Inflammatory markers in outpatients with schizophrenia diagnosis in regular use of clozapine: a cross-sectional study.

It is known that inflammation worsen the course of schizophrenia and induce high clozapine serum levels. However, no study evaluated this change in function of clozapine daily dose in schizophrenia. We assessed the correlation between inflammation and severity symptoms in patients with schizophrenia that take and do not take clozapine. We also assessed the correlation between clozapine daily dose and inflammatory markers to patients who take this drug. Patients were recruited from Schizophrenia Ambulatory and Psychosocial Care Center of Clinical Hospital of Porto Alegre and from an association of relatives of patients with schizophrenia. Exam results, and other important clinical exam were assessed in patients record or patients were asked to show their exam in the case of outpatients. We included 104 patients, 90 clozapine users and 14 non-clozapine users. We calculate the systemic inflammatory markers [neutrophil-lymphocyte ratio (NLR), systemic immune inflammation index (SII), and the psychopathology severity by the Brief Psychiatric Rating Scaled anchored (BPRS-a)]. These variables were compared between clozapine users and non-clozapine users. It was used mean/median test according to data distributing, with study factor (SII, MLR, and PLR), the clinical outcome: severity of symptomatology (BPRS score), and clozapine daily dose as adjustment factor. Clozapine users exhibited a significantly higher neutrophil count (mean ± SD: 5.03 ± 2.07) compared to non-clozapine users (mean ± SD: 3.48 ± 1.27; p = 0.031). After controlling for comorbidity, other parameters also showed significant differences. These findings are consistent with previous studies that have demonstrated an inflammatory response following the administration of clozapine.

Allergic reaction induced by subcutaneous administration of ketamine: a case report.

Ketamine can be used for depression and suicidal ideation due to its effectiveness and low complication rates; moreover, allergic reactions are rare. Immediately after subcutaneous (SC) ketamine administration, a 22-year-old man rapidly developed hives on the trunk and face without oxygen desaturation. Symptoms disappeared after treatment with prednisolone. This case presents an allergic reaction to ketamine compatible with mast cell activation and release of preformed mediators, without being able to prove whether the event was mediated by immunoglobulin E. This is the only case reported to date of an allergic reaction to SC ketamine for psychiatric treatment.

Perda significativa de peso em pacientes com esquizofrenia na dieta hipocalórica de longo prazo: estudo piloto / Significant weight loss in patients with schizophrenia in long-term hypocaloric diet: a pilot study

Objetivo: A esquizofrenia está associada ao aumento da obesidade e morbidade por doença cardiovascular. O objetivo do presente estudo foi avaliar alterações no peso e índice de massa corporal (IMC) de pacientes com esquizofrenia após tratamento nutricional de longo prazo. Método: Estudo piloto retrospectivo envolvendo 42 indivíduos com esquizofrenia em tratamento nutricional entre 2004 e 2010. Os prontuários médicos foram revisados após aprovação institucional e coleta de dados para peso, índice de massa corporal (IMC), idade, gênero e dieta. O peso e o IMC foram avaliados no início do tratamento nutricional, após seis meses, após 12 meses e no momento da coleta de dados. Resultados: Houve perda significativa de peso e diminuição significativa do IMC quando comparados a cada grupo com o valor basal (p<0,001). Conclusões: Demonstramos que as intervenções nutricionais podem promover uma significativa perda de peso na esquizofrenia. Estes resultados suportam a importância da intervenção nutricional na esquizofrenia e trazem evidências de que a perda de peso permanece ao longo do tempo.(AU)

Objective: Schizophrenia is associated with increased obesity and morbidity from cardiovascular disease. The aim of the present study was to evaluate changes in weight and body mass index (BMI) of patients with schizophrenia following a long-term nutritional treatment. Methods: Retrospective pilot study involving 42 individuals with schizophrenia on nutritional treatment from 2004 to 2010. Medical charts were reviewed after institutional approval and data collection was conducted for weight, body mass index (BMI), age, gender and diet prescription. Weight and BMI were evaluated at baseline of nutrition treatment, after six months, after 12 months and at the time of data collection. Results: There was a significant weight loss and significant decreased in BMI when compared each group to baseline (p<0.001). Conclusions: We demonstrate that nutritional interventions can promote a significant weight loss in schizophrenia. These results support the importance of nutritional intervention in schizophrenia and bring evidences that weight loss remains along the time.(AU)

Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity.

