Ingrid Dieset

Childhood trauma is associated with severe clinical characteristics of bipolar disorders.

OBJECTIVE Beyond genetic risk variants, the pathophysiology of bipolar disorders is likely to be partly determined by environmental susceptibility factors. Our study is one of the first to investigate, in a large sample of well-characterized bipolar patients, associations between clinical presentations and childhood trauma subtypes, including neglect and abuse items. METHOD 587 patients with DSM-IV-defined bipolar disorder were recruited from France and Norway between 1996-2008 and 2007-2012, respectively. History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Clinical variables were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders (Norwegian sample) or the Diagnostic Interview for Genetic Studies (French sample). RESULTS Earlier age at onset of bipolar illness, suicide attempts, rapid cycling, and an increased number of depressive episodes each had significant associations (P ≤ .001) with at least 1 subtype of childhood trauma (emotional abuse, sexual abuse, and emotional neglect). Multivariate analyses investigating trauma variables together showed that both emotional and sexual abuse were independent predictors of lower age at onset (P = .002 for each) and history of suicide attempts (OR = 1.60 [95% CI, 1.07 to 2.39], P = .023; OR = 1.80 [95% CI, 1.14 to 2.86], P = .012, respectively), while sexual abuse was the strongest predictor of rapid cycling (OR = 2.04 [95% CI, 1.21 to 3.42], P = .007). Females reported overall higher childhood trauma frequency and greater associations to clinical expressions than males (P values < .05). CONCLUSIONS Our results demonstrate consistent associations between childhood trauma and more severe clinical characteristics in bipolar disorder. Further, they show the importance of including emotional abuse as well as the more frequently investigated sexual abuse when targeting clinical characteristics of bipolar disorder.

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.

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

BACKGROUND Previous 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. METHODS Plasma 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. RESULTS After 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. CONCLUSIONS This 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.

Cardiovascular risk factors during second generation antipsychotic treatment are associated with increased C-reactive protein

OBJECTIVE Severe mental disorder and cardiovascular disease (CVD) are often associated, and inflammation is implicated in both disorders. We investigated whether there is a relationship between CVD risk factors and inflammation in schizophrenia or bipolar disorder, and if second generation antipsychotics (SGA) interact. METHODS We included 361 patients in a naturalistic cross-sectional study, 235 subjects on current SGA treatment and 126 subjects not treated with SGA as controls. Cardiovascular parameters were measured and current medication recorded. Fasting plasma levels of the following cytokines were measured: high sensitivity CRP (hsCRP), soluble tumor necrosis factor receptor 1 (sTNF-R1), osteoprotegerin (OPG), soluble CD40 ligand (sCD40L), interleukin-1 receptor antagonist (IL-1Ra), von Willebrand factor (vWf) and interleukin-6 (IL-6). RESULTS In this relatively young sample of patients with a mean age of 33.3years, the following CVD risk factors were associated with elevated inflammation markers after adjusting for confounders: BMI, triglycerides and glucose with hsCRP (p=0.041-0.001), HDL-cholesterol and triglycerides with sTNF-R1 (p=0.009-0.001) and triglycerides with vWf (p=0.004). In patients treated with SGA, elevated hsCRP was significantly associated with high BMI (p=0.012), and with high glucose levels (p=0.003). CONCLUSION Several CVD risk factors are associated with elevated levels of inflammation markers in young patients with severe mental illness. The interaction between SGA and CVD risk factors on hsCRP levels might indicate a specific inflammatory activation related to SGA induced overweight and hyperglycemia. This suggests that hsCRP could be a valuable marker for future cardiovascular events, particularly in patients treated with SGA.

Inflammatory markers are associated with general cognitive abilities in schizophrenia and bipolar disorder patients and healthy controls

BACKGROUND The mechanisms underlying cognitive impairment in schizophrenia and bipolar disorders are largely unknown. Immune abnormalities have been found in both disorders, and inflammatory mediators may play roles in cognitive function. We investigated if inflammatory markers are associated with general cognitive abilities. METHODS Participants with schizophrenia spectrum (N=121) and bipolar spectrum (N=111) disorders and healthy controls (N=241) were included. General intellectual abilities were assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serum concentrations of the following immune markers were measured: Soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin 1 receptor antagonist (IL-1Ra), osteoprotegerin, von Willebrand factor, C-reactive protein, interleukin-6 and CD40 ligand. RESULTS After adjusting for age, sex and diagnostic group, significant negative associations with general cognitive function were found for sTNF-R1 (p=2×10(-5)), IL-1Ra (p=0.002) and sCD40 ligand (p=0.003). Among patients, the associations remained significant (p=0.006, p=0.005 and p=0.02) after adjusting for possible confounders including education, smoking, psychotic and affective symptoms, body mass index, cortisol, medication and time of blood sampling. Subgroup analysis, showed that general cognitive abilities were significantly associated with IL-1Ra and sTNF-R1 in schizophrenia patients, with sCD40L and IL-1Ra in bipolar disorder patients and with sTNF-R1 in healthy controls. CONCLUSION The study shows significant negative associations between inflammatory markers and general cognitive abilities after adjusting for possible confounders. The findings strongly support a role for inflammation in the neurophysiology of cognitive impairment.

