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.

Physical activity and childhood trauma experiences in patients with schizophrenia or bipolar disorders.

BACKGROUND: Physical activity promotes resilience and reduces stress. Here we aimed to clarify the impact of physical activity and childhood trauma experiences on current mood and cognitive function in patients with schizophrenia (SZ) or bipolar disorders (BD). METHODS: Three-hundred-and-six patients with DSM-IV schizophrenia (SZ) or bipolar disorder (BD) were included in the study. Diagnoses were assessed using the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Physical activity was measured as hours spent on any regular physical activity per week. All patients underwent a neuropsychological test battery. History of Childhood trauma was assessed using the Childhood Trauma Questionnaire and mood symptoms were assessed with the Inventory of Depressive Symptoms. RESULTS: Patients with childhood trauma who were physically inactive (˂90 min per week) had the most severe clinical profile, characterised by the highest depressive symptoms (p ˂ 0.001) and lowest performance on working memory tasks (p ˂ 0.001). Among patients with childhood trauma, those who were physically active (≥90 min per week) had better working memory performance than physically inactive patients (p = 0.02). DISCUSSION: A history of childhood trauma was associated with poorer working memory and more depressive symptoms only in patients who were physically inactive, suggesting a possible protective factor of physical activity in severe mental disorder.

Improvement in verbal learning over the first year of antipsychotic treatment is associated with serum HDL levels in a cohort of first episode psychosis patients.

To investigate whether changes in serum lipids are associated with cognitive performance in first episode psychosis (FEP) patients during their first year of antipsychotic drug treatment. One hundred and thirty-two antipsychotic-treated FEP patients were included through the TOP study along with 83 age- and gender-matched healthy controls (HC). Information regarding cognitive performance, psychotic symptoms, lifestyle, body mass index, serum lipids [total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, and triglycerides] and antipsychotic treatment was obtained at baseline and after 1 year. The cognitive test battery is comprised of assessments for verbal learning, processing speed, working memory, verbal fluency, and inhibition. Mixed-effects models were used to study the relationship between changes over time in serum lipids and cognitive domains, controlling for potential confounders. There was a significant group by HDL interaction effect for verbal learning (F = 11.12, p = 0.001), where an increase in HDL levels was associated with improvement in verbal learning in FEP patients but not in HC. Practice effects, lifestyle, and psychotic symptoms did not significantly affect this relationship. Antipsychotic-treated FEP patients who increased in HDL levels during the first year of follow-up exhibited better verbal learning capacity. Further investigations are needed to clarify the underlying mechanisms.

Association between olanzapine treatment and brain cortical thickness and gray/white matter contrast is moderated by cholesterol in psychotic disorders.

Altered cortical brain morphology is observed in psychotic disorders. Despite the importance of lipid homeostasis for healthy brain functioning, knowledge about its role in cortical alterations in psychosis is limited. In a sample of patients with psychotic disorders, we investigated the relationship between treatment with olanzapine (OLZ), and cortical thickness and gray/white matter intensity contrast, and the association between these measures and serum lipid levels. We included 33 OLZ users, 19 unmedicated psychotic patients and 76 healthy controls (HC). Data on serum lipids and cortical measures based on MR brain images processed with FreeSurfer were analyzed with General Linear Models. We found that intensity contrast was similar in OLZ users as compared to HC and that the cortex (frontal, orbitofrontal, medial temporal) was thinner in OLZ users (p < 0.05, Bonferroni corrected). An OLZ-specific HDL interaction effect was further found for the pericentral cortical thickness measure (p < 0.05, Bonferroni corrected). Additionally, nominally significant findings indicated similar OLZ-specific interaction effects for cortical thickness in several regions, and an OLZ-specific interaction with LDL for occipital lobe contrast (p < 0.05, uncorrected). Our findings may suggest a drug-related lipid-effect on brain myelination. Experimental studies and replications in different study samples are needed to clarify these complex relationships further.

VRK2 gene expression in schizophrenia, bipolar disorder and healthy controls.

BACKGROUND: Common variants in the Vaccinia-related kinase 2 (VRK2) gene have been associated with schizophrenia, but the relevance of its encoded protein VRK2 in the disorder remains unclear. AIMS: To identify potential differences in VRK2 gene expression levels between schizophrenia, bipolar disorder, psychosis not otherwise specified (PNOS) and healthy controls. METHOD: VRK2 mRNA level was measured in whole blood in 652 individuals (schizophrenia, n = 201; bipolar disorder, n = 167; PNOS, n = 61; healthy controls, n = 223), and compared across diagnostic categories and subcategories. Additionally, we analysed for association between 1566 VRK2 single nucleotide polymorphisms and mRNA levels. RESULTS: We found lower VRK2 mRNA levels in schizophrenia compared with healthy controls (P<10(-12)), bipolar disorder (P<10(-12)) and PNOS (P = 0.0011), and lower levels in PNOS than in healthy controls (P = 0.0042) and bipolar disorder (P = 0.00026). Expression quantitative trait loci in close proximity to the transcription start site of the short isoforms of the VRK2 gene were identified. CONCLUSIONS: Altered VRK2 gene expression seems specific for schizophrenia and PNOS, which is in accordance with findings from genome-wide association studies. These results suggest that reduced VRK2 mRNA levels are involved in the underlying mechanisms in schizophrenia spectrum disorders.

Clinical characteristics in schizophrenia patients with or without suicide attempts and non-suicidal self-harm--a cross-sectional study.

