Cytokine Imbalance as a Biomarker of Treatment-Resistant Schizophrenia

Treatment-resistant schizophrenia (TRS) is an important and unresolved problem in biological and clinical psychiatry. Approximately 30% of cases of schizophrenia (Sch) are TRS, which may be due to the fact that some patients with TRS may suffer from pathogenetically “non-dopamine” Sch, in the development of which neuroinflammation is supposed to play an important role. The purpose of this narrative review is an attempt to summarize the data characterizing the patterns of production of pro-inflammatory and anti-inflammatory cytokines during the development of therapeutic resistance to APs and their pathogenetic and prognostic significance of cytokine imbalance as TRS biomarkers. This narrative review demonstrates that the problem of evaluating the contribution of pro-inflammatory and anti-inflammatory cytokines to maintaining or changing the cytokine balance can become a new key in unlocking the mystery of “non-dopamine” Sch and developing new therapeutic strategies for the treatment of TRS and psychosis in the setting of acute and chronic neuroinflammation. In addition, the inconsistency of the results of previous studies on the role of pro-inflammatory and anti-inflammatory cytokines indicates that the TRS biomarker, most likely, is not the serum level of one or more cytokines, but the cytokine balance. We have confirmed the hypothesis that cytokine imbalance is one of the most important TRS biomarkers. This hypothesis is partially supported by the variable response to immunomodulators in patients with TRS, which were prescribed without taking into account the cytokine balance of the relation between serum levels of the most important pro-inflammatory and anti-inflammatory cytokines for TRS

Association of the HTR2A T102C SNP with Weight Gain and Changes in Biochemical Markers in Patients Receiving Antipsychotics

The purpose of our research was to study the association of the HTR2A T102C (rs6313) SNP with anthropometric and biochemical markers in patients treated with typical and atypical antipsychotics in monotherapy mode. Materials and methods: One hundred and seventeen white inpatients (95 men and 22 women) with F2 disorders (ICD-10, 1995) were enrolled in the study. All patients were divided into two groups by the antipsychotic class with which they were treated (Group 1 included 40 patients treated with typical antipsychotics; Group 2 included 77 patients treated with atypical antipsychotics) and two subgroups by weight change criteria during the study (Subgroup 1 included patients with weight change >6%; Subgroup 2 included patients with weight change <6%). The following examinations were performed: physical examination, anthropometric measurements (BMI. WC, TC), clinical examination, blood test (ALT, AST, FPG, VLDL-C, LDL-C, HDL-C, total cholesterol, triglycerides, total protein, albumin, creatinine, uric acid, carbamide), and genotyping for the HTR2A T102C (rs6313) SNP. Results: There were no statistically significant differences in the distribution of genotypes of the HTR2A T102C (rs6313) SNP between Group 1 and Group 2 (P>0.05). Kruskal-Wallis one-way analysis of variance between subgroups showed statistically significant differences between carbamide levels in the second visit in Group 2 (P=0.02). A Dunn post hoc test with Bonferroni adjustment showed statistically significant differences between TT and CT genotypes of the HTR2A T102C SNP: carbamide level was greater in TT carriers (P=0.02). The strength of associations and risks between alleles of the HTR2A T102C SNP and antipsychotic-induced weight change were as follows: ORC=0.49; CIC [0.25; 0.95]; RRC=0.58 CIC [0.35; 0.97]; ORT=2.03; CIT [1.05; 3.94]; RRT=1.7 CIT [1.02; 2.81]. Conclusion: Our results of the pilot pharmacogenetic studies show an association of the T allele carriage of the HTR2A T102C SNP with risk of antipsychotic-induced weight gain. The continuation of this study and an increase in the sample size will allow establishing valid pharmacogenetic markers for the risk of antipsychotic-induced weight gain

The effects of improving sleep on mental health (OASIS): a randomised controlled trial with mediation analysis

