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.

Determinants of Stress Levels and Behavioral Reactions in Individuals With Affective or Anxiety Disorders During the COVID-19 Pandemic in Russia.

Introduction: Individuals with affective and anxiety disorders are among those most vulnerable to the negative effects of the COVID-19 pandemic. Aim: This study aims to analyze the determinants of stress levels and protective behavioral strategies associated with the COVID-19 pandemic in Russian-speaking people with affective or anxiety disorders (AADs). Materials and Methods: In this cross-sectional online survey, the psychological distress and behavioral patterns of respondents with self-reported AAD (n = 1,375) and without disorders (n = 4,278) were evaluated during three periods of restrictive measures in Russia (March-May 2020). Distress levels were verified using the Psychological Stress Measure (PSM-25). Results: Stress levels among respondents with AAD were higher at all study periods than for those with no mental disorder (Cohen's d 0.8-1.6). The stress level increased (Cohen's d = 0.4) in adolescents (16-18 years) with AAD and remained the same in those without disorders; in youths (19-24 years) with and without disorders, an increase (Cohen's d = 0.3) and a decrease (Cohen's d = 0.3) in the stress were observed, correspondingly; the stress in adults (25-44 years) with disorders did not change and decreased in those without disorders (Cohen's d = 0.4). Individuals with bipolar disorders demonstrated lower stress than individuals with depressive (Cohen's d = 0.15) and anxiety disorders (Cohen's d = 0.27). Respondents with depressive and bipolar disorders employed fewer protective measures simultaneously and were less likely to search for information about COVID-19. Conclusion: The presence of affective or anxiety disorders is associated with a more acute response to the COVID-19 pandemic. Apparently, the type of mental disorder influenced stress levels and protective behavior patterns.

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 & Francis Online, Science Direct, and eLIBRARY.RU using keywords and their combinations. The search depth was the last 10 years (2010-2020). 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-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>A) of the NPY5R gene (chromosome localization-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 < 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.

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's 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 self-isolation, 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.

Incidence of the Diagnosis of Anxiety Disorders in the Russian Federation: Results of a Web-Based Survey of Psychiatrists.

INTRODUCTION: According to the official Russian source, in 2017 only 0.27% of the population of Russia was diagnosed with International Classification of Diseases, tenth revision (ICD-10) F4 category disorders (neurotic, stress-related and somatoform disorders), despite these disorders being among the most prevalent mental disorders worldwide. Here we report the results of a large-scale survey among Russian psychiatrists with the primary objective to assess the proportion of psychiatrists who use the diagnoses of interest (mixed anxiety and depression disorder [MADD], adjustment disorder [AdD], panic disorder [PD], agoraphobia, generalized anxiety disorder [GAD], social phobia, simple phobia, acute stress disorder and posttraumatic stress disorder) and compare results with those of a recent World Psychiatric Association (WPA) and World Health Organization (WHO) survey. We also compared the incidence of these diagnoses between state and non-state psychiatric services in Russia. METHODS: Mean proportions and distribution of proportions of participants who made diagnoses of interest at different rates were calculated and compared with the results of the recent WPA and WHO survey. Risk ratios (RR) of the incidence of these diagnoses made at a frequency of at least once a week were calculated to compare state and non-state psychiatric services. The 95% confidence intervals of the RRs were calculated using the Koopman asymptotic score method. RESULTS: Responses of 960 Russian psychiatrists were included in the analysis. Of these 95, 89 and 87% reported making diagnoses of MADD, AdD and PD, respectively, during the preceding 12 months, a far larger proportion compared to other disorders of interest. In general, a significantly smaller proportion of participants in our survey made diagnoses of anxiety disorders compared to respondents in the international WPA-WHO survey. Based on RRs, diagnoses of MADD, AdD, PD, GAD and acute stress disorder were less frequently made in the state-operated psychiatric service. CONCLUSION: Our survey revealed a serious underdiagnosis of anxiety disorders in Russia that may be associated with complex factors that include, but are not limited to the current stigma associated with the state-operated psychiatric service, which is still the exclusive source of official statistical data in Russia.

Development of molecular tools for diagnosis of Alzheimer's disease that are based on detection of amyloidogenic proteins.

