enhances the formation of the brain protein beta-amyloid (Aβ). The results of modern studies are presented, indicating that platelets are involved in systemic inflammatory reactions, where they interact with monocytes to form monocyte-platelet aggregates (MTA), which induce the activation of monocytes with a pro inflammatory phenotype. In the last decade, it has been established that activated platelets and other cells of the immune system, including monocytes, detached microvesicles (MV) from the membrane. It has been shown that MV are involved as messengers in the transport of biologically active lipids, cytokines, complement, and other molecules that can cause exacerbation of systemic inflammatory reactions. The presented review allows us to expand our knowledge about the cellular and molecular aspects of the interaction of monocytes/macrophages with microglial cells and platelets in the development of neuroinflammation and cognitive decline in the pathogenesis of mental diseases and in AD, and also helps in the search for specific biomarkers of the clinical severity of mental disorder in patients and the prospects for their response to treatment.

Oxidative DNA Damage of Peripheral Blood Cells and Blood Plasma Сell-Free DNA as an Indicator of the Oxidative Stress Level in Children with Autism Spectrum Disorders and Schizophrenia

Background: pathogen heterogeneity and complexity are the main obstacles for schizophrenia and autism spectrum disorders (ASD) differential diagnosis in children. The role of oxidative stress in the molecular mechanisms of schizophrenia and autism pathogenesis is beyond doubt. Free radicals that accumulate during stress can cause oxidative modifications and the formation of breaks in the сell-free DNA (cfDNA) and nuclear DNA of blood cells. To date, it has been proven that 8-hydroxy-2’- deoxyguanosine (8-OHdG) can be considered as an oxidative stress biomarker. However, it is still unclear how pronounced the genotoxic consequences of oxidative stress are in ASD of varying severity and in childhood onset schizophrenia (COS). Objective: to study the relationship between the oxidative DNA damage level in peripheral blood cells and the circulating cell-free DNA characteristics with the severity of COS and the course of ASD in children. Patients and methods: blood samples of 96 patients with childhood autism (CA — F84.0 according to ICD-10), atypical autism (AA — F84.1 according to ICD-10) and with childhood onset schizophrenia (COS — F20.8 according to ICD-10) were obtained from the Child Psychiatry Department of the Mental health research center. Blood samples of the control group (34 people) — from the collection of samples of the Research Centre for medical Genetics. The selection of patients was carried out using the clinical and psychopathological method. Cell-free DNA was isolated by extraction with organic solvents. The concentration of cfDNA was determined fluorimetrically. The level of 8-OHdG in cell-free DNA was determined by binding of the corresponding antibodies on membrane filters, endonuclease activity was determined by radial diffusion in a gel. G0-peripheral blood lymphocytes were isolated by gradient centrifugation. The level of 8-OHdG and the level of the phosphorylated form of histone H2AX (yH2AX) in G0-peripheral blood lymphocytes were analyzed in fixed cells by flow cytofluorometry using appropriate antibodies. Statistical processing was carried out using Microsoft Office Excel, Statistica 6.0, StatGraph. Results and conclusions: oxidative stress has different severity in ASD, occurring in severe form (AA) and mild/moderate form (CA). In CA, the level of oxidative damage to the DNA of lymphocytes tends to increase, but does not reach statistically significant level; the level of oxidative damage to cfDNA does not differ from the control. In AA and, to an even stronger extent, in COS, the level of oxidative damage to the DNA of cells and cfDNA is significantly increased, which indicates the development of systemic oxidative stress, which is not compensated by the body’s antioxidant system. The level of 8-OHdG in the composition of the cfDNA and DNA of the nuclei of peripheral blood cells can be a marker of oxidative stress, which is important not only for diagnosing the severity of the pathological process, but also for treatment regimens development for COS and ASD in children.