BACKGROUND: Sleep difficulties might be a contributory causal factor in the occurrence of mental health problems. If this is true, improving sleep should benefit psychological health. We aimed to determine whether treating insomnia leads to a reduction in paranoia and hallucinations. METHODS: We did this single-blind, randomised controlled trial (OASIS) at 26 UK universities. University students with insomnia were randomly assigned (1:1) with simple randomisation to receive digital cognitive behavioural therapy (CBT) for insomnia or usual care, and the research team were masked to the treatment. Online assessments took place at weeks 0, 3, 10 (end of therapy), and 22. The primary outcome measures were for insomnia, paranoia, and hallucinatory experiences. We did intention-to-treat analyses. The trial is registered with the ISRCTN registry, number ISRCTN61272251. FINDINGS: Between March 5, 2015, and Feb 17, 2016, we randomly assigned 3755 participants to receive digital CBT for insomnia (n=1891) or usual practice (n=1864). Compared with usual practice, the sleep intervention at 10 weeks reduced insomnia (adjusted difference 4·78, 95% CI 4·29 to 5·26, Cohen's d=1·11; p<0·0001), paranoia (-2·22, -2·98 to -1·45, Cohen's d=0·19; p<0·0001), and hallucinations (-1·58, -1·98 to -1·18, Cohen's d=0·24; p<0·0001). Insomnia was a mediator of change in paranoia and hallucinations. No adverse events were reported. INTERPRETATION: To our knowledge, this is the largest randomised controlled trial of a psychological intervention for a mental health problem. It provides strong evidence that insomnia is a causal factor in the occurrence of psychotic experiences and other mental health problems. Whether the results generalise beyond a student population requires testing. The treatment of disrupted sleep might require a higher priority in mental health provision. FUNDING: Wellcome Trust

Suicide trends in the early months of the COVID-19 pandemic: an interrupted time-series analysis of preliminary data from 21 countries

BackgroundThe COVID-19 pandemic is having profound mental health consequences for many people. Concerns have been expressed that at its most extreme, this may manifest itself in increased suicide rates.MethodsWe sourced real-time suicide data from around the world via a systematic internet search and recourse to our networks and the published literature. We used interrupted time series analysis to model the trend in monthly suicides prior to COVID-19 in each country/area-within-country, comparing the expected number of suicides derived from the model with the observed number of suicides in the early months of the pandemic. Countries/areas-within countries contributed data from at least 1 January 2019 to 31 July 2020 and potentially from as far back as 1 January 2016 until as recently as 31 October 2020. We conducted a primary analysis in which we treated 1 April to 31 July 2020 as the COVID-19 period, and two sensitivity analyses in which we varied its start and end dates (for those countries/areas-within-countries with data beyond July 2020).OutcomesWe sourced data from 21 countries (high income [n=16], upper-middle income [n=5]; whole country [n=10], area(s)-within-the-country [n=11]). In general, there does not appear to have been a significant increase in suicides since the pandemic began in the countries for which we had data. In fact, in a number of countries/areas-within-countries there appears to have been a decrease.InterpretationThis is the first study to examine suicides occurring in the context of the COVID-19 pandemic in multiple countries. It offers a consistent picture, albeit from high- and upper-middle income countries, of suicide numbers largely remaining unchanged or declining in the early months of the pandemic. We need to remain vigilant and be poised to respond if the situation changes as the longer-term mental health and economic impacts of the pandemic unfold

Role of nitric oxide and related molecules in schizophrenia pathogenesis: biochemical, genetic and clinical aspects

Currently, schizophrenia is considered a multifactorial disease. Over the past 50 years, many investigators have considered the role of toxic free radicals in the etiology of schizophrenia. This is an area of active research which is still evolving. Here, we review the recent data and current concepts on the roles of nitric oxide (NO) and related molecules in the pathogenesis of schizophrenia. NO is involved in storage, uptake and release of mediators and neurotransmitters, including glutamate, acetylcholine, noradrenaline, GABA, taurine and glycine. In addition, NO diffuses across cell membranes and activates its own extrasynaptic receptors. Further, NO is involved in peroxidation and reactive oxidative stress. Investigations reveal significant disturbances in NO levels in the brain structures (cerebellum, hypothalamus, hippocampus, striatum) and fluids of subjects with schizophrenia. Given the roles of NO in central nervous system development, these changes may result in neurodevelopmental changes associated with schizophrenia. We describe here the recent literature on NOS gene polymorphisms on schizophrenia, which all point to consistent results. We also discuss how NO may be a new target for the therapy of mental disorders. Currently there have been 2 randomized double-blind placebo-controlled trials of L-lysine as an NOS inhibitor in the CNS

Mental Disorders in Patients at Geriatrician Attendance : Basic Variants and Influence on Social Functioning (The Experience in Russia)