Alzheimer's disease (AD) is the most common form of dementia that usually occurs among older people. AD results from neuronal degeneration that leads to the cognitive impairment and death. AD is incurable, typically develops over the course of many years and is accompanied by a loss of functional autonomy, making a patient completely dependent on family members and/or healthcare workers. Critical features of AD are pathological polymerization of Aß peptide and microtubule-associated protein tau, accompanied by alterations of their conformations and resulting in accumulation of cross-ß fibrils (amyloids) in human brains. AD apparently progresses asymptomatically for years or even decades before the appearance of symptoms. Therefore, development of the early AD diagnosis at a pre-symptomatic stage is essential for potential therapies. This review is focused on current and potential molecular tools (including non-invasive methods) that are based on detection of amyloidogenic proteins and can be applicable to early diagnosis of AD.Abbreviations: Aß - amyloid-ß peptide; AßO - amyloid-ß oligomers; AD - Alzheimer's disease; ADRDA - Alzheimer's Disease and Related Disorders Association; APH1 - anterior pharynx defective 1; APP - amyloid precursor protein; BACE1 - ß-site APP-cleaving enzyme 1; BBB - brain blood barrier; CJD - Creutzfeldt-Jakob disease; CRM - certified reference material; CSF - cerebrospinal fluid; ELISA - enzyme-linked immunosorbent assay; FGD - 18F-fluorodesoxyglucose (2-deoxy-2-[18F]fluoro-D-glucose); IP-MS - immunoprecipitation-mass spectrometry assay; MCI - mild cognitive impairment; MDS - multimer detection system; MRI - magnetic resonance imaging; NIA-AA - National Institute on Ageing and Alzheimer's Association; NINCDS - National Institute of Neurological and Communicative Disorders and Stroke; PEN2 - presenilin enhancer 2; PET - positron emission tomography; PiB - Pittsburgh Compound B; PiB-SUVR - PIB standardized uptake value ratio; PMCA - Protein Misfolding Cycling Amplification; PrP - Prion Protein; P-tau - hyperphosphorylated tau protein; RMP - reference measurement procedure; RT-QuIC - real-time quaking-induced conversion; SiMoA - single-molecule array; ThT - thioflavin T; TSEs - Transmissible Spongiform Encephslopathies; T-tau - total tau protein.

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

BACKGROUND: The COVID-19 pandemic is having profound mental health consequences for many people. Concerns have been expressed that, at their most extreme, these consequences could manifest as increased suicide rates. We aimed to assess the early effect of the COVID-19 pandemic on suicide rates around the world. METHODS: We sourced real-time suicide data from countries or areas within countries through a systematic internet search and recourse to our networks and the published literature. Between Sept 1 and Nov 1, 2020, we searched the official websites of these countries' ministries of health, police agencies, and government-run statistics agencies or equivalents, using the translated search terms "suicide" and "cause of death", before broadening the search in an attempt to identify data through other public sources. Data were included from a given country or area if they came from an official government source and were available at a monthly level from at least Jan 1, 2019, to July 31, 2020. Our internet searches were restricted to countries with more than 3 million residents for pragmatic reasons, but we relaxed this rule for countries identified through the literature and our networks. Areas within countries could also be included with populations of less than 3 million. We used an interrupted time-series analysis to model the trend in monthly suicides before COVID-19 (from at least Jan 1, 2019, to March 31, 2020) in each country or area within a country, comparing the expected number of suicides derived from the model with the observed number of suicides in the early months of the pandemic (from April 1 to July 31, 2020, in the primary analysis). FINDINGS: We sourced data from 21 countries (16 high-income and five upper-middle-income countries), including whole-country data in ten countries and data for various areas in 11 countries). Rate ratios (RRs) and 95% CIs based on the observed versus expected numbers of suicides showed no evidence of a significant increase in risk of suicide since the pandemic began in any country or area. There was statistical evidence of a decrease in suicide compared with the expected number in 12 countries or areas: New South Wales, Australia (RR 0·81 [95% CI 0·72-0·91]); Alberta, Canada (0·80 [0·68-0·93]); British Columbia, Canada (0·76 [0·66-0·87]); Chile (0·85 [0·78-0·94]); Leipzig, Germany (0·49 [0·32-0·74]); Japan (0·94 [0·91-0·96]); New Zealand (0·79 [0·68-0·91]); South Korea (0·94 [0·92-0·97]); California, USA (0·90 [0·85-0·95]); Illinois (Cook County), USA (0·79 [0·67-0·93]); Texas (four counties), USA (0·82 [0·68-0·98]); and Ecuador (0·74 [0·67-0·82]). INTERPRETATION: This is the first study to examine suicides occurring in the context of the COVID-19 pandemic in multiple countries. In high-income and upper-middle-income countries, suicide numbers have remained largely unchanged or declined in the early months of the pandemic compared with the expected levels based on the pre-pandemic period. We need to remain vigilant and be poised to respond if the situation changes as the longer-term mental health and economic effects of the pandemic unfold. FUNDING: None.