Schizophrenia (SZ) is a debilitating neurodevelopmental disorder that strikes at a critical period of a young person's life. Its pathophysiology could be the result of deregulation of synaptic plasticity, with downstream alterations of inflammatory immune processes regulate by cytokines, impaired antioxidant defense and increased lipid peroxidation. The aim of this study was to examine serum oxidative stress markers and inflammatory cytokines in early and late phases of chronic SZ. Twenty-two patients at early stage (within first 10 years of a psychotic episode), 39 at late stage (minimum 10 years after diagnosis of SZ) and their respective matched controls were included. Each subject had 5 ml blood samples collected by venipuncture to examined thiobarbituric acid-reactive substances (TBARS), total reactive antioxidant potential (TRAP), protein carbonyl content (PCC), Interleukins 6 and 10 (IL-6, IL-10) and tumor necrosis factor alpha (TNF-alpha). TBARS, IL-6 and PCC levels were significantly higher in patients with SZ at early and late stages than in controls. There were no differences for TRAP and TNF-alpha levels in patients with SZ at early and late stages than in controls. IL-10 levels were decreased in patients at late stage and a decrease trend in early stage was found. Results provided evidence consistent with comparable biological markers across chronic SZ. The concept of biochemical staging proposed by others for bipolar disorder is not seen in this cohort of patients with SZ, at least for cytokines and oxidative stress markers. Our findings reinforce the need of assessment of individuals in ultra high risk to develop psychosis and first-episode population.

Reduced serum non-enzymatic antioxidant defense and increased lipid peroxidation in schizophrenic patients on a hypocaloric diet.

INTRODUCTION: Growing evidence suggests that oxidative stress (OS) may be associated with the pathophysiology underlying schizophrenia (SZ). Some studies indicate that nutritional supplements offer protection from OS, but there is no data about the effect of a hypocaloric diet on OS in this population. Therefore, we aimed to study the effect of a hypocaloric dietary intervention on OS in subjects with SZ. METHODS: A cross-sectional study of 96 participants in outpatient treatment for SZ comprised patients separated into two groups: one group of subjects followed a hypocaloric diet (HD) program (n=42), while the other group followed a regular diet (RD) with no nutritional restrictions (n=54). The serum total radical-trapping antioxidant parameter (TRAP), total antioxidant reactivity (TAR) and thiobarbituric acid reactive species (TBARS) levels were assessed. RESULTS: TRAP levels were lower and TBARS levels were higher in the HD group than in the RD group (p=0.022 and p=0.023, respectively). There were no differences in TAR levels between the groups. Additionally, there was a positive correlation between TRAP and TBARS levels after adjusting for BMI and clozapine dose (partial correlation=0.42, p<0.001). There were no correlations among the length of illness or diet and the levels of TRAP, TBARS, and TAR. CONCLUSIONS: Subjects with SZ on a hypocaloric diet displayed different OS parameters than those not following a HD. Serum TRAP levels were lower and TBARS levels were higher among SZ subjects with HD compared to SZ subjects without HD. Lower TRAP levels may reflect decreased oxidative stress, whereas higher TBARS levels most likely reflect a biochemical reaction to the decreased TRAP levels. Additionally, TAR levels were similar between groups, suggesting a similar quality of antioxidant defenses, despite quantitative differences between the two dietary protocols in SZ patients under outpatient care.

Altered oxygen metabolism associated to neurogenesis of induced pluripotent stem cells derived from a schizophrenic patient.

Schizophrenia has been defined as a neurodevelopmental disease that causes changes in the process of thoughts, perceptions, and emotions, usually leading to a mental deterioration and affective blunting. Studies have shown altered cell respiration and oxidative stress response in schizophrenia; however, most of the knowledge has been acquired from postmortem brain analyses or from nonneural cells. Here we describe that neural cells, derived from induced pluripotent stem cells generated from skin fibroblasts of a schizophrenic patient, presented a twofold increase in extramitochondrial oxygen consumption as well as elevated levels of reactive oxygen species (ROS), when compared to controls. This difference in ROS levels was reverted by the mood stabilizer valproic acid. Our model shows evidence that metabolic changes occurring during neurogenesis are associated with schizophrenia, contributing to a better understanding of the development of the disease and highlighting potential targets for treatment and drug screening.

Concurrent Validity and Reliability of the Brazilian Version of the Functioning Assessment Short Test in Patients with Schizophrenia.

OBJECTIVE: Many studies have documented the high rates of functional impairment among patients with schizophrenia. The majority of the available instruments used to assess functioning, however, focus on global measures of functional recovery rather than specific domains of psychosocial functioning. Most of these instruments have important limitations regarding use in psychiatry. The aim of the present study was to evaluate the psychometric properties of the Brazilian version of the Functioning Assessment Short Test (FAST) in patients with schizophrenia. METHODS: A convenience sample of 107 chronic outpatients with schizophrenia and 108 controls was assessed in a university hospital (Hospital de Clínicas de Porto Alegre, Brazil). Psychometric properties of FAST (internal consistency, concurrent validity, and test-retest reliability) were analyzed. RESULTS: The internal consistency obtained was high; the Cronbach's alpha was 0.89. FAST total score was higher in patients than in the control group (Z = 11.95; P<0.001). FAST test-retest agreement was excellent (intraclass correlation coefficient = 0.93; 95% confidence interval 0.81-0.97). In addition, FAST displayed a positive correlation with the Brief Psychiatric Rating Scale (ρ = 0.41; P<0.001) and a negative correlation with the Global Assessment of Functioning scale (ρ =-0.71; P = 0.001). CONCLUSIONS: Psychotic symptoms, comorbidity, and functional and cognitive impairment contribute to the decreased quality of life of patients with schizophrenia. It is important to obtain a valid and reliable instrument that is capable of evaluating the functional domains in this pathology. In this context, FAST showed accurate psychometrics properties and was able to detect functional differences between patients with the diagnosis of schizophrenia and healthy subjects.

Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance.

OBJECTIVE: Previous reports suggest that cytokines act as potential mediators of the interaction between the immune and neuroendocrine systems, and that a proinflammatory state may be associated with bipolar disorder and schizophrenia. The aim is to compare cytokine levels in both disorders. METHOD: Twenty euthymic bipolar disorder patients, 53 chronic stabilized schizophrenia patients and 80 healthy controls were recruited. Subjects were all non-smokers and non-obese. Cytokines TNF-α, IL-6, and IL-10 were examined by sandwich ELISA. RESULTS: IL-6 levels were increased in schizophrenia patients when compared to controls (p < 0.0001) and euthymic bipolar disorder patients (p < 0.0001). IL-6 levels were no different in controls compared to euthymic bipolar disorder patients (p = 0.357). IL-10 was lower in controls compared to schizophrenia patients (p = 0.001) or to bipolar disorder patients (p = 0.004). There was no significant difference in TNF-α serum levels among the groups (p = 0.284). Gender-based classification did not significantly alter these findings, and no correlation was found between the antipsychotic dose administered and cytokine levels in patients with schizophrenia. DISCUSSION: These findings evidence a chronic immune activation in schizophrenia. Bipolar disorder seems to present an episode-related inflammatory syndrome. Increased anti-inflammatory factor IL-10 in bipolar disorder and schizophrenia suggests different patterns of inflammatory balance between these two disorders. Results further support the need to investigate cytokines as possible biomarkers of disease activity or treatment response.

Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance / Níveis séricos de IL-6, IL-10 e TNF-α em pacientes com transtorno bipolar e esquizofrenia: diferenças no equilíbrio pró e antiinflamatório

OBJECTIVE: Previous reports suggest that cytokines act as potential mediators of the interaction between the immune and neuroendocrine systems, and that a proinflammatory state may be associated with bipolar disorder and schizophrenia. The aim is to compare cytokine levels in both disorders. METHOD: Twenty euthymic bipolar disorder patients, 53 chronic stabilized schizophrenia patients and 80 healthy controls were recruited. Subjects were all non-smokers and non-obese. Cytokines TNF-α, IL-6, and IL-10 were examined by sandwich ELISA. RESULTS: IL-6 levels were increased in schizophrenia patients when compared to controls (p < 0.0001) and euthymic bipolar disorder patients (p < 0.0001). IL-6 levels were no different in controls compared to euthymic bipolar disorder patients (p = 0.357). IL-10 was lower in controls compared to schizophrenia patients (p = 0.001) or to bipolar disorder patients (p = 0.004). There was no significant difference in TNF-α serum levels among the groups (p = 0.284). Gender-based classification did not significantly alter these findings, and no correlation was found between the antipsychotic dose administered and cytokine levels in patients with schizophrenia. DISCUSSION: These findings evidence a chronic immune activation in schizophrenia. Bipolar disorder seems to present an episode-related inflammatory syndrome. Increased anti-inflammatory factor IL-10 in bipolar disorder and schizophrenia suggests different patterns of inflammatory balance between these two disorders. Results further support the need to investigate cytokines as possible biomarkers of disease activity or treatment response.

OBJETIVO: Pesquisas sugerem as citocinas como potenciais mediadores da interação entre os sistemas imune e neuroendócrino, e que existe um estado pró-inflamatório associado com transtorno bipolar e esquizofrenia. O objetivo deste estudo é comparar os níveis de citocinas entre os dois distúrbios. MÉTODO: Vinte pacientes com transtorno bipolar eutímicos, 53 pacientes com esquizofrenia crônica estabilizados e 80 controles saudáveis foram recrutados. Todos os indivíduos eram não-fumantes e não-obesos. As citocinas TNF-α, IL-6 e IL-10 foram examinadas por ELISA sanduíche. RESULTADOS: A IL-6 estava aumentada nos pacientes com esquizofrenia quando comparados aos controles (p < 0,0001) e aos pacientes bipolares eutímicos (p < 0,0001). Os níveis de IL-6 não foram diferentes nos controles em comparação com pacientes com transtorno bipolar eutímicos (p = 0,357). Os níveis de IL-10 foram menores nos controles quando comparados aos pacientes com esquizofrenia (p = 0,001) ou aos bipolares (p = 0,004). Não houve diferença significativa nos níveis séricos de TNF-α entre os grupos (p = 0,284). A separação por sexo não mostrou diferenças significativas e não houve correlação entre a dose de antipsicóticos e os níveis de citocinas em pacientes com esquizofrenia. DISCUSSÃO: Estes resultados evidenciam uma ativação imune crônica na esquizofrenia. O transtorno bipolar parece apresentar um aumento da atividade inflamatória relacionado ao episódio de humor. Níveis maiores de IL-10 no transtorno bipolar e esquizofrenia sugerem diferentes padrões de equilíbrio inflamatório entre esses dois transtornos. Resultados fornecem apoio adicional para a investigação de citocinas como possíveis biomarcadores para a atividade da doença ou resposta ao tratamento.

Serum brain-derived neurotrophic factor and clozapine daily dose in patients with schizophrenia: a positive correlation.

Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF signaling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. Clozapine (CLZ) has been shown a beneficial effect on cognition in SZ in some studies and a detrimental effect in others. To examine serum BDNF, two groups of chronically medicated DSM-IV SZ patients (n=44), on treatment with clozapine (n=31) and typical antipsychotics (n=13) had 5ml blood samples collected by venipuncture. Serum BDNF levels were significantly correlated with CLZ daily dose (r=0.394, p=0.028), but not with typical antipsychotic daily dose (r=0.208, p=0.496). This study suggests that serum BDNF levels are correlated with CLZ daily dose, and this may lead to the cognitive enhancement as seen in patients with SZ under CLZ. Despite the strong evidence that chronic administration of CLZ is effective for patients with SZ, it is still unknown whether atypical antipsychotic drugs regulate BDNF expression. Serum BDNF levels concentration in SZ merits further investigations with regard to the role of neurotrophins in the cognitive response to treatment with CLZ and other atypical antipsychotics.

A falácia da adequação da cobertura dos Centros de Atenção Psicossocial no estado do Rio Grande do Sul / The fallacy of adequate coverage offered by Psychosocial Care Centers in the state of Rio Grande do Sul

Introdução: A análise dos resultados da expansão da rede de atenção à saúde mental para a população brasileira tem utilizado como medida de desfecho o indicador de cobertura dos Centros de Atenção Psicossocial (CAPS), que considera adequada a existência de um CAPS para cada 100 mil habitantes. O Rio Grande do Sul encontra-se classificado em terceiro lugar no ranking nacional, com índice de 0,7 CAPS/100.000 habitantes. Este estudo objetivou testar a variabilidade de cobertura de cada região para verificar se esse índice global representava as realidades regionais. Método: Foram utilizados dados do Cadastro Nacional de Estabelecimentos de Saúde (CNES) e dados populacionais do ano de 2009 disponibilizados pelo site do Departamento de Informática do Sistema Único de Saúde do Ministério da Saúde. Foram calculados os indicadores de cobertura para as 19 regionais de saúde, sendo gerado índice de cobertura resultante da razão entre o indicador observado e o esperado de acordo com a população de cada região geográfica analisada. Resultados: Analisada a variabilidade de cobertura de cada região, foi evidenciada a ocorrência de sete regiões com cobertura insuficiente, representando 49 por cento da população do estado com cobertura inadequada. Conclusão: O estudo demonstrou que o uso do índice global é falacioso, pois não representa as realidades regionais, sendo que cerca de metade das regiões com excesso de cobertura mascaram as regiões deficientes. Isso sugere que as análises de cobertura devem ser realizadas por áreas geográficas para identificar carências regionais e fornecer subsídios para a extensão da rede de forma igualitária para usuários de diferentes regiões do estado.

Introduction: Analysis of the results of the ongoing expansion of the Brazilian public mental health care network has used the indicator of coverage offered by Psychosocial Care Centers (Centros de Atenção Psicossocial, CAPS), which considers the rate of one CAPS per 100,000 inhabitants to be adequate, as its outcome measure. The state of Rio Grande do Sul ranks third in nationwide CAPS coverage standings, with 0.7 centers per 100,000 inhabitants. The present study sought to assess the variability of coverage in different regions in order to verify the representativeness of the overall coverage rate. Method: We used data collected from the National Database of Health Facilities (Cadastro Nacional de Estabelecimentos de Saúde, CNES) and 2009 population data made available at the website of the Ministry of Health Department of Information Technology. We calculated 19 coverage indicators, one for each health region, and computed a coverage rate based on the ratio between the actual indicator and the expected indicator according to the population of each region. Results: Analysis of the variability of coverage for each region showed that seven regions had inadequate coverage, with 49 percent of the state population receiving inadequate coverage. Conclusion: This study showed that the use of an overall rate for mental health care coverage can be considered a fallacy, as it fails to represent regional realities; roughly half of the regions with excessive coverage masked the regions with poor coverage. This finding suggests that analysis of care coverage must be broken down into geographic areas, in order to identify regional needs and provide support for equal expansion of the community mental health care network for users living in different geographic areas.

Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a double-blind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine.

BACKGROUND: Glutamate deregulation may be involved in the neuropathology of schizophrenia, mainly through N-methyl-d-aspartate (NMDA) receptor dysfunction. Memantine, a drug approved by the FDA for the treatment of moderate to severe Alzheimer's disease, acts as a weak nonselective NMDA receptor antagonist. The aim of this study was to examine the efficacy of memantine as an adjunctive treatment to clozapine in patients with refractory schizophrenia. METHOD: In this double-blind, placebo-controlled study, outpatients with refractory schizophrenia according to DSM-IV clinical criteria were randomly assigned, from March 2005 to February 2008, to receive either 20 mg/d memantine (n = 10) or placebo (n = 11), in addition to clozapine, for 12 weeks. The primary outcome measure was the total score on the 18-item Brief Psychiatry Rating Scale (BPRS) and BPRS subscales of positive and negative symptoms. Secondary outcomes were global severity of disease as measured by the Clinical Global Impressions scale (CGI), cognition as assessed by the Mini-Mental State Examination (MMSE), and extrapyramidal symptoms as assessed by the Simpson-Angus Scale (SAS). RESULTS: Twenty-one participants completed the study and were used in the analysis. Significant improvement (P < .01) on the total BPRS score, its subscales of positive (effect size [ES] = -1.38) and negative (ES = -3.33) symptoms, the CGI score (ES = 1.56), and the MMSE score was observed with memantine as compared with placebo. No significant changes in extrapyramidal symptoms were observed. CONCLUSIONS: Memantine add-on to clozapine therapy was associated with improvement in negative and positive symptoms in refractory schizophrenia patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00757978.

[Electroconvulsive therapy in major depression: current aspects]. / Eletroconvulsoterapia na depressão maior: aspectos atuais.

OBJECTIVE: The efficacy of electroconvulsive therapy in treating depressive symptoms has been established by means of innumerable studies developed along the last decades. Electroconvulsive therapy is the most effective biological treatment for depression currently available. The objective of this study was to demonstrate the role of electroconvulsive therapy in the treatment of depression and highlight present aspects related to its practice. METHOD: We reviewed in the literature studies on efficacy, symptom remission, predictive response factors as well as current aspects regarding quality of life, the patients' perception, mechanism of action, technique and cognitive impairment. RESULTS: The main results found in the this revision were: 1) electroconvulsive therapy is more effective than any antidepressant medication; 2) the remission of depression with electroconvulsive therapy varies, in general, from 50 to 80%; 3) The effect of electroconvulsive therapy in brain-derived neurotrophic factor levels is still controversial; 4) electroconvulsive therapy has a positive effect in the improvement of quality of life; 5) patients submitted to electroconvulsive therapy have, in general, a positive perception about the treatment. CONCLUSION: Electroconvulsive therapy remains a highly efficacious treatment in treatment-resistant depression. With the improvement of its technique, electroconvulsive therapy has become an even safer and more useful procedure both for the acute phase and for the prevention of new depressive episodes.

Serum brain-derived neurotrophic factor (BDNF) is not associated with response to electroconvulsive therapy (ECT): a pilot study in drug resistant depressed patients.

Refractory depression is a highly debilitating mental condition that originates major social and economic burden. About 50% of the patients experience a chronic course of illness and up to 20% show an insufficient response to drug treatments. Electroconvulsive therapy (ECT) is the most effective treatment method in refractory depression, although its mechanism of action is still unknown. Brain-derived neurotrophic factor (BDNF) is decreased in depressive episodes, and increases with antidepressant treatment, being suggested as a biomarker of response to ECT. We report the findings of a study on the effects of ECT on BDNF and clinical outcomes in a group of drug resistant depressive patients before and after ECT. The patients post-ECTs have shown an important improvement of depressive symptomatology on the HDRS (p=0.001), of psychotic features on the BPRS (p=0.001) and of the severity of illness on the CGI (p=0.001). There were no changes in the serum BDNF before and after the ECT treatment (p=0.89). These results do not support the hypothesis that the clinical improvement following ECT is due to changes in the BDNF.