Introduction: Data exists showing a significant prevalence of mental disorders in the growing elderly population, but indices have a fairly wide range. This study’s aim was to analyze the frequency and variants of such disorders of the elderly in geriatrician attendance and their influence on social functioning. Material and methods: Of newly-admitted geriatrician patients, 37.2% were found to have deviations at the time of screening (Geriatric Depression Scale, Zung anxiety scale, MMSE and the clock drawing test). Of these 32 patients (24 women) were 69.5±4.4 years old and had somatic illnesses, mainly cardiovascular diseases and diabetes. The detailed assessment included the Neuropsychiatric Inventory Questionnaire, the Clinical Global Assessment, and the Global Assessment of Functioning scales. Statistics were based on Student's criterion (taking into account the normal distribution of the sample data). Results and their discussion: Fully 93.7% of the disorders met the International Classification of Diseases (10th edition) criteria for adaptation disorder, organic anxiety disorder, recurrent depressive disorder with a moderate depressive episode. Two patients had dementia with confusion (delirium). The significant ranking of the anxiety-depressive disorders can be explained by their prevalence in the elderly population as a whole, the close relationship of such disorders with somatic pathology, and in dementia and psychotic cases, more frequent visits to psychiatrists. About a third of the patients manifested signs of impaired functioning, dependent on the presence of family (t = 2.9; p < 0.05) and their relationships within the family (the complex ones excluded indices above 70 points of GAF). Conclusions: More than a third of newly-admitted geriatric patients have mental disorders, mostly those on the anxiety-depressive depressive spectrum. Biological factors and psychosocial influences are both present represented as their reasons. Social functioning may suffer and highly depends on microsocial environments

BEHAVIORAL AND EMOTIONAL REACTIONS OF THE RUSSIAN POPULATION TO THE BEGINNING OF THE COVID-19 PANDEMIC: AN ON-LINE SURVEY RESULTS

Background: The study aimed to identify the patterns of adaptive and behavioral strategies in different population groups, also to evaluate their association with the infection prevention strategies and the distress during the COVID-19 pandemic. Methods: The data were obtained from the on-line survey of 1958 respondents (mean age 31±12 years) from March 30, 2020 to April 5, 2020. 578 respondents reported a history of affective disorders; 884 respondents - a history of somatic disease. The level of anxiety distress was evaluated with the Psychological Stress Measure (PSM-25). The analysis of variance was used for statistics. p<0.05 was considered significant. The effect sizes (ES) were evaluated according to Cohen\u27s d and Cramer’s V criteria. Results: The average PSM-25 score corresponded to moderate stress intensity. An increased level of psychological stress was associated with the young age of the respondents, the history of affective disorders and somatic diseases, the compliance with selfisolation, the practice of social distancing, and the use of sanitizer. Concerns about the availability of protective equipment were specifically associated with the self-isolation compliance (ES=0.1); the combination of concerns about the contagiousness of the virus (ES=0.12) and the inaccessibility of daily medications (ES=0.11) - with the principles of social distance. Moreover, the concerns about the lack of specific treatment, the danger to one’s own life, the contagiousness of the virus, and the lack of protective equipment were associated with the protective behavior resulting in increased hand hygiene. The history of affective disorders was rarely associated with wearing masks and gloves, but more often - with the use of self-isolation strategies. Conclusions: The psychological reactions of the population during the COVID-19 pandemic are specifically associated with adaptive behavior in the process of anti-epidemic measures. Respondents with affective disorders experienced specific patterns of anxiety about coronavirus infection in combination with high rates of psychological stress

Cytokine Imbalance as a Biomarker of Treatment-Resistant Schizophrenia

Treatment-resistant schizophrenia (TRS) is an important and unresolved problem in biological and clinical psychiatry. Approximately 30% of cases of schizophrenia (Sch) are TRS, which may be due to the fact that some patients with TRS may suffer from pathogenetically &ldquo;non-dopamine&rdquo; Sch, in the development of which neuroinflammation is supposed to play an important role. The purpose of this narrative review is an attempt to summarize the data characterizing the patterns of production of pro-inflammatory and anti-inflammatory cytokines during the development of therapeutic resistance to APs and their pathogenetic and prognostic significance of cytokine imbalance as TRS biomarkers. This narrative review demonstrates that the problem of evaluating the contribution of pro-inflammatory and anti-inflammatory cytokines to maintaining or changing the cytokine balance can become a new key in unlocking the mystery of &ldquo;non-dopamine&rdquo; Sch and developing new therapeutic strategies for the treatment of TRS and psychosis in the setting of acute and chronic neuroinflammation. In addition, the inconsistency of the results of previous studies on the role of pro-inflammatory and anti-inflammatory cytokines indicates that the TRS biomarker, most likely, is not the serum level of one or more cytokines, but the cytokine balance. We have confirmed the hypothesis that cytokine imbalance is one of the most important TRS biomarkers. This hypothesis is partially supported by the variable response to immunomodulators in patients with TRS, which were prescribed without taking into account the cytokine balance of the relation between serum levels of the most important pro-inflammatory and anti-inflammatory cytokines for TRS