Screening of Depressive Symptoms in a Russian General Population Sample: A Web-based Cross-sectional Study.

BACKGROUND AND OBJECTIVE: Web-based screening of depressive symptoms in general non-clinical population can provide better insights into actual prevalence of depressive symptoms and associated risk factors. To study the current prevalence of depressive symptoms in Russian non-clinical population we conducted screening using an online survey based on Depression subscale of Hospital Anxiety and Depression Scale (HADS-D). METHODS: The online survey covered 2610 Russian-speaking respondents and included HADS-D, questions about sex, age and presence of cardiovascular diseases (CVD) diagnoses or symptoms in respondents. RESULTS: The proportion of respondents with depressive symptoms, estimated by online HADS-D, was 14.4% (11.5% - at subclinical level, 2.9% - at clinical level). The overall HADS-D score was higher in women (p=0.003), in young individuals under 30 y.o vs. participants over 42 y.o. (p=0.004) and in individuals with self-reported CVD symptoms (p=0.00002). Linear regression analysis showed that self-reported CVD symptoms increase HADS-D score (p<0.001), but male sex (p=0.002) and older age (p<0.001) decrease it. Logistic regression showed that CVD symptoms increase the risk of depressive symptoms by HADS-D (p=0.033, OR=1.29), but older age (p=0.015, OR=0.87) and male sex (as a trend, p=0.052, OR=0.80) decrease this risk. CONCLUSION: Online survey based on HADS-D showed new patterns of depressive symptoms prevalence in Russian non-clinical population. Depressive symptoms prevalence did not differ between men and women and was higher among young people. The reported association between depressive symptoms and CVD was confirmed.

Inherited Metabolic Diseases as a Multisystem Model of Mental Disorders Research

Abstract Recent biological and genetic research data confirm shared pathological mechanisms of inherited metabolic diseases and mental disorders. We suggest that for further research a model of synergistic heterozygosity can become a convenient tool. In that case the use of inherited metabolic disorders as a multisystem research model can provide both significant theoretical and practical results. At the initial stage of this hypothesis evaluation, it seems efficient to screen for mental symptoms the families of patients with inherited metabolic disorders.

Suicides in the COVID-19 Pandemic - Are We Well Informed Regarding Current Risks and Future Prospects?

Background: Suicides are predicted to drop in the acute phase of any crisis that poses a threat to the entire population, though data on this are inconsistent. A pandemic is the most severe global crisis one can imagine. There is an urgent need to identify objective trends in suicide rates across countries and populations in a real-time manner in order to be better informed regarding prospects and adaptation of preventive strategies. Objectives: To evaluate suicidal behaviour in a metropolis immediately after the introduction of severe containment measures due to the pandemic. Methods: Cases of completed suicides in St. Petersburg were obtained from the local city Bureau of Forensic Medical Examinations for the period 1 January 2016 to 31 July 2020. Data were accurately collected and monthly frequencies per 100,000 of the population in April-May 2020 (introduction of the most severe stay at home measures) were compared with corresponding data from 2016-2019. Confidence intervals were calculated according to Wilson. Results: Suicide frequencies in the population of St. Petersburg in April 2020 did not go up, in contrast, they were 30.3% lower than the average for the previous four years. The decrease in April was more pronounced in males than in females (36.3% and12.4%, respectively). When looking at age groups it was found that the biggest drop in suicides was in older males ( 55 years). In this group, suicide indices were 58.5% lower than average for the previous four years. However, in females, there was a 50% rise in suicides in June, while in young males (15-34 years) there was an 87.9% rise in May. Total number of suicides for the first half of 2020 was very close to the average seen in previous years. None of the registered changes were statistically significant. Conclusions: The analysis is preliminary and does not account for possible seasonality, however, we consider that the reduction in completed suicides immediately after crisis exposure deserves attention. It supports views that in the acute phase of the crisis, suicidal behaviour may decline, which may be quickly replaced by a rise. Such a rise in females and younger males points on possible risk groups and requires a response from society. More studies are needed to have a clearer picture of suicide dynamics in Russia during the different waves of the pandemic, and prevention should be prioritized regardless of the tendencies.

Stress and Stigmatization in Health-Care Workers during the COVID-19 Pandemic.