BACKGROUND: To investigate whether schizophrenia patients with both suicide attempts and non-suicidal self-harm have earlier age of onset of psychotic and depressive symptoms and higher levels of clinical symptoms compared to patients with only suicide attempts or without suicide attempt. METHODS: Using a cross-sectional design, 251 patients (18-61 years old, 58% men) with schizophrenia treated at hospitals in Oslo and Innlandet Hospital Trust, Norway, were assessed with a comprehensive clinical research protocol and divided into three groups based on their history of suicide attempts and non-suicidal self-harm. RESULTS: Suicide attempts were present in 88 patients (35%); 52 had suicide attempts only (29%) and 36 had both suicide attempts and non-suicidal self-harm (14%). When compared with nonattempters and those with suicide attempts without non-suicidal self-harm, patients with both suicide attempts and non-suicidal self-harm were more frequently women, younger at the onset of psychotic symptoms, had longer duration of untreated psychosis, and had higher levels of current impulsivity/aggression and depression. Patients with both suicide attempts and non-suicidal self-harm were more likely to repeat suicide attempts than patients with suicide attempts only. CONCLUSIONS: Patients with both suicide attempts and non-suicidal self-harm had different illness history and clinical characteristics compared to patients with only suicide attempts or patients without suicidal behavior. Our study suggests that patients with both suicide attempts and non-suicidal self-harm represent a distinct subgroup among patients with schizophrenia and suicidal behavior with their early onset of psychotic symptoms, high rate of repeated suicidal behavior and significant treatment delay.

High prevalence of childhood trauma in patients with schizophrenia spectrum and affective disorder.

OBJECTIVE: Childhood trauma (CT) is a major risk factor for various psychiatric disorders. We wanted to determine the prevalence of CT in a catchment area-based sample of schizophrenia spectrum and affective disorder (including bipolar disorder and depressive episodes with psychotic features) and to explore potential differences in types of CT between the diagnostic groups. METHOD: Three hundred five patients were recruited consecutively from psychiatric units at 3 major hospitals in Oslo, Norway, diagnosed with Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Traumatic childhood events were assessed with Childhood Trauma Questionnaire. RESULTS: Eighty-two percent of the patients had experienced one or more CT events, the most frequent subtype of trauma being emotional neglect. The schizophrenia spectrum group reported significantly more physical abuse and physical neglect than the affective group. CONCLUSION: A high prevalence of CT in patients with severe mental disorder was detected. This reminds us of the importance of exploring this issue when we treat such patients. The mechanisms behind these differences are unclear. Further research is needed to study potential associations between CT and the clinical picture of the disorder.

Is cognitive impairment following early life stress in severe mental disorders based on specific or general cognitive functioning?

Schizophrenia spectrum and bipolar disorder are characterized by high levels of childhood trauma as well as of cognitive dysfunction. Our aim is to investigate the association between these two factors in the largest study in the literature so far. A total of 406 patients with schizophrenia spectrum- or bipolar disorders were recruited from a catchment area based organization in Oslo, Norway. Information about early life stress was obtained using the Childhood Trauma Questionnaire (CTQ). Cognitive function was assessed through a comprehensive and standardized neuropsychological test battery. Physical abuse, sexual abuse and physical neglect were significantly associated with reduced scores on working memory and executive function scales (p=0.04 to p<0.001), and verbal and performance tasks from the Wechsler Abbreviated Scale of Intelligence (WASI) (p=0.059 to p<0.001). When verbal and performance tasks from the WASI were added into a multivariate regression model, the association between CTQ and the specific cognitive domains decreased, and only WASI scores remained statistically significant. Our results indicate that childhood trauma is associated with a reduction in cognitive function across cognitive domains in patients with schizophrenia spectrum- and bipolar disorders, in particular working memory and executive function as well as general cognition. Moreover, these dysfunctions seem to be driven by underlying deficits in general cognitive tasks as measured by the WASI.

Affective symptoms are associated with markers of inflammation and immune activation in bipolar disorders but not in schizophrenia.

OBJECTIVE: Elevated levels of inflammation are reported in bipolar disorders (BP), but how this relates to affective symptoms is unclear. We aimed to determine if immune markers that consistently have been reported elevated in BP were associated with depressive and manic symptoms, and if this was specific for BP. METHODS: From a catchment area, 112 BP patients were included together with 153 schizophrenia (SCZ) patients and 239 healthy controls. Depression and mania were assessed and the patients were grouped into depressed, neutral, and elevated mood. We measured the immune markers tumor necrosis factor receptor 1 (sTNF-R1), interleukin 1 receptor antagonist (IL-1Ra), interleukin 6 (IL-6), high sensitive C-reactive protein (hsCRP), osteoprotegerin (OPG) and von Willebrand factor (vWf) which have been found increased in severe mental disorders. RESULTS: In BP all inflammatory markers were lowest in depressed state, with significant group differences after control for confounders with respect to TNF-R1 (p = 0.04), IL-1Ra (p = 0.02), OPG (p = 0.004) and IL-6 (p = 0.005). STNF-R1 was positively correlated with the item elevated mood (p = 0.02) whereas sad mood was negatively correlated with OPG (p = 0.0003), IL-1Ra (p = 0.001) and IL-6 (p = 0.006). Compared to controls the neutral mood group had significantly higher levels of OPG (p = 0.0003) and IL-6 (p = 0.005), and the elevated mood group had higher levels of TNF-R1 (p = 0.000005) and vWf (p = 0.002). There were no significant associations between affective states orsymptoms in SCZ. CONCLUSIONS: The current associations between inflammatory markers and affective symptomatology in BP and not SCZ suggest that immune related mechanisms are associated with core psychopathology of BP.