Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness.

BACKGROUND AND HYPOTHESIS: Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI. STUDY DESIGN: We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation. STUDY RESULTS: Our main findings were: (1) higher levels of sMAdCAM-1 (P = .002), I-FABP (P = 7.6E-11), CCL25 (P = 9.6E-05) and LBP (P = 2.6E-04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E-04) were observed in SCZ and I-FABP (P = 2.5E-10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4. CONCLUSIONS: Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation.

Systemic Cell Adhesion Molecules in Severe Mental Illness: Potential Role of Intercellular CAM-1 in Linking Peripheral and Neuroinflammation.

BACKGROUND: Cell adhesion molecules (CAMs) orchestrate leukocyte trafficking and could link peripheral and neuroinflammation in patients with severe mental illness (SMI), by promoting inflammatory and immune-mediated responses and mediating signals across blood-brain barrier. We hypothesized that CAMs would be dysregulated in SMI and evaluated plasma levels of different vascular and neural CAMs. Dysregulated CAMs in plasma were further evaluated in vivo in leukocytes and brain tissue and in vitro in induced pluripotent stem cells. METHODS: We compared plasma soluble levels of different vascular (VCAM-1, ICAM-1, P-SEL) and neural (JAM-A, NCAD) CAMs in circulating leukocytes in a large SMI sample of schizophrenia (SCZ) spectrum disorder (n = 895) and affective disorder (n = 737) and healthy control participants (n = 1070) controlling for age, sex, body mass index, C-reactive protein, and freezer storage time. We also evaluated messenger RNA expression of ICAM1 and related genes encoding ICAM-1 receptors in leukocytes using microarray (n = 842) and in available RNA sequencing data from the CommonMind Consortium (CMC) in postmortem samples from the dorsolateral prefrontal cortex (n = 474). The regulation of soluble ICAM-1 in induced pluripotent stem cell-derived neurons and astrocytes was assessed in patients with SCZ and healthy control participants (n = 8 of each). RESULTS: Our major findings were 1) increased soluble ICAM-1 in patients with SMI compared with healthy control participants; 2) increased ITGB2 messenger RNA, encoding the beta chain of the ICAM-1 receptor, in circulating leukocytes from patients with SMI and increased prefrontal cortex messenger RNA expression of ICAM1 in SCZ; and 3) enhanced soluble ICAM-1 release in induced pluripotent stem cell-derived neurons from patients with SCZ. CONCLUSIONS: Our results support a systemic and cerebral dysregulation of soluble ICAM-1 expression in SMI and especially in patients with SCZ.

Quality of clinical management of cardiometabolic risk factors in patients with severe mental illness in a specialist mental health care setting.

PURPOSE: Cardiometabolic disease in patients with severe mental illness is a major cause of shortened life expectancy. There is sparse evidence of real-world clinical risk prevention practice. We investigated levels of assessments of cardiometabolic risk factors and risk management interventions in patients with severe mental illness in the Norwegian mental health service according to an acknowledged international standard. METHODS: We collected data from 264 patients residing in six country-wide health trusts for: (a) assessments of cardiometabolic risk and (b) assessments of levels of risk reducing interventions. Logistic regressions were employed to investigate associations between risk and interventions. RESULTS: Complete assessments of all cardiometabolic risk variables were performed in 50% of the participants and 88% thereof had risk levels requiring intervention according to the standard. Smoking cessation advice was provided to 45% of daily smokers and 4% were referred to an intervention program. Obesity was identified in 62% and was associated with lifestyle interventions. Reassessment of psychotropic medication was done in 28% of the obese patients. Women with obesity were less likely to receive dietary advice, and use of clozapine or olanzapine reduced the chances for patients with obesity of getting weight reducing interventions. CONCLUSIONS: Nearly nine out of the ten participants were identified as being at cardiometabolic high risk and only half of the participants were adequately screened. Women with obesity and patients using antipsychotics with higher levels of cardiometabolic side effects had fewer adequate interventions. The findings underscore the need for standardized recommendations for identification and provision of cardiometabolic risk reducing interventions in all patients with severe mental illness.

Objectively Assessed Daily Steps-Not Light Intensity Physical Activity, Moderate-to-Vigorous Physical Activity and Sedentary Time-Is Associated With Cardiorespiratory Fitness in Patients With Schizophrenia.

People with schizophrenia often have an unhealthy sedentary lifestyle with low level of physical activity and poor cardiorespiratory fitness-an important predictor of cardiovascular disease. We investigated the relations between cardiorespiratory fitness and both sedentary time and different aspects of physical activity, such as daily steps, light intensity physical activity, and moderate-to-vigorous physical activity. Using accelerometer as an objective measure of sedentary time and physical activity we estimated their relations to cardiorespiratory fitness in 62 patients with schizophrenia with roughly equal gender distribution, mean age of 36 and 15 years illness duration. We found a significant association between daily steps and cardiorespiratory fitness when accounting for gender, age, sedentary time, light intensity physical activity, and respiratory exchange ratio (maximal effort). Moderate-to-vigorous physical activity was not significantly associated with cardiorespiratory fitness. In conclusion, the amount of steps throughout the day contributes to cardiorespiratory fitness in people with schizophrenia, independently of light intensity physical activity and sedentary time. We did not find a significant relationship between moderate-to-vigorous physical activity and cardiorespiratory fitness. This may have implications for the choice of strategies when helping patients with schizophrenia improve their cardiorespiratory fitness.

Effects of high-intensity aerobic exercise on psychotic symptoms and neurocognition in outpatients with schizophrenia: study protocol for a randomized controlled trial.

BACKGROUND: The focus in recent years on physical inactivity and metabolic disturbances in individuals with schizophrenia raises the question of potential effects of physical activity. Physical activity has shown beneficial effects on cognition in healthy older individuals as well as on symptom severity in depression. However, opinions diverge regarding whether aerobic high-intensity interval training reduces cognition and key symptoms in schizophrenia. The main objective for the trial is to investigate the potential effects of aerobic high-intensity interval training on neurocognitive function and mental symptoms in outpatients with schizophrenia. METHODS/DESIGN: The trial is designed as a randomized controlled, observer-blinded clinical trial. Patients are randomized to 1 of 2 treatment arms with 12-week duration: aerobic high-intensity interval training or computer gaming skills training. All participants also receive treatment as usual. Primary outcome measure is neurocognitive function. Secondary outcome measures will be positive and negative symptoms, wellbeing, tobacco-smoking patterns and physiological/metabolic parameters. Patient recruitment takes place in catchment area-based outpatient clinics. TRIAL REGISTRATION: ClinicalTrials.gov NCT02205684 . Registered 29 July 2014.

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.

Verbal learning contributes to cognitive insight in schizophrenia independently of affective and psychotic symptoms.

OBJECTIVE: Patients with schizophrenia exhibit distorted beliefs and experiences, and their own evaluation of this is labeled cognitive insight. We examined the relationship between cognitive insight and neurocognition, as well as the contribution of neurocognition in explaining cognitive insight. METHOD: Clinically characterized patients with schizophrenia (n=102) were assessed with a measure of cognitive insight, Beck Cognitive Insight Scale (BCIS) and a neuropsychological test battery. The contribution of neurocognition to the explained variance in BCIS components self-reflectiveness (i.e. objectivity and reflectiveness) and self-certainty (i.e. overconfidence in own beliefs) was examined controlling for current affective and psychotic symptoms. RESULTS: A significant negative correlation was found between self-certainty and verbal learning, whereas no associations were found between self-reflectiveness and any of the neuropsychological tests. Verbal learning was added significantly to the explained variance in self-certainty after controlling for potential confounders. CONCLUSION: High self-certainty was associated with poor verbal learning. This suggests that overconfidence in own beliefs is associated with cognitive dysfunction in schizophrenia.

Neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends on history of psychosis rather than diagnostic group.