Altered systemic cortisol metabolism in bipolar disorder and schizophrenia spectrum disorders

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is suggested as a pathophysiological factor in bipolar disorder and schizophrenia. Increased clearance of cortisol was recently indicated as a component in the HPA axis hyperdrive. The aim of the present study was to test the model of increased cortisol metabolism in a new replication sample separately and combined with a previously published sample of bipolar disorder and schizophrenia. Spot urine was sampled from 212 healthy controls (HC) and 221 patients with a schizophrenia spectrum disorder (SCZ, n = 115) and bipolar disorder (BD, n = 106). Of these, a subsample of 169 HC and 155 patients was included in a previous report. Urinary free cortisol, cortisone and their metabolites were measured, and the activities of 5α-reductase, 5β-reductase and 11β-HSD were estimated and analyzed for differences between groups. In the new sample, there was increased enzyme activity in SCZ for 5β-reductase (p = 0.024 vs HC; p = 0.027 vs BD) and 11β-HSD2 (p = 0.014 vs HC; p = 0.004 vs BD). In the combined sample, there was increased activity in SCZ for 5α-reductase (p < 0.001 vs HC; p = 0.020 vs BD), 5β-reductase (p < 0.001 vs HC; p = 0.045 vs BD) and 11β-HSD2 (p < 0.001 vs HC; p = 0.043 vs BD), and in BD for 5β-reductase (p = 0.002), 11β-HSD2 (p = 0.039) and 5α-reductase (trend, p = 0.084) (all vs HC). The findings confirm increased systemic cortisol metabolism in BD and SCZ. This is most consistent in SCZ, with BD taking an intermediate position. The design makes it impossible to determine the direction of the effect. However, the findings merit further study of cortisol metabolism as a possible component in the HPA axis dysfunction and pathophysiology of BD and SCZ.

Up-regulation of NOTCH4 gene expression in bipolar disorder.

OBJECTIVE Immunopathogenic mechanisms have been implicated in schizophrenia and bipolar disorder, and genome-wide association studies (GWAS) point to the major histocompatibility complex, a region that contains many immune-related genes. One of the strongest candidate risk genes for schizophrenia and bipolar disorder is the NOTCH4 gene within the major histocompatibility complex. The authors investigated the NOTCH4 gene expression in individuals with bipolar disorder and schizophrenia relative to healthy comparison subjects and identified putative expression quantitative trait loci in and around the NOTCH4 gene. METHOD The authors measured and compared NOTCH4 mRNA in whole blood in 690 individuals (479 patients and 211 healthy comparison subjects) and adjusted for a range of confounders. The authors also genotyped 20 single-nucleotide polymorphisms (SNPs) and investigated possible associations between expression quantitative trait loci and NOTCH4 expression. RESULTS The authors found a strong association between NOTCH4 expression and bipolar disorder after adjusting for a range of confounders and multiple testing. In addition, seven SNPs within the NOTCH4 gene region were associated with enhanced NOTCH4 mRNA levels. Three of these expression quantitative trait loci were independent (not in linkage disequilibrium). CONCLUSIONS The results indicate that the association between NOTCH4 DNA markers and bipolar disorder is related to altered function at the mRNA level, supporting the notion that NOTCH4 pathways are involved in the pathophysiology of bipolar disorder.