BACKGROUND: The health-care workers showed the highest risks of the adverse psychological reactions from the COVID-19 pandemic. AIM: This study aimed to evaluate the structure and severity of psychological distress and stigmatization in different categories of health-care workers during the COVID-19 pandemic. MATERIALS AND METHODS: This study included two phases of online survey in 1800 Russian-speaking health-care workers (March 30 - April 5 and May 4 - May 10, 2020). The Psychological Stress Scale (PSM-25) and modified Perceived Devaluation-Discrimination scale (Cronbach's α = 0.74) were used. Dispersion analysis was performed with P = 0.05, Cohen's d, and Cramer's V calculated (effect size [ES]). RESULTS: The psychological stress levels decreased in the second phase (ES = 0.13), while the stigma levels (ES = 0.33) increased. Physicians experienced more stress compared with nurses and paramedical personnel (ES = 0.34; 0.64), but were less likely to stigmatize SARS-CoV-2-infected individuals (ES = 0.43; 0.41). The increasing probability of contact with infected individuals was associated with higher levels of psychological stress (probable contact ES = 0.48; definite contact ES=0.97). The highest rates of contacts with COVID-19 patients were reported by physicians (χ2 = 123.0; P = 0.00, Cramer's V = 0.2), the youngest (ES = 0.5), and less experienced medical workers (ES = 0.33). CONCLUSION: Direct contact with coronavirus infection is associated with a significant increase in stress among medical personnel. The pandemic compromises the psychological well-being of the youngest and highly qualified specialists. However, the stigmatizing reactions are not directly associated with the risks of infection and are most prevalent among nurses and paramedical personnel.

Opening up new horizons for psychiatric genetics in the Russian Federation: moving toward a national consortium.

We provide an overview of the recent achievements in psychiatric genetics research in the Russian Federation and present genotype-phenotype, population, epigenetic, cytogenetic, functional, ENIGMA, and pharmacogenetic studies, with an emphasis on genome-wide association studies. The genetic backgrounds of mental illnesses in the polyethnic and multicultural population of the Russian Federation are still understudied. Furthermore, genetic, genomic, and pharmacogenetic data from the Russian Federation are not adequately represented in the international scientific literature, are currently not available for meta-analyses and have never been compared with data from other populations. Most of these problems cannot be solved by individual centers working in isolation but warrant a truly collaborative effort that brings together all the major psychiatric genetic research centers in the Russian Federation in a national consortium. For this reason, we have established the Russian National Consortium for Psychiatric Genetics (RNCPG) with the aim to strengthen the power and rigor of psychiatric genetics research in the Russian Federation and enhance the international compatibility of this research.The consortium is set up as an open organization that will facilitate collaborations on complex biomedical research projects in human mental health in the Russian Federation and abroad. These projects will include genotyping, sequencing, transcriptome and epigenome analysis, metabolomics, and a wide array of other state-of-the-art analyses. Here, we discuss the challenges we face and the approaches we will take to unlock the huge potential that the Russian Federation holds for the worldwide psychiatric genetics community.

Cognitive deficit in patients with paranoid schizophrenia: Its clinical and laboratory correlates.

The aim of this study was to search for correlates of cognitive impairment in patients with paranoid schizophrenia among clinical, demographic, anamnestic and biochemical markers (NSE, S100B protein, BDNF, hs-CRP). Patients with paranoid schizophrenia (n=125) were examined using the Brief Assessment of Cognitive Function in Schizophrenia, the Rey-Osterrieth Complex Figure task, and a number of clinical scales including the Positive and Negative Syndrome Scale. The majority of patients demonstrated cognitive impairment. The type of impairment was highly heterogeneous and individual. Relationships were found between the degree of executive functioning and family history of mental illness; working memory and age of onset of schizophrenia; and visual memory and psychopathological symptomatology. Negative and affective symptoms were not significantly associated with cognitive functioning. Treatment with first generation antipsychotics was associated with a more frequent impairment of motor skills, and concomitant anticholinergic drugs, with reduced accuracy. Use of second-generation antipsychotics only was associated with better accuracy, working memory and speech fluency. Among the patients, 21.4% had signs of a systemic inflammatory response, indicating a possible role of inflammatory response in the development of schizophrenia. CRP, S100B and NSE levels reflected features of the course of illness and therapeutic response. Patients with lower concentrations of BDNF were characterized by lower processing speeds.

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.

Association of adipokines with metabolic disorders in patients with schizophrenia: Results of comparative study with mental healthy cohort.