Clinical and Therapeutic Factors Affecting the Social Adaptation of Patients with Schizophrenia

Background: сurrently, the question remains open about the factors that affect the social functioning of patients with schizophrenia, including the role of negative symptoms and neurocognitive deficits. The aim: to study factors that affect the social functioning of patients with schizophrenia. Patients and methods: 64 in-patient with schizophrenia (mean age 35.9 ± 10.9 years) were examined at the stage of remission. The disease duration was 9.71 ± 6.0 years. The majority of patients suffered from paranoid and hallucinatory-paranoid attacs (43 and 23%, respectively). The study used follow-up, clinical and psychopathological methods as well as psychometric scales: PANSS, SANS, ВАСS, Calgary scales and UKU scales. An integrative indicator was introduced to assess the social adaptation of patients. Results: it is shown that as the duration of the disease increases, the indicator of social adaptation decreases. The presence of side effects of antipsychotic therapy is associated with restrictions on the social functioning of patients, but the use of second-generation antipsychotics contributes to an increase in the level of social functioning of patients. Patients with more pronounced apathetic-abulic disorders, flattened affect, anhedonia-asociality and social isolation are characterized by a lower level of social functioning. Adapted patients differ from maladapted patients by better indicators of auditory-speech memory, motor skills, information processing speed, ability to plan and problem solving behavior. Conclusion: the integrative indicator of social adaptation of patients with schizophrenia is associated with a number of cognitive and negative symptoms, features of antipsychotic therapy and the duration of the disease.

Metabolic Syndrome in a Population of In-Patients with Schizophrenia in the Western Siberia

Background. The relevance of this work is due to the incomplete nature of existing studies on risk factors of metabolic syndrome (MS) in patients with schizophrenia. Aim: to study the MS prevalence in schizophrenia in-patients and their clinical, therapeutic and socio-demographic features. Patients and methods: 517 in-patients diagnosed with schizophrenia according to the ICD-10 criteria were examined. All patients underwent a structured clinical interview (SCID); measurement of waist circumference, blood pressure and assessment of biochemical parameters for verification of MS based on the criteria of the IDF (International Diabetes Fediration). An assessment of the severity of clinical and psychopathological symptoms was performed using the PANSS. Results: the prevalence of MS in in-patients with schizophrenia in the Western Siberia is similar to that reported in the literature. It was found that in-patients with schizophrenia and MS are characterized by a predominance of women and older age, as well as a large proportion of divorced, and a smaller proportion of never married. Women with MS were older, got longer duration of illness, and got later onset of disease than men with MS. The age of disease onset was significantly greater in patients with MS than in patients without MS. Atypical antipsychotics were more often used as the basic antipsychotic treatment in the group of patients with MS but this difference between the groups did not reach statistical significance. Conclusions: the main risk factors in patients with schizophrenia and MS coincide with risk factors of MS in general population. A later onset of the disease can act as an independent risk factor. The relationship and mutual influence of risk factors for the development of MS in patients with schizophrenia needs further study.

Position Statement on Religion and Spirituality in Psychiatry: Seven Recommendations

Background: in December 2015 the Executive Committee of the World Psychiatric Association approved a Position Statement on religion, spirituality in psychiatry. Since then, the World Psychiatric Association Section of Religion, Spirituality and Psychiatry has committed to publicizing the Position Statement worldwide. Aim: to bring this statement, especially the seven recommendations, to the attention of the international psychiatric community, in particular the Russian psychiatric community. Method: a narrative review and the seven recommendations in the Position Statement are explained, thus demonstrating its importance. Conclusion: religion and spirituality in psychiatry are part of daily psychiatric practice, scientific research, residency training and continuous medical education, and the political and public realm. With the publication of the Position Statement, the Executive Committee of the World Psychiatric Association has made a major accomplishment that benefits psychiatry around the world.

Citicoline in the Treatment of Mild Cognitive Impairment in Blood Relatives of Patients with Alzheimer’s Disease: Immediate and Long-Term Effects of Course Therapy

The aim was to study immediate and long-term (post-therapeutic) effects of a three-month course of therapy with citicoline in 1st-degree relatives of patients with Alzheimer’s disease (AD). All the included relatives of patients with AD revealed signs of minimal cognitive dysfunction (MCD) and mild cognitive decline syndrome (MCI — Mild Cognitive Impairment, ICD-10 code F06.7). Study participants: the study involved 90 first-degree relatives: 24 with MCI and 66 with MCD. Study design: an open-label comparative multidisciplinary study of the six-month dynamics of cognitive functioning of two groups of relatives who received a three-month course of citicoline therapy. The baseline indicators of the cognitive functioning of relatives with MCI syndrome and MKD were compared with the indicators at the end of the three-month course of therapy with citicoline at a daily dose of 1000 mg as well as 3 months after the end of the course of treatment. Methods: clinical, psychopathological, neuropsychological, psychometric, genetic, statistical ones. Results: а significant positive effect of the course therapy with citicoline on the cognitive impairment of 1st degree AD-patients’ relatives with minimal cognitive dysfunction and more pronounced cognitive impairments met the diagnostic criteria for MCI syndrome has been found. A significantly greater value of both immediate and long-term therapeutic effect of MKD compared with MCI in relatives was established by psychometric and neuropsychological indicators characterizing voluntary memorization of verbal and visual stimuli, optical and spatial activity, voluntary attention, and associative verbal thinking. Conclusion: the results of the study can be used as the basis for a model of prevention of the progression of cognitive deficit and the development of dementia in persons with a high risk of developing AD, i.e. in individuals with both genetic risk and signs of cognitive impairment.

Mental Disorder in Chronic Heart Failure

The aim: analysis of scientific publications on the problem of clinical structure of mental disorders in patients with a chronic heart failure, taking into account cardiological pathology. Material and method: according to the keywords “chronic heart failure”, “mental disorders”, “depression”, “anxiety”, “hypochondria”, “dissociative disorders”, “denial”, “personality”, “coping strategies”, articles were searched in databases MEDLINE/PubMed, Scopus, Webofscience, eLibrary. Conclusion: mental disorders are widespread among patients with chronic heart failure (CHF). They are heterogeneous psychopathological phenomena, the features of which are determined by the specifics of the clinical manifestations of symptoms and the course of the cardiological pathology. Mental disorders in patients with CHF negatively affect the quality of life, lead to an increase in readmission times and a high risk of mortality through maladaptive behavior in illness. At the same time, despite the relevance of the study of mental pathology in CHF, dissociative disorders, leading to the most severe maladaptive disorders of behavior in illness, asthenic disorders, which are one of the most subjectively painful and prognostically significant symptoms, as well as the contribution of personality characteristics to the formation of mental disorders, remain insufficiently studied.

The Relationship Between Depression and Dementia in the Context of the Impact on Mortality Rates

The aim of the study was to summarize research data on depressive disorders in dementia and to clarify the presence of their impact on mortality rates in dementia. Materials and methods: To compile a literature review on the keywords “dementia”, “mortality” and “depression”, papers were selected and analyzed in the MEDLINE/PubMed and eLibrary databases from 2000 to 2020, as well as relevant references of the analyzed papers. Of the 245 Russian-language and 142 English-language papers, 64 publications were selected for further analysis. Results: the relationship between depression and dementia in late life is complex and is still under debate. Depression can be both a risk factor for the development of dementia and prodromal syndrome, or accompany the development of dementia. Depression is common in all types of dementia and in all stages of the disease, including mild cognitive impairment. Depression and vascular dementia may have a synergistic effect on mortality. Conclusion: the results obtained in the course of the study are important for integral understanding of the peculiarities of managing patients with various types of dementia.

Evaluation of Platelet Glutamate Dehydrogenase Activity in Late-Life Depressions

The aim of the study is to evaluate the activity of platelet glutamate dehydrogenase (GDH) in late-life depression compared to the healthy control group and to reveal possible correlations with clinical data. Patients and methods: 42 elderly patients (60–86 years old) with depressive episodes of different nosological categories according to ICD-10 were examined: a single depressive episode (F32.0, F32.1), a depressive episode in recurrent depressive disorder (RDD — F33.0, F33.1) and a depressive episode in bipolar affective disorder (BD — F31.3). The activity of GDH and the severity of depression (using the Hamilton depressive scale, HAMD-17, and the Hamilton scale for assessing anxiety, HARS) were evaluated twice: before the starting the course of antidepressant therapy (day 0) and on the 28th day of the treatment course. Results: patients showed a significant decrease in the activity of GDH compared to the control group (p < 0.0008). Before the treatment, GDH activity was significantly reduced compared to the control in both RDD and BD (p < 0.002 and p < 0.004), whereas after the treatment, the decreased GDH activity was observed only in patients with BD (p < 0.002). When compared with the control group, male patients showed a significant decrease in GDH activity both before and after the treatment course (p < 0.017 and p < 0.027), whereas women patients showed the decrease only before the treatment (p < 0.014). Conclusion: the decreased platelet GDH activity in elderly depressions may indicate an impairment of glutamate metabolism. Gender differences were revealed in the reversal of GDH activity level after the therapy: in men, the level of GDH activity did not recover to control values after the treatment course. An elevation in the level of GDH to control values over a 28-day course of therapy occurred only in patients with RDD, but not in patients with BD.

Depression with Mixed Features (for DSM-5): Distinguishing Indicators Imaginary Coherence EEG Rest

Background: The neuronal correlates of depression with mixed traits (according to DSM-5) at rest have not been studied. Objective: to determine the indicators of imaginary coherence of EEG-rest, which distinguish patients with depression with mixed features (according to DSM-5) from patients with depression without mixed features and healthy subjects, and also to trace the dependence of the identified neurophysiological characteristics on the diagnostic belonging of the symptom complex to bipolar II type or recurrent depressive disorder. Patients and methods: on a background free from drug therapy, 80 patients with depression with mixed features (XD; n = 40 — with bipolar II disorder (XB) and n = 40 — with recurrent depressive disorder (XR)), 80 patients with depression without mixed traits (TD; n = 40 — for bipolar II type (TB) and n = 40 — for recurrent depressive disorder (TR), as well as 80 healthy subjects (N). The study groups were matched by sex and age. The study used clinical-psychopathological, psychometric, neurophysiological and statistical research methods. According to the Kruskal–Wallis criterion for independent samples the parameters of imaginary coherence (modulo) of standard frequency ranges (delta (δ) — 0.5–4 Hz, theta (θ) — 4–8 Hz, alpha (α) — 8–13 Hz, beta-1 (β1) — 13–20 Hz, beta-2 (β2) — 20–30 Hz, gamma (γ) — 30–45 Hz) between pairs of 14 cutaneous standard EEG derivations (according to the “10–20” system) in three (XD, TD and N), and then in five (XB, XR, TB, TR and N) comparison groups. Post-hoc analysis was performed using the U-test. The significance level was adjusted according to the Bonferroni correction. Results: three indicators were identified: α-ICoh(C3–P4), β1-ICoh(C3–P3) and β2-ICoh(F3–C4). For all three parameters, the H-test values for the “Group” factor (n = 3 and n = 5) were highly significant. In this case, α-ICoh(C3– P4) — XD = TD, XD < N, TD < N; β1-ICoh(C3–P3) — XD < TD, XD < N; TD < N; β2-ICoh(F3–C4) — XD > TD; XD > N, TD > N. The groups of patients with XD within the framework of recurrent depressive and bipolar II disorders significantly differed in terms of β1- ICoh(C3–P3) — XR > XB. At the level of statistical trends, in type II bipolar disorder — XB > TB according to α-ICoh(C3–P4), and in recurrent depressive disorder — XR > TR according to β2-ICoh(F3–C4). Conclusion. Thus, depression with mixed features can be considered in terms of dysfunctional interactions of the left frontal, bilateral central and parietal cortical zones, depending on the diagnostic affiliation of the depressive symptom complex and reflecting violations of automatic and voluntary regulation of affect, cognitive and behavioral changes.