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Objective: This study examines if YKL‐40 is increased in individuals with psychotic disorders and if elevated YKL‐40 levels at baseline is associated with subsequent development of type 2 diabetes. Method: A total of 1383 patients with a diagnosis of schizophrenia or affective psychosis and 799 healthy controls were recruited in the period 2002–2015. Plasma YKL‐40 and metabolic risk factors were measured and medication was recorded. Using national registry data, association between baseline risk factors and later development of type 2 diabetes was assessed using Cox proportional hazards models. Results: Plasma YKL‐40 was higher in patients vs. healthy controls also after adjusting for metabolic risk factors, with no difference between the schizophrenia and affective psychosis groups. Patients were diagnosed with type 2 diabetes at a significantly younger age. Multivariate Cox regression analyses showed that elevated YKL‐40 (hazard ratio (HR) = 5.6, P = 0.001), elevated glucose (HR = 3.6, P = 0.001), and schizophrenia diagnosis (HR = 3.0, P = 0.014) at baseline were associated with subsequent development of type 2 diabetes. Conclusions: Patients with psychotic disorders have at baseline increased levels of YKL‐40 beyond the effect of comorbid type 2 diabetes and metabolic risk factors. Elevated YKL‐40 level at baseline is associated with later development of type 2 diabetes. [ABSTRACT FROM AUTHOR]

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., (© 2023. The Author(s).)

Purpose: Psychotropic and somatic medications are both used in treating severe mental disorders (SMDs). Realistic estimates of the prevalence of use across medication categories are needed. We obtained this in a clinical cohort of patients with SMD and healthy controls (HCs)., Materials and Methods: Prescriptions filled at Norwegian pharmacies the year before and after admittance to the Thematically Organized Psychosis (TOP) study were examined in 1406 patients with SMD (mean age 32.5 years, 48.2% women) and 920 HC (34.1 years, 46.2% women). Using data from the Norwegian Prescription Database (NorPD), the number of users in different anatomical therapeutic chemical (ATC) categories was compared using logistic regression. Population estimates were used as reference data., Results: Use of antipsychotics (N05A), antiepileptics (N03A), antidepressants (N06A), anxiolytics (N05B), hypnotics and sedatives (N05C), anticholinergics (N04A), psychostimulants, attention deficit hyperactivity disorder and nootropic agents (N06B) and drugs for addiction disorders (N07B) was significantly more prevalent in patients with SMD than HC. Use of diabetes treatment (A10), antithrombotic drugs (B01), beta blockers (C07), lipid modifiers (C10), and thyroid and endocrine therapeutics (H03) was also more prevalent in patients with SMD, but with two exceptions somatic medication use was comparable to the general population. Among HC, there was low prevalence of use for most medication categories., Conclusion: Patients were using psychiatric medications, but also several types of somatic medications, more often than HC. Still, somatic medication use was mostly not higher than in the general population. The results indicate that HC had low use of most medication types.

Objectives: The goal of the current project was to enhance the feeling of dignity for patients in the seclusion unit in an acute psychiatric ward through environmental design changes and to evaluate the effect of the refurbishment., Background: Treating people with dignity is essential in all health-related work and important for our mental health. Hospital architecture and design signal values that can promote dignity. Patients who must spend time in seclusion are at their most vulnerable mental state and the often worn-down like environment can challenge the feeling of dignity. How environmental design can promote dignity in seclusion units have not been studied., Methods: To reach suggestions for design changes enhancing dignity, we used service design that included a broad user group. The effect of design changes was evaluated by a questionnaire answered by the nursing staff during a 4-week period pre- and post refurbishment and included a control group., Results: The design concepts agreed upon were a welcoming atmosphere, contact with nature, room for privacy, close contact with staff, and a designated smoking area inside the unit. The evaluation found that the environmental design changes significantly supported the patients in their situation and the staff in their work., Conclusion: We conclude that dignity design concepts are highly applicable also in an acute psychiatric setting and improve the situation of secluded mental health patients, which is much needed. Findings align with other environmental changes in psychiatric wards that improve the patients' well-being and reduce aggression.