OBJECTIVES: Neurocognitive dysfunction is milder in bipolar disorders than in schizophrenia spectrum disorders, supporting a dimensional approach to severe mental disorders. The aim of this study was to investigate the role of lifetime history of psychosis for neurocognitive functioning across these disorders. We asked whether neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends more on history of psychosis than diagnostic category or subtype. METHODS: A sample of individuals with schizophrenia (n=102), schizoaffective disorder (n=27), and bipolar disorder (I or II) with history of psychosis (n=75) and without history of psychosis (n=61) and healthy controls (n=280), from a large ongoing study on severe mental disorder, were included. Neurocognitive function was measured with a comprehensive neuropsychological test battery. RESULTS: Compared with controls, all 3 groups with a history of psychosis performed poorer across neurocognitive measures, while the bipolar group without a history of psychosis was only impaired on a measure of processing speed. The groups with a history of psychosis did not differ from each other but performed poorer than the group without a history of psychosis on a number of neurocognitive measures. These neurocognitive group differences were of a magnitude expected to have clinical significance. In the bipolar sample, history of psychosis explained more of the neurocognitive variance than bipolar diagnostic subtype. CONCLUSIONS: Our findings suggest that neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders is determined more by history of psychosis than by Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnostic category or subtype, supporting a more dimensional approach in future diagnostic systems.

Medication adherence in outpatients with severe mental disorders: relation between self-reports and serum level.

Medication nonadherence in severe mental disorders is an important clinical issue, but estimates vary between studies. There is a need for valid self-reports for both research and clinical practice. This study examined the level of adherence to prescribed medication in outpatients with severe mental disorders and evaluated the validity of a simple self-report rating of adherence. From an ongoing study of severe mental disorders, 280 patients with schizophrenia and bipolar disorder who were prescribed psychopharmacological agents were included. We assessed adherence with serum concentration of medicines and tested the sensitivity and specificity of a simple self-report questionnaire for patients and compared with a report from health personnel. Adherence rate defined by serum concentrations within reference level was 61.6% in the total sample, 58.4% for schizophrenia and 66.3% for bipolar disorder. The patients' self-report scores overestimated adherence, but correlated significantly to health personnel scores (r = 0.50) and to serum concentration of medication (r = 0.52); the positive predictive value was 70%, and the negative predictive value was 91%. In this naturalistic sample, outpatients with severe mental disorders showed relatively good adherence to prescribed medication, and self-report questionnaires seem to be a valid method for measuring adherence.

Delusions are associated with poor cognitive insight in schizophrenia.

The purpose of the study was to investigate the relationship between the symptoms delusions and hallucinations measured by the Positive and Negative Syndrome Scale and cognitive insight as assessed with the Beck Cognitive Insight Scale (BCIS) in patients with schizophrenia. The BCIS is based on 2 subscales, self-reflectiveness and self-certainty, measuring objectivity, reflectiveness and openness to feedback, and mental flexibility. Overall cognitive insight was defined as the difference between self-reflectiveness and self-certainty. This cross-sectional study of 143 patients showed that the occurrence of delusions is associated with low self-reflectiveness and high self-certainty, reflecting low cognitive insight. Hallucinations in the absence of delusions were associated with high self-reflectiveness and low self-certainty, possibly reflecting more open-mindedness and higher cognitive insight. The present findings suggest that delusions are associated with low cognitive insight, whereas solitary hallucinations may be associated with high cognitive insight.

Using the Wisconsin Card Sorting Test to assess learning potential in normal IQ schizophrenia: does it have potential?

BACKGROUND: Learning potential, a dynamic multi-administration approach to assessment, is claimed to predict functional outcome in schizophrenia better than traditional single-administration neuropsychological tests. AIMS: This study investigates the relation between learning potential and clinical and demographic variables, social functioning and neuropsychological abilities in a sample of 30 participants with schizophrenia with a mean IQ score within the normal range (mean Wechsler Abbreviated Scale of Intelligence (WASI) IQ=106). METHODS: Two Wisconsin Card Sorting Test (WCST) based methods for assessing learning potential are compared. RESULTS: The dimensional approach (calculation of gain scores following training) identified one aspect of executive functioning (set shifting) to be related to learning potential. Associations with other neuropsychological tests and social functioning were however limited. The categorical approach (separating high-achievers from learners and non-learners) was not sensitive within this normal IQ sample. CONCLUSIONS: Although there seems to be a relation between learning potential and some aspects of executive functioning, the two existing WCST methods should be used with caution when assessing learning potential in individuals with schizophrenia who have IQ scores within the normal range.

Measurement of insight in patients with bipolar disorder: are self-rated scales developed for patients with schizophrenia applicable?

Our aim was to study if the Birchwood Insight Scale has acceptable psychometric properties when used for patients with bipolar disorders. Patients with schizophrenia (n = 101), bipolar I (n = 57), and bipolar II disorder (n = 37) completed the self-report scale. The items form 3 subscales, awareness of illness, relabeling of symptoms, and need for treatment. The total scale had good internal consistency for patients with schizophrenia, fairly good for bipolar I, but poor for bipolar II disorder. On subscale level the internal consistency was mostly marginal to poor for all patient groups. The level of insight was similar in schizophrenia and bipolar I disorder. The psychometric properties for the insight scale were poorer in bipolar disorders than in schizophrenia, and the scale did not work for patients with bipolar II disorder. This suggests a cautious use of the scale across different diagnostic groups.

Can learning potential in schizophrenia be assessed with the standard CVLT-II? An exploratory study.

This study examined the potential of using the regular administration of a common neuropsychological test, the CVLT-II, to assess learning potential in schizophrenia. Based on List A trial 1 performance and the learning slope, a schizophrenia sample was divided into three learning potential groups (non-learners, learners and high-achievers) that differed in the use of learning strategies. High-achievers utilized more semantic clustering than learners and non-learners, and non-learners were less consistent in words recalled than the other two groups. This standard administration approach is a promising, time-saving alternative to the modified tests of learning potential used so far.

Dyslipidemia independent of body mass in antipsychotic-treated patients under real-life conditions.

OBJECTIVE: Antipsychotic (AP) treatment, in particular with some second-generation drugs, is associated with weight gain and other metabolic side effects. However, the relationship between drug-induced weight gain and dyslipidemia is not well understood. We investigated how cardiometabolic risk factors were related to body mass during treatment with different APs under real-life conditions. METHODS: This cross-sectional naturalistic study included 242 subjects with severe mental disorders who were on monotherapy with olanzapine (OLZ) or clozapine (CLZ) (n = 80), monotherapy with other APs (n = 80), or unmedicated (n = 82). Groups were adjusted for age and compared for prevalence of the metabolic syndrome and its components. Groups were further adjusted for body mass and compared for mean values of blood pressure, lipids, and fasting glucose. RESULTS: There was no significant intergroup difference in the prevalence of metabolic syndrome, obesity, hypertension, or hyperglycemia. Despite similar body mass index, OLZ/CLZ-treated subjects had significantly higher prevalence of dyslipidemia (high triglyceride and low HDL cholesterol levels) than unmedicated subjects. They also had higher mean values of triglycerides (P = 0.003) and lower mean values of HDL cholesterol (P < 0.001). Patients treated with other APs had intermediate values. CONCLUSIONS: Intergroup differences in body mass index were minimal in this naturalistic setting, probably because of awareness of this treatment hazard among clinicians. However, independently of body mass, dyslipidemia was significantly associated with AP treatment, in particular with OLZ and CLZ. These findings indicate a primary effect of APs on lipid regulation, important in understanding their mechanism of action, and with clinical implications.

Neurocognitive profiles in bipolar I and bipolar II disorder: differences in pattern and magnitude of dysfunction.

OBJECTIVES: Studies on neurocognitive functioning in bipolar disorder, reporting deficits in memory, attention, and executive functioning, have primarily focused on bipolar I disorder. The aim of this study was to examine whether patients with bipolar I and bipolar II disorder have different neurocognitive profiles. METHODS: Forty-two patients with bipolar I disorder, 31 patients with bipolar II and 124 healthy controls, from a large ongoing study on psychotic disorders, were included. Neurocognitive function was measured with a comprehensive neuropsychological test battery. RESULTS: The bipolar I group performed significantly poorer than the healthy control group and the bipolar II group on all measures of memory. Compared with the control group, the bipolar I group also had significantly reduced performance on most measures of attention and executive functioning, while the bipolar II group only had a significantly reduced performance on a subset of these measures. On average, 24% of the bipolar I group had clinically significant cognitive impairment (< or =1.5 SD below the control group mean) across measures, compared with 13% of the bipolar II group. CONCLUSIONS: Patients with bipolar I and bipolar II disorder in this study have different neurocognitive profiles. Bipolar I patients have more widespread cognitive dysfunction both in pattern and magnitude, and a higher proportion has clinically significant cognitive impairments compared with patients with bipolar II. This may suggest neurobiological differences between the two bipolar subgroups.

Measuring cognitive insight in schizophrenia and bipolar disorder: a comparative study.

BACKGROUND: Beck Cognitive Insight Scale (BCIS) has been designed for assessment of self-reflection on patients' anomalous experiences and interpretations of own beliefs. The scale has been developed and validated for patients with schizophrenia. We wanted to study the utility of the scale for patients with bipolar disorder. The relationship between the BCIS as a measure of cognitive insight and established methods for assessment of insight of illness was explored in both diagnostic groups. METHODS: The BCIS self-report inventory was administered to patients with schizophrenia (n = 143), bipolar disorder (n = 92) and controls (n = 64). The 15 items of the inventory form two subscales, self-reflectiveness and self-certainty. RESULTS: The internal consistency of the subscales was good for the patient groups and the controls. The mean subscale scores were not significantly different for the three groups. Four items in subscale self-reflectiveness referring to psychotic experiences gave, however, different results in the control subjects. Self-certainty and scores on insight item PANSS correlated significantly in the schizophrenia, but not in the bipolar group. CONCLUSION: BCIS with its two subscales seems applicable for patients with bipolar disorder as well as for patients with schizophrenia. The self-report inventory can also be applied to control subjects if the items referring to psychotic experiences are omitted. In schizophrenia high scores on self-certainty is possibly associated with poor insight of illness. For the bipolar group the subscales are largely independent of traditional insight measures.

The level of cardiovascular risk factors in bipolar disorder equals that of schizophrenia: a comparative study.

OBJECTIVE: In schizophrenia, increased rates of somatic mortality have been shown to correspond with a high prevalence of cardiovascular risk factors, including smoking and the metabolic syndrome. In bipolar disorder, the amount of cardiovascular risk is still largely unknown. This study compares the prevalence of smoking and metabolic disturbances in bipolar disorder and schizophrenia in a representative sample of patients under naturalistic conditions. It also compares the prevalence of risk factors in each diagnostic group with the general population. METHOD: Longitudinal data on clinical groups from October 2002 through December 2005 were from the Oslo TOP Study (DSM-IV bipolar disorder [N = 110] and schizophrenia [N = 163]). Reference data were from the 2000 to 2001 Oslo Health Study (18,770 individuals of the same area). Background variables, prevalence of smoking, and age-adjusted levels of metabolic risk factors were compared between diagnostic groups. Risk factors in both groups were then compared with the general population. RESULTS: Patients with bipolar disorder had higher levels of education, better social functioning, fewer psychiatric symptoms, and less use of medication than patients with schizophrenia. There was no significant difference between diagnostic groups in the prevalence of smoking, obesity, metabolic syndrome, or diabetes. The mean level of high density lipoprotein cholesterol was lower in schizophrenia (p < .001), and systolic blood pressure was higher in bipolar disorder (p < .05). Both diagnostic groups had a prevalence of cardiovascular risk factors about twice that of the general population. CONCLUSION: The prevalence of cardiovascular risk factors was alarmingly high for bipolar disorder and schizophrenia patients compared with the general population, and the prevalence was approximately the same in both diagnostic groups.

Sociodemographic characteristics and cardiovascular risk factors in patients with severe mental disorders compared with the general population.

OBJECTIVE: To study the prevalence and distribution of cardiovascular risk factors in a group of patients with severe mental disorders compared with the general population and investigate if differences in sociodemographic background variables between groups were associated with differences in risk profile. METHOD: We compared data from the ongoing Ulleval 600 Study (205 pharmacologically stable outpatients with DSM-IV psychotic disorders) with data from the 2000-2001 Oslo Health Study (18,770 individuals from the general population of the same area). Subjects were stratified according to age and gender and compared for ethnic background, level of education, marital status, and prevalence of risk factors. RESULTS: Patients had an overall prevalence of smoking, obesity, hypertension, dyslipidemia, and diabetes mellitus about twice that of the reference group. Patients aged 18 through 50 years had the highest level of risk factors when compared with the general population. There was no major difference in ethnic background or educational level between cohorts. CONCLUSION: The increased cardiovascular risk profile in patients is particularly pronounced in young individuals and could not be explained by sociodemographic variables alone.