Genetic Predisposition to Schizophrenia and Depressive Disorder Comorbidity

Background: Patients with schizophrenia have an increased risk of depressive disorders compared to the general population. The comorbidity between schizophrenia and depression suggests a potential coincidence of the pathophysiology and/or genetic predictors of these mental disorders. The aim of this study was to review the potential genetic predictors of schizophrenia and depression comorbidity. Materials and Methods: We carried out research and analysis of publications in the databases PubMed, Springer, Wiley Online Library, Taylor &amp; Francis Online, Science Direct, and eLIBRARY.RU using keywords and their combinations. The search depth was the last 10 years (2010&ndash;2020). Full-text original articles, reviews, meta-analyses, and clinical observations were analyzed. A total of 459 articles were found, of which 45 articles corresponding to the purpose of this study were analyzed in this topic review. Results: Overlap in the symptoms and genetic predictors between these disorders suggests that a common etiological mechanism may underlie the presentation of comorbid depression in schizophrenia. The molecular mechanisms linking schizophrenia and depression are polygenic. The most studied candidate genes are GRIN1, GPM6A, SEPTIN4, TPH1, TPH2, CACNA1C, CACNB2, and BCL9. Conclusion: Planning and conducting genome-wide and associative genetic studies of the comorbid conditions under consideration in psychiatry is important for the development of biological and clinical predictors and a personalized therapy strategy for schizophrenia. However, it should be recognized that the problems of predictive and personalized psychiatry in the diagnosis and treatment of schizophrenia and comorbid disorders are far from being resolved

Association of a Single-Nucleotide Variant rs11100494 of the NPY5R Gene with Antipsychotic-Induced Metabolic Disorders

Background: The usage of antipsychotics (APs) is the most robust and scientifically based approach in the treatment of schizophrenia spectrum disorders (SSDs). The efficiency of APs is based on a range of target receptors of the central nervous system (CNS): serotoninergic, dopaminergic, adrenergic, histaminergic and cholinergic. Metabolic disorders are the most severe adverse drug reactions (ADRs) and lead to cardiovascular diseases with a high rate of mortality in patients with SSDs. Neuropeptide Y receptor Y5 (NPY5R) is known in the chain of interaction to target receptors for APs, agouti-related peptide receptors and proopiomelanocortin receptors. We studied the association of the single-nucleotide variants (SNVs) rs11100494 and rs6837793 of the NPY5R gene, and rs16147, rs5573, rs5574 of the NPY gene, with metabolic disorders in Russian patients with SSDs. Methods: We examined 99 patients with SSDs (mean age&mdash;24.56 years old). The mean duration of APs monotherapy was 8 weeks. The biochemical blood test included levels of glucose, cholesterol, lipoproteins, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein and albumin. Anthropometry included weight, height, waist circumference and hip circumference. We used real-time PCR to study the carriage of major and minor alleles of the SNV rs11100494 (1164C&gt;A) of the NPY5R gene (chromosome localization&mdash;4q32.2). Group 1 comprised 25 patients with SSDs taking APs with a change in body weight of more than 6% since the start of APs therapy. Group 2 comprised 74 patients with SSDs taking APs with a change in body weight of less than 6% since the start of APs therapy. Results: We show the significance of genetic risk factors (carriage of major allele C of SNV rs11100494 of the NPY5R gene) for the development of AP-induced weight gain in Russian patients with SSDs. The allele C predisposes to AP-induced weight gain (OR = 33.48 [95% CI: 12.62; 88.82], p-value &lt; 0.001). Additionally, the results of our study demonstrate that first-generation APs (FGAs) are more likely to cause an increase in serum transaminase levels but are less likely to increase body weight. Second-generation APs (SGAs) are more likely to cause weight gain and changes in serum glucose levels. Conclusion: Our study shows the predictive role of the allele C of SNV rs11100494 of the NPY5R gene in the development of AP-induced weight gain. However, we did not find a significant association between biochemical markers and this SNV in Russian patients with SSDs