Objective: Agitation is a challenging clinical feature in severe mental disorders, but its biological correlates are largely unknown. Inflammasome-related abnormalities have been linked to severe mental disorders and implicated in animal models of agitation. We investigated if levels of circulating inflammasome-related immune markers were associated with agitation in severe mental disorders., Methods: Individuals with a psychotic or affective disorder (N = 660) underwent blood sampling and clinical characterization. Plasma levels of interleukin (IL)-18, IL-18 binding protein (IL-18BP), IL-18 receptor 1 (IL-18R1), IL-18 receptor accessory protein (IL-18RAP), and IL-1 receptor antagonist (IL-1RA) were measured. Agitation levels were estimated with the Positive and Negative Syndrome Scale Excited Component. Multiple linear- and logistic regression were used to investigate the associations between agitation and the immune markers, while controlling for confounders. The influence of psychotic and affective symptoms was assessed in follow-up analyses., Results: Agitation was positively associated with IL-18BP (β = 0.13, t = 3.41, p = 0.0007) after controlling for multiple confounders, including BMI, smoking, medication, and substance use. Adjustment for psychotic, manic, and depressive symptoms did not affect the results. There were no significant associations between agitation and the other investigated immune markers (IL-1RA (β = 0.06, t = 1.27, p = 0.20), IL-18 (β = 0.05, t = 1.25, p = 0.21), IL-18R1 (β = 0.04, t = 1.01, p = 0.31), IL-18RAP (odds ratio = 0.96, p = 0.30)). In a subsample (N = 463), we also adjusted for cortisol levels, which yielded unaltered results., Conclusion: Our findings add to the accumulating evidence of immune system disturbances in severe mental disorders and suggest the IL-18 system as a part of the biological correlate of agitation independent of affective and psychotic symptoms., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Selective serotonin reuptake inhibitors (SSRIs) are prescribed both to patients with schizophrenia and bipolar disorder. Previous studies have shown associations between SSRI treatment and cardiometabolic alterations. The aim of the present study was to investigate genetic variants associated with cardiometabolic adverse effects in patients treated with SSRIs in a naturalistic setting, using a genome-wide cross-sectional approach in a genetically homogeneous sample. We included and genotyped 1981 individuals with schizophrenia or bipolar disorder, of whom 1180 had information available on the outcomes low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein cholesterol (HDL-cholesterol), triglycerides, and body mass index (BMI) and investigated interactions between SNPs and SSRI use (N = 246) by conducting a genome-wide GxE analysis. We report 13 genome-wide significant interaction effects of SNPs and SSRI serum concentrations on LDL-cholesterol, HDL-cholesterol, and BMI, located in four distinct genomic loci. This study provides new insight into the pharmacogenetics of SSRI but warrants replication in independent populations., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) associated with elevated cardiovascular disease (CVD) risk, including obesity. Leptin and adiponectin are secreted by adipose tissue, with pro- and anti-inflammatory properties, respectively. The second generation antipsychotics (AP) olanzapine, clozapine, and quetiapine have been associated with high leptin levels in SMI. However, the link between inflammatory dysregulation of leptin and adiponectin and CVD risk in SMI, and how this risk is influenced by body mass and AP medication, is still not completely understood. We investigated herein if leptin, adiponectin or their ratio (L/A ratio) could predict increased CVD risk in SCZ, BD, and in subgroups according to use of antipsychotic (AP) treatment, independent of other cardio-metabolic risk factors. Methods: We measured fasting plasma levels of leptin and adiponectin, and calculated the L/A ratio in n = 1,092 patients with SCZ and BD, in subgroups according to AP treatment, and in n = 176 healthy controls (HC). Differences in the levels of adipokines and L/A between groups were examined in multivariate analysis of covariance, and the correlations between adipokines and body mass index (BMI) with linear regression. CVD risk was defined by total cholesterol/high-density lipoprotein (TC/HDL) and triglyceride/HDL (TG/HDL) ratios. The adipokines and L/A ratios ability to discriminate individuals with TG/HDL and TC/HDL ratios above threshold levels was explored by ROC analysis, and we investigated the possible influence of other cardio-metabolic risk factors on the association in logistic regression analyses. Results: We observed higher leptin levels and L/A ratios in SMI compared with HC but found no differences in adiponectin. Both adipokines were highly correlated with BMI. The low adiponectin levels showed a fair discrimination in ROC analysis of individuals with CVD risk, with AUC between 0.7 and 0.8 for both TC/HDL and TG/HDL, in all groups examined regardless of diagnosis or AP treatment. Adiponectin remained significantly associated with an elevated TC/HDL and TG/HDL ratio in SMI, also after further adjustment with other cardio-metabolic risk factors. Conclusions: Adiponectin is not dysregulated in SMI but is associated with CVD risk regardless of AP treatment regime., Competing Interests: OA has received speaker's honorarium from Lundbeck and is a consultant for HealhLytix. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Reponen, Tesli, Dieset, Steen, Vedal, Szabo, Werner, Lunding, Johansen, Rødevand, Andreassen and Ueland.)