Inflammatory evidence for the psychosis continuum model

BACKGROUND Inflammation and immune activation have been implicated in the pathophysiology of severe mental disorders. Previous studies of inflammatory markers, however, have been limited with somewhat inconsistent results. AIMS We aimed to determine the effect sizes of inflammatory marker alterations across diagnostic groups of the psychosis continuum and investigate association to antipsychotic medications. METHODS Plasma levels of soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin 1 receptor antagonist (IL-1Ra), osteoprotegerin (OPG), and von Willebrand factor (vWf) were measured in patients (n=992) with schizophrenia spectrum (SCZ, n=584), schizoaffective disorder (SA, n=93), affective spectrum disorders (AFF, n=315), and healthy controls (HC, n=638). RESULTS Levels of sTNF-R1 (p=1.8×10(-8), d=0.23) and IL-1Ra (p=0.002, d=0.16) were increased in patients compared to HC. The SCZ group had higher levels of sTNF-R1 (p=8.5×10(-8), d=0.27) and IL-1Ra (p=5.9×10(-5), d=0.25) compared to HC, and for sTNF-R1 this was also seen in the SA group (p=0.01, d=0.3) and in the AFF group (p=0.002, d=0.12). Further, IL-1Ra (p=0.004, d=0.25) and vWf (p=0.02, d=0.21) were increased in the SCZ compared to the AFF group. There was no significant association between inflammatory markers and use of antipsychotic medication. CONCLUSION We demonstrate a small increase in sTNF-R1 and IL-1Ra in patients with severe mental disorders supporting a role of inflammatory mechanisms in disease pathophysiology. The increase was more pronounced in SCZ compared to AFF supporting a continuum psychosis model related to immune factors.

Association between altered brain morphology and elevated peripheral endothelial markers — Implications for psychotic disorders

BACKGROUND Increased inflammation, endothelial dysfunction, and structural brain abnormalities have been reported in both schizophrenia and bipolar disorder, but the relationships between these factors are unknown. We aimed to identify associations between markers of inflammatory and endothelial activation and structural brain variation in psychotic disorders. METHODS We measured von Willebrand factor (vWf) as a marker of endothelial cell activation and six inflammatory markers (tumor necrosis factor-receptor 1, osteoprotegerin, interleukin-1-receptor antagonist, interleukin-6, C-reactive protein, CD40 ligand) in plasma and 16 brain structures obtained from MRI scans of 356 individuals (schizophrenia spectrum; n=121, affective spectrum; n=95, healthy control subjects; n=140). The relationship between the inflammatory and endothelial markers and brain measurements were investigated across groups. RESULTS There was a positive association (p=2.5×10(-4)) between plasma levels of vWf and total volume of the basal ganglia which remained significant after correction for multiple testing. Treatment with first generation antipsychotics was associated with basal ganglia volume only (p=0.009). After adjusting for diagnosis and antipsychotic medication, vWf remained significantly associated with increased basal ganglia volume (p=0.008), in particular the right globus pallidus (p=3.7×10(-4)). The relationship between vWf and basal ganglia volume was linear in all groups, but the intercept was significantly higher in the schizophrenia group (df=2, F=8.2, p=3.4×10(-4)). CONCLUSION Our results show a strong positive correlation between vWf levels and basal ganglia volume, in particular globus pallidus, independent of diagnosis. vWf levels were significantly higher in schizophrenia, which could indicate a link between endothelial cell activation and basal ganglia morphology in schizophrenia patients.

Low vitamin D is associated with negative and depressive symptoms in psychotic disorders

BACKGROUND There are indications that low S-25(OH)D is associated with increased disease severity in psychotic disorder. Our first aim was to investigate the relations between low S-25(OH)D and positive, negative and depressive symptoms. Our second aim was to explore if associations between S-25(OH)D and symptoms were influenced by levels of inflammatory markers. METHODS Participants (N=358) with a medical history of one or more psychotic episodes were recruited. Current symptomatology was assessed by The Structured Interview for the Positive and Negative Syndrome Scaleanalyzed by a five-factor model. The Calgary Depression Scale for Schizophrenia was used to assess depression and suicidal ideation. Blood samples were analyzed for S-25(OH)D, CRP, sTNF-R1, IL-Ra and OPG. We performed bivariate correlations and multiple regression models to evaluate the effect of S-25(OH)D on the outcomes. RESULTS Low S-25(OH)D was significantly associated with negative symptoms (adjusted R2=0.113, F(6,357)=8.58, p<0.001) and with depression (adjusted R2=0.045, F(4,357)=5.233, p<0.001) when adjusting for possible confounding factors (i.e. gender, education, diagnose, hospitalization status, ethnicity, season and thyroid status). CRP was correlated with both S-25(OH)D (rho=-0.13, p=0.02) and negative symptoms (rho=0.14, p=0.01), but did not act as a mediator. The correlations between S-25(OH)D and the inflammatory markers sTNF-R1, IL-Ra and OPG were not significant. CONCLUSION There is a strong association between low S-25(OH)D and higher negative and depressive symptoms in psychotic disorders. Randomized controlled trials should be performed to investigate the effect of vitamin D supplementation as adjuvant treatment strategy in patients with prominent negative or depressive symptoms.