Genome-wide association study identifies genetic loci associated with body mass index and high density lipoprotein-cholesterol levels during psychopharmacological treatment - a cross-sectional naturalistic study.

Metabolic and cardiovascular side effects are serious clinical problems related to psychopharmacological treatment, but the underlying mechanisms are mostly unknown. We performed a genome-wide association study of metabolic and cardiovascular risk factors during pharmacological therapy. Twelve indicators of metabolic side effects as well as cardiovascular risk factors were analyzed in a naturalistic sample of 594 patients of Norwegian ancestry. We analyzed interactions between gene variants and three categories of psychopharmacological agents based on their reported potential for side effects. For body mass index (BMI), two significantly associated loci were identified on 8q21.3. There were seven markers in one 30-kb region, and the strongest signal was rs7838490. In another locus 140kb away, six markers were significant, and rs6989402 obtained the strongest signal. Both of these loci are located upstream of the gene matrix metalloproteinase 16 (MMP16). For high density lipoprotein cholesterol (HDL-C), marker rs11615274 on 12q21 was significant. The results highlight three genomic regions potentially harboring susceptibility genes for drug-induced metabolic side effects, identifying MMP16 as a candidate gene. This deserves to be replicated in additional populations to provide more evidence for molecular genetic mechanisms of side effects during psychopharmacological treatment.

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.

Hormonal markers of metabolic dysregulation in patients with severe mental disorders after olanzapine treatment under real-life conditions.

OBJECTIVE: Dyslipidemia independent of body mass has previously been reported in humans after antipsychotic treatment. The present study investigated the levels of several metabolic regulatory hormones in psychiatric outpatients treated with different antipsychotics under real-life conditions. METHODS: The study included cross-sectional data from 234 subjects on stable monotherapy with any of the following: olanzapine (n = 72), any other antipsychotic (n = 80), or no medications (n = 82). Groups were well matched for sex, body mass index (BMI), ethnicity, and smoking. After adjustment for differences in age and illness duration, groups were compared for the insulin resistance index (homeostatic model assessment of insulin resistance) and fasting concentrations of glucose, lipids, insulin, sex hormone-binding globulin (SHBG), adiponectin, leptin, and cortisol. Correlations were examined between serum olanzapine and hormonal levels, and between leptin concentrations and BMI in both sexes. RESULTS: Significant intergroup differences in concentrations of insulin (P = 0.025), SHBG (P = 0.001), adiponectin (P = 0.017), and cortisol (P = 0.003) but no significant difference for homeostatic model assessment of insulin resistance (P = 0.051) were found, independent of body mass. Olanzapine-treated subjects had the highest insulin concentrations and the lowest SHBG, adiponectin, and cortisol concentrations. Olanzapine-treated female subjects had significantly higher leptin (P = 0.005) and lower SHBG (P = 0.023) concentrations than other subjects. In female subjects, serum olanzapine concentrations were correlated with hormonal levels, and a significant proportion of olanzapine-treated female subjects had abnormal correlations between serum leptin levels and BMI. CONCLUSIONS: Alterations in several interrelated metabolic hormonal markers were associated with olanzapine treatment, independent of body mass, particularly in female subjects.

Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor.

BACKGROUND: Alterations in the inflammatory system have been associated with schizophrenia and major depression, while bipolar disorder has been less studied. Most previous studies examined small samples, and the literature is inconsistent with regard to specific underlying immune mechanisms. In the present study, we examined markers representing different inflammatory pathways, and the aim was to investigate whether the levels of inflammatory parameters in a representative sample of bipolar disorder and schizophrenia are elevated compared to healthy controls, and to investigate whether the inflammatory profile is different between the groups. METHODS: Plasma levels of soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), high-sensitivity CRP (hs-CRP), soluble CD40L ligand (sCD40L), and von Willebrand factor (vWf) were measured with ELISA techniques in a catchment area based sample of consecutively referred patients with severe mental disorders [N = 311, comprising bipolar disorder (n = 125) and schizophrenia (n = 186)] and in healthy volunteers (n = 244). RESULTS: Plasma levels of sTNF-R1 and vWf were statistically significantly increased in both bipolar disorder and schizophrenia compared to controls (p < 0.00001), and were also increased in unmedicated patients, but there were no major differences between the two diagnostic groups. Controlling for age, gender, ethnicity, cardiovascular disorders, kidney and liver function, and other confounders did not affect the results. There were no differences in other inflammation factors between the groups. CONCLUSION: The present results indicate specific alterations of endothelium-related inflammation processes in both bipolar disorder and schizophrenia.