This current cross sectional survey was carried out amongst patients and staff in an acute psychiatric inpatient unit in the very first weeks of the ongoing pandemic outbreak of COVID-19 in Norway. Most patients found the visiting restrictions difficult, many reported that the pandemic made them feel unsafe, affected their sleep and that they feared transmission from other patients. Among staff, almost half were afraid that they would contract the virus, a majority feared they would bring the virus home and infect their family and one third were concerned that the pandemic compromised the treatment provided for the patients., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Patient satisfaction (PS) with treatment is one of different outcome- and quality measures used by health care providers worldwide to improve service. We report from a study of patients admitted to the Department of Acute Psychiatry at the Oslo University Hospital where we investigated PS and difference between genders, days of hospital stay, diagnostic groups, voluntary-and involuntary admitted patients according to hospital records and perceived voluntary-and involuntary admittance. Materials and methods: All admitted patients during a 9-month period in 2014 were asked to participate by written consent. We used The Psychiatric Inpatient Questionnaire (PIPEQ), a self-report survey validated for assessment post-discharge. Analyses were conducted for a general dimension of PS and individual questions. A user representative was a part of the study from the beginning. Results: A total of 357 patients were asked and 256 consented. Results show that 68% were over all satisfied and 14% dissatisfied. Highest PS was found for cooperation with relatives and lowest for influence on choice of treatment and medication. We found no significant difference in PS between men and women, but patients with a personality disorder and with short stay were less satisfied. PS was significantly less for those perceiving involuntary admission regardless of legal status. Conclusion: The PIPEQ gives important input of patient's experience with the delivery of care. Answers range from very much satisfied to not at all depending on what was asked for. Exploring PS provides valuable information for quality improvements for different patient groups.

Background: Cardiovascular disease (CVD) is a major cause of premature death in patients with psychotic disorders, where dyslipidemia occurs frequently. In the pathogenesis of these serious mental disorders, a low-grade inflammation seems to be a possible contributor. Concurrently, systemic inflammation and its interplay with dyslipidemia is a central driver in the pathogenesis of CVD. We hypothesize that evaluation of atherogenic lipid ratios together with inflammatory markers reflecting different inflammatory pathways with relevance for atherogenesis, could give novel information on immune-related mechanisms involved in early CVD risk in patients with psychotic disorders., Methods: As a measure for CVD risk we calculated atherogenic lipid ratios using established sex-specific cut-offs: Total cholesterol/high-density lipoprotein; HDL-c (TC/HDL) and triglyceride/HDL-c (TG/HDL) were evaluated in 571 schizophrenia (SCZ) and 247 bipolar disorder (BD) patients, and in 99 healthy controls (HC). In addition, as a measure of low-grade inflammation, we measured fasting plasma levels of nine stable atherogenic inflammatory markers in patients (SCZ, BD) and in HC. The elevated inflammatory markers and CVD risk in patients, as reflected by TC/HDL and TG/HDL, were further assessed in multivariable analyses adjusting for comorbid cardio-metabolic risk factors., Results: A markedly higher proportion (26%-31%) of patients had increased TC/HDL and TG/HDL ratios compared with HC. Plasma levels of high-sensitivity C-reactive protein (hs-CRP) and myeloperoxidase (MPO) were higher (p<0.05, p<0.001) in patients with psychotic disorders than in HC, and hs-CRP and MPO were independently associated with atherogenic lipid ratios in the multivariable analyses., Conclusions: Our findings suggest that low-grade inflammation and abnormal neutrophil activation may cause increased CVD risk in patients with psychotic disorders. These mechanisms should be further examined to determine the potential for development of novel risk evaluation strategies., (Copyright © 2020 Reponen, Dieset, Tesli, Mørch, Aas, Vedal, Haug, Drange, Steen, Hope, Szabo, Gohar, Wedervang-Resell, Djurovic, Melle, Aukrust, Andreassen and Ueland.)

The complex effects of plant cannabinoids on human physiology is not yet fully understood, but include a wide spectrum of effects on immune modulation. The immune system and its inflammatory effector pathways are recently emerging as possible causative factors in psychotic disorders. The present study aimed to investigate whether self-administered Cannabis use was associated with changes in circulating immune and neuroendocrine markers in schizophrenia (SCZ) and bipolar disorder (BD) patients. A screening of 13 plasma markers reflecting different inflammatory pathways was performed in SCZ (n = 401) and BD patients (n = 242) after subdividing each group into Cannabis user and non-user subgroups. We found that i) soluble gp130 (sgp130) concentrations were significantly elevated among Cannabis users in the SCZ group (p = 0.002) after multiple testing correction, but not in BD. ii) Nominally significant differences were observed in the levels of IL-1RA (p = 0.0059), YKL40 (p = 0.0069), CatS (p = 0.013), sTNFR1 (p = 0.031), and BDNF (p = 0.020), where these factors exhibited higher plasma levels in Cannabis user SCZ patients than in non-users. iii) These differences in systemic levels were not reflected by altered mRNA expression of genes encoding sgp130, IL-1RA, YKL40, CatS, sTNFR1, and BDNF in whole blood. Our results show that Cannabis self-administration is associated with markedly higher sgp130 levels in SCZ, but not in BD, and that this phenomenon is independent of the modulation of peripheral immune cells. These findings warrant further investigation into the potential IL-6 trans-signaling modulatory, anti-inflammatory, neuroimmune, and biobehavioral-cognitive effects of Cannabis use in SCZ., (Copyright © 2020 Szabo, Akkouh, Ueland, Lagerberg, Dieset, Bjella, Aukrust, Le Hellard, Stavrum, Melle, Andreassen and Djurovic.)

Background: We aimed at exploring potential pathophysiological processes across psychotic disorders, applying metabolomics in a large and well-characterized sample of patients and healthy controls., Methods: Patients with schizophrenia and bipolar disorders (N = 212) and healthy controls (N = 68) had blood sampling with subsequent metabolomics analyses using electrochemical coulometric array detection. Concentrations of 52 metabolites including tyrosine, tryptophan and purine pathways were compared between patients and controls while controlling for demographic and clinical characteristics. Significant findings were further tested in medication-free subsamples., Results: Significantly decreased plasma concentrations in patients compared to healthy controls were found for 3-hydroxykynurenine (3OHKY, p = 0.0008), xanthurenic acid (XANU, p = 1.5×10-5), vanillylmandelic acid (VMA, p = 4.5×10-5) and metanephrine (MN, p = 0.0001). Plasma concentration of xanthine (XAN) was increased in the patient group (p = 3.5×10-5). Differences of 3OHKY, XANU, VMA and XAN were replicated across schizophrenia spectrum disorders and bipolar disorders subsamples of medication-free individuals., Conclusions: Although prone to residual confounding, the present results suggest the kynurenine pathway of tryptