Increased mortality in schizophrenia due to cardiovascular disease - a non-systematic review of epidemiology, possible causes and interventions

Background: Schizophrenia is among the major causes of disability worldwide and the mortality from cardiovascular disease (CVD) is significantly elevated. There is a growing concern that this health challenge is not fully understood and efficiently addressed. Methods: Non-systematic review using searches in PubMed on relevant topics as well as selection of references based on the authors’ experience from clinical work and research in the field. Results: In most countries, the standardized mortality rate in schizophrenia is about 2.5, leading to a reduction in life expectancy between 15 and 20 years. A major contributor of the increased mortality is due to CVD, with CVD mortality ranging from 40 to 50% in most studies. Important causal factors are related to lifestyle, including poor diet, lack of physical activity, smoking, and substance abuse. Recent findings suggest that there are overlapping pathophysiology and genetics between schizophrenia and CVD-risk factors, further increasing the liability to CVD in schizophrenia. Many pharmacological agents used for treating psychotic disorders have side effects augmenting CVD risk. Although several CVD-risk factors can be effectively prevented and treated, the provision of somatic health services to people with schizophrenia seems inadequate. Further, there is a sparseness of studies investigating the effects of lifestyle interventions in schizophrenia, and there is little knowledge about effective programs targeting physical health in this population. Discussion: The risk for CVD and CVD-related deaths in people with schizophrenia is increased, but the underlying mechanisms are not fully known. Coordinated interventions in different health care settings could probably reduce the risk. There is an urgent need to develop and implement effective programs to increase life expectancy in schizophrenia, and we argue that mental health workers should be more involved in this important task

Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An Integrative Review Translating Descriptives Into Diagnostics

Schizophrenia is considered a syndrome comprised by several disease phenotypes, covering a range of underlying pathologies. One of these disease mechanisms seems to involve immune dysregulation and neuroinflammation. While the current dopamine receptor-blocking antipsychotic drugs decrease psychotic symptoms and prevent relapse in the majority of patients with schizophrenia, there is a huge need to explore new treatment options that target other pathophysiological pathways. Such studies should aim at identifying robust biomarkers in order to diagnose and monitor the immune biophenotype in schizophrenia and develop better selection procedures for clinical trials with anti-inflammatory and immune-modulating drugs. In this focused review, we describe available methods to assess inflammatory status and immune disturbances in vivo. We also outline findings of immune disturbances and signs of inflammation at cellular, protein, and brain imaging levels in patients with schizophrenia. Furthermore, we summarize the results from studies with anti-inflammatory or other immune-modulating drugs, highlighting how such studies have dealt with participant selection. Finally, we propose a strategy to construct an immune signature that may be helpful in selecting and monitoring participants in studies with immune modulating drugs and also applicable in regular clinical work

Interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor 1 are associated with general severity and psychotic symptoms in schizophrenia and bipolar disorder

AbstractBackgroundPrevious studies suggest elevated inflammation in schizophrenia and bipolar disorder, with increased activity of the Interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor (TNF)-alpha, von Willebrand factor (vWf) and osteoprotegerin (OPG). It is unclear how immune activation is involved in the psychopathology. We investigated if elevated inflammation was associated with disease severity (trait) or current symptom level (state), comparing psychotic with general characteristics.MethodsPlasma levels of sTNF receptor 1 (sTNF-R1), IL-1 receptor antagonist (IL-1Ra), IL-6, vWf and OPG were measured with ELISA techniques in 322 patients with schizophrenia spectrum and bipolar disorder. Current symptom level (state) was measured with Global Assessment of Functioning (GAF) and Positive and Negative Syndrome Scale (PANSS). Disease severity (trait) was measured with premorbid adjustment scale (PAS), age at onset, number of psychotic episodes and number and length of hospitalizations.ResultsAfter controlling for confounders, IL-1Ra and TNF-R1 were independently associated with GAF, and significantly correlated with PANSS negative and positive, respectively. In addition, Il-1Ra was associated with PAS, and sTNF-R1 with number of hospitalizations and psychotic episodes. VWf was significantly correlated with psychotic episodes, OPG with hospitalizations and IL-6 with history of psychosis. Linear regression analysis showed that GAF remained associated with sTNF-R1 and IL-1Ra with PANSS, after controlling for the other clinical measures.ConclusionsThis supports that inflammatory markers, particularly IL-1Ra and sTNF-R1 are associated with both general disease severity and psychotic features. This supports a role of immune activation in the core pathological mechanisms of severe mental disorders

Association between leptin levels and severity of suicidal behaviour in schizophrenia spectrum disorders

Objective: Associations between suicidality and lipid dysregulation are documented in mental illness, but the potential role of leptin remains unclear. We examined the association between leptin and suicidal behaviour in schizophrenia, together with the influence of other clinical and biological indices. Method: We recruited a sample of 270 participants with schizophrenia spectrum diagnoses. Blood samples were analysed for leptin, while symptom severity was assessed by Positive and Negative Syndrome Scale (PANSS ) and Inventory of Depressive Symptomatology (IDS ‐C). Patients' history of suicidal behaviour was categorized into three subgroups based on IDS ‐C suicide subscale: No suicidal behaviour, mild/moderate suicidal behaviour and severe suicidal behaviour with/without attempts. Results: Mild/moderate suicidal behaviour was present in 17.4% and severe suicidal behaviour in 34.8%. Both groups were significantly associated with female gender (OR = 6.0, P = 0.004; OR = 5.9, P = 0.001), lower leptin levels (OR = 0.4, P = 0.008; OR = 0.5, P = 0.008) and more severe depression (OR = 1.2, P < 0.001; OR = 1.1, P < 0.001) respectively. Smoking (OR = 2.6, P = 0.004), younger age of onset (OR = 0.9, P = 0.003) and less use of leptin‐increasing medications (OR = 0.5, P = 0.031) were associated with severe/attempts group, while higher C‐reactive protein CRP (OR = 1.3, P = 0.008) was associated with mild/moderate group. Conclusion: Lower leptin levels were associated with higher severity of suicidal behaviour in schizophrenia.publishedVersio

Polygenic risk for schizophrenia and bipolar disorder in relation to cardiovascular biomarkers

Individuals with schizophrenia and bipolar disorder are at an increased risk of cardiovascular disease (CVD), and a range of biomarkers related to CVD risk have been found to be abnormal in these patients. Common genetic factors are a putative underlying mechanism, alongside lifestyle factors and antipsychotic medication. However, the extent to which the altered CVD biomarkers are related to genetic factors involved in schizophrenia and bipolar disorder is unknown. In a sample including 699 patients with schizophrenia, 391 with bipolar disorder, and 822 healthy controls, we evaluated 8 CVD risk biomarkers, including BMI, and fasting plasma levels of CVD biomarkers from a subsample. Polygenic risk scores (PGRS) were obtained from genome-wide associations studies (GWAS) of schizophrenia and bipolar disorder from the Psychiatric Genomics Consortium. The CVD biomarkers were used as outcome variables in linear regression models including schizophrenia and bipolar disorder PGRS as predictors, age, sex, diagnostic category, batch and 10 principal components as covariates, controlling for multiple testing by Bonferroni correction for the number of independent tests. Bipolar disorder PGRS was significantly (p = 0.03) negatively associated with BMI after multiple testing correction, and schizophrenia PGRS was nominally negatively associated with BMI. There were no other significant associations between bipolar or schizophrenia PGRS, and other investigated CVD biomarkers. Despite a range of abnormal CVD risk biomarkers in psychotic disorders, we only found a significant negative association between bipolar disorder PGRS and BMI. This has previously been shown for schizophrenia PGRS and BMI, and warrants further exploration

Identification of shared genetic variants between schizophrenia and lung cancer.

Epidemiology studies suggest associations between schizophrenia and cancer. However, the underlying genetic mechanisms are not well understood, and difficult to identify from epidemiological data. We investigated if there is a shared genetic architecture between schizophrenia and cancer, with the aim to identify specific overlapping genetic loci. First, we performed genome-wide enrichment analysis and second, we analyzed specific loci jointly associated with schizophrenia and cancer by the conjunction false discovery rate. We analyzed the largest genome-wide association studies of schizophrenia and lung, breast, prostate, ovary, and colon-rectum cancer including more than 220,000 subjects, and included genetic association with smoking behavior. Polygenic enrichment of associations with lung cancer was observed in schizophrenia, and weak enrichment for the remaining cancer sites. After excluding the major histocompatibility complex region, we identified three independent loci jointly associated with schizophrenia and lung cancer. The strongest association included nicotinic acetylcholine receptors and is an established pleiotropic locus shared between lung cancer and smoking. The two other loci were independent of genetic association with smoking. Functional analysis identified downstream pleiotropic effects on epigenetics and gene-expression in lung and brain tissue. These findings suggest that genetic factors may explain partly the observed epidemiological association of lung cancer and schizophrenia

Mudanças climáticas e o fitoplâncton marinho : uma revisão

Orientador: Prof. Dr. Carlos Roberto SanquettaMonografia (especialização) - Universidade Federal do Paraná, Setor de Ciências Agrárias, Curso de Especialização em Projetos Sustentáveis, Mudanças Climáticas e Mercado de CarbonoInclui referênciasResumo: Uma revisão bibliográfica de artigos nacionais e internacionais foi realizada objetivando avaliar os principais impactos e respostas provocados pelas mudanças climáticas sobre o fitoplâncton marinho. Compreender como o ambiente marinho é afetado pelas alterações ambientais é fundamental, pois os oceanos são responsáveis pela absorção de mais de 80% do calor adicionado ao clima. A busca dos artigos foi realizada nas bases de dados Portal de Periódicos Capes, SciELO e Sciencedirect, entre maio e agosto de 2012 para o período compreendido entre 1980 e 2012. O fitoplâncton, além de bioindicador ambiental, é a base da cadeia alimentar e quaisquer alterações em sua composição ou abundância podem provocar graves consequências para os demais níveis tróficos, inclusive o homem. Dentre os impactos no ambiente marinho, observa-se o aquecimento da superfície da água do mar, provocando a estratificação da coluna de água e impedindo a ciclagem dos nutrientes; o aumento da temperatura atmosférica, favorecendo maiores índices de precipitação, o derretimento das geleiras e o aumento do nível do mar; a acidificação e a desoxigenação da água do mar. As respostas do fitoplâncton às mudanças climáticas compreendem alterações na taxa de crescimento, mudanças na composição específica e distribuição biogeográfica das espécies, maior risco de ocorrência de florações nocivas e de bioinvasões, dentre outras. Apesar de crescente o número de publicações sobre mudanças climáticas nos últimos anos, muitas são as incertezas sobre a real extensão desses impactos e quais outras ameaças podem decorrer das mudanças climáticas sobre o fitoplâncton marinho

Relationship of suicide rates with climate and economic variables in Europe during 2000-2012

The derived models explained 62.4 % of the variability of male suicidal rates. Economic variables alone explained 26.9 % and climate variables 37.6 %. For females, the respective figures were 41.7, 11.5 and 28.1 %. Male suicides correlated with high unemployment rate in the frame of high growth rate and high inflation and low GDP per capita, while female suicides correlated negatively with inflation. Both male and female suicides correlated with low temperature. Data from 29 European countries covering the years 2000-2012 and concerning male and female standardized suicidal rates (according to WHO), economic variables (according World Bank) and climate variables were gathered. The statistical analysis included cluster and principal component analysis and categorical regression. It is well known that suicidal rates vary considerably among European countries and the reasons for this are unknown, although several theories have been proposed. The effect of economic variables has been extensively studied but not that of climate. The current study reports that the climatic effect (cold climate) is stronger than the economic one, but both are present. It seems that in Europe suicidality follows the climate/temperature cline which interestingly is not from south to north but from south to north-east. This raises concerns that climate change could lead to an increase in suicide rates. The current study is essentially the first successful attempt to explain the differences across countries in Europe; however, it is an observational analysis based on aggregate data and thus there is a lack of control for confounders. RESULTS METHODS BACKGROUND DISCUSSIO

Endothelial and inflammation markers in schizophrenia and bipolar disorder

Schizophrenia and bipolar disorder are complex disorders, with an etiology that involves multiple genes and a variety of environmental risk factors. Despite a high heritability rate, very little is known about the underlying biological mechanisms, but several molecular pathways are probably involved. The diagnostic criteria are descriptive based on partly overlapping symptom profiles and current treatment options only offer symptom relief and are often accompanied with adverse effects. In the recent years, promising results from genetic, molecular as well as epidemiological studies have implicated alterations involving inflammatory mechanisms to be involved in the pathophysiolology of both disorders. In this project, we investigated the role of inflammation and endothelial markers and their putative involvement in schizophrenia and bipolar disorder pathology. By using a translational approach we explored: i) the expression of NOTCH4 (a gene within the major histocompatibility complex) previously found to be associated with schizophrenia in genome wide association studies in schizophrenia and bipolar disorder and the association with potential expression quantitative trait loci (eQTL) within the NOTCH4 gene ii) the role of inflammation in relation to cardiovascular disease (CVD) risk factors associated with second generation antipsychotic treatment iii) whether inflammation and altered endothelial activity are associated with brain morphology in schizophrenia and bipolar disorder. The expression of NOTCH4 was significantly increased in patients with bipolar disorder and NOTCH4 expression was associated with three loci within the NOTCH4 gene. Overweight and increased glucose levels were associated with elevated levels of CRP in patients treated with second generation antipsychotics. Von Willebrand factor levels were highly associated with basal ganglia volume across all groups, in particular globus pallidus volume. This association remained significant after adjustment for diagnoses and antipsychotic treatment. Taken together, the findings support that i) mechanisms related to endothelial activity and inflammation and more specifically the NOTCH4 pathway are involved in bipolar disorder pathophysiology ii) cardiovascular disease risk factors and potentially atherosclerosis induced by second generation antipsychotics may in part be mediated through inflammatory mechanisms iii) and finally that von Willebrand factor, an endothelial marker also known to be involved in inflammation may have a role in the pathophysiological process underlying the enlarged basal ganglia volume seen in schizophrenia. In summary, the results indicate that endothelial-related inflammation is involved in both disorders but through different molecular mechanisms