AIM: The role of adipose tissue hormones, adipokines, in formation of metabolic disorders in schizophrenia is not fully understood. The aim was to investigate the association of leptin and adiponectin plasma levels with metabolic parameters in antipsychotic treated patients with schizophrenia and in the group of age, gender and body mass index matched mental healthy persons. METHODS: One hundred patients with diagnosis of schizophrenia, who took antipsychotic medication, and equal number of control subjects, were enrolled for cross-sectional evaluation. Fasting blood plasma levels of glucose, lipids, insulin, adiponectin, leptin concentrations and insulin resistance HOMA index were determined. RESULTS: In both groups plasma leptin concentration positively correlated with body mass index, insulin plasma level and HOMA index, while adiponectin level had negative correlations with adiposity measures and positive associations with high density lipoprotein cholesterol content. At the same time, in schizophrenia group, but not in control subjects, leptin level positively associated with cholesterol and triglycerides concentrations and adiponectin negatively correlated with plasma insulin content, HOMA index and triglycerides levels. After controlling for confounders significant correlations remained for leptin concentration with HOMA index and plasma triglycerides level in schizophrenic patients and for adiponectin concentration with plasma high density lipoprotein cholesterol concentrations in both studied groups. CONCLUSIONS: Both adipokines associate with metabolic parameters in antipsychotic treated patients with schizophrenia. Leptin can play more specific role in pathogenesis of metabolic syndrome in schizophrenic persons than in mental healthy subjects.

Premorbid functioning and treatment response in recent-onset schizophrenia: prospective study with risperidone long-acting injectable.

Premorbid functioning may be associated with treatment response, but this is confounded by a lack of prospective longitudinal data and controls for medication compliance. This study tested the hypothesis that good premorbid functioning will be associated with better antipsychotic treatment response after controlling for drug adherence by using a long-acting injectable antipsychotic. This was a 6-month, open label, multicenter, phase IV trial in recent-onset schizophrenia treated with flexible doses of risperidone long-acting injectable (25-50 mg every 14 days). Premorbid functioning was assessed with the Premorbid Adjustment Scale (PAS)-Structured Interview; efficacy was evaluated with clinician-rated Positive and Negative Syndrome Scale, Clinical Global Impression scale of Severity of Illness, Clinical Global Impression scale of Change, Global Assessment of Functioning Scale, and trial participant completed SF-36. Analyses controlled for baseline scores and demographics. With the use of a priori PAS scoring criteria, the participants' premorbid functioning was categorized as stable-good (n = 142), stable-poor (n = 116), and deteriorating (n = 36). At baseline, the stable-good group had the best functioning on most efficacy measures. All groups showed significant improvement on efficacy measures with treatment. Improvement was significantly higher for the stable-good group. The PAS global assessment of highest level of functioning scale (excellent, n = 75; good, n = 117; fair, n = 78; and poor, n = 31) showed a strong association with baseline functioning and improvement and had a significant linear association with meeting Remission in Schizophrenia Working Group symptom criteria at baseline (P = 0.003) and attained and sustained remission for 3 months during study (47.7%, 49.3%, 29.6%, and 22.2%; P = 0.006). Good premorbid functioning corresponds with better treatment response in recent-onset psychosis as captured on both clinician and patient-reported measures.

Atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: a 6-week, randomized, placebo-controlled, double-blind trial in Russia.

The objective of the study was to compare the efficacy and tolerability of once-daily atomoxetine (< or =1.8 mg/(kg day) with those of placebo in children and adolescents (aged 6-16 years) with attention-deficit/hyperactivity disorder [ADHD (DSM-IV)]. This randomized, placebo-controlled, double-blind trial was conducted in Russia. The primary efficacy measure was baseline-to-end point changes in Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv) total score. Tolerability measures included treatment-emergent signs and symptoms (TESS), laboratory values and weight. Compared with patients in the placebo group (n = 33), patients treated with atomoxetine (n = 72) with a mean final dose of 1.4 mg/kg showed significantly greater improvement in ADHDRS-IV-Parent:Inv total score (least-squares mean: atomoxetine, -15.8; placebo, -11.4; p = 0.013). The most common TESS in the atomoxetine group included anorexia [atomoxetine, n = 13 (18.1%); placebo, n = 2 (6.1%)], somnolence, n = 11 versus n = 3 (15.3% vs. 9.1%, respectively), abdominal pain n = 9 versus n = 1 (12.5% vs. 3.0%, respectively) and nausea, n = 8 versus n = 1 (11.1% vs. 3.0%, respectively). Seven patients in the atomoxetine group and two in the placebo group experienced clinically important weight loss during the study (> or =7% from baseline; mean change, kg: atomoxetine, -0.6; placebo, 0.1; p = 0.032). Atomoxetine is efficacious in improving ADHD symptoms in children and adolescents. Atomoxetine treatment may be associated with a numerically higher incidence of anorexia, somnolence, abdominal pain and nausea, as well as statistically greater losses in body weight.