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.

Emotion perception and learning potential: mediators between neurocognition and social problem-solving in schizophrenia?

Social cognition and learning potential have been proposed as mediating variables between neurocognition and functional outcome in schizophrenia. The present study examined this relation in a schizophrenia group (N = 26) with normal IQ. Neurocognition was measured with a composite score from tests of verbal learning, psychomotor speed, and executive functioning. Functional outcome was defined as social problem-solving skills and assessed with a role-play test. Social cognition was indexed by tests of visual and auditory emotion perception; and learning potential by estimating a gain score using a triple administration of the WCST. Neurocognition was confirmed to be a strong predictor of social problem-solving, and emotion perception was related to both neurocognition and social problem-solving. When controlling for emotion perception, the association between neurocognition and social problem-solving was weakened, implying a mediating role of emotion perception. Learning potential was not significantly related to neurocognition or social problem-solving, and thus not found to mediate the studied relation. In conclusion, our study indicates that emotion perception is a mediator between neurocognition and functional outcome as assessed with a social problem-solving task and thus a key factor in understanding functional outcome of schizophrenia.

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.

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.

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.

Bipolar disorder patients have similar levels of education but lower socio-economic status than the general population.

BACKGROUND: There is conflicting evidence regarding the educational level and its importance for social and occupational functioning in bipolar disorder (BD). The aim of this study was to investigate how educational achievement relates to function in BD compared with the general population, and which clinical factors are associated with level of education. METHODS: Hospitalized patients with DSM-IV BD (N=257; 69.3% BD I; 25.7% BD II; 5.1 BD NOS; 51.4% females) were consecutively recruited from mental health clinics throughout Norway and compared with a geographically matched reference sample from the general population (N=56,540) on levels of education, marital status, income, and disability benefits. Further analyses of association were carried out using logistic regression analyses. RESULTS: A significantly higher proportion of subjects in the BD group than in the reference group was single, had low income, or was disabled. No between-group difference was found in educational level. In the reference group education was inversely correlated with the risk of being disabled, but no such relationship was found in the BD group. Rapid cycling and recurring depressive episodes were the only clinical characteristics associated with low educational level. LIMITATIONS: Acutely admitted patients might not be representative for milder forms of disease. CONCLUSIONS: Despite similar levels of education, BD patients had lower social and occupational function than the general population, and no association was found between education and disability for BD patients.

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.

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.

Increased expression of lipid biosynthesis genes in peripheral blood cells of olanzapine-treated patients.

Recent in-vitro studies show that antipsychotic drugs increase lipid biosynthesis through changes in gene expression. Based on these finding we compared the expression of two central lipid biosynthesis genes, fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD), in whole blood of olanzapine-treated and unmedicated patients. Patients with psychotic disorders were consecutively selected from an ongoing, naturalistic study, and divided into two groups according to the following criteria: (1) strict monotherapy with olanzapine (n=19) or (2) no current medication (n=19). The groups were matched on gender, race and body mass index. Blood lipid levels were examined, and gene expression in whole blood was assessed with quantitative real-time PCR. Expression of FASN (p=0.003) and SCD (p=0.002) was significantly up-regulated in olanzapine-treated compared to unmedicated patients. Transcriptional activation of lipid biosynthesis genes in peripheral blood cells of olanzapine-treated patients suggests a direct lipogenic action of antipsychotic drugs, which may be related to metabolic adverse effects.

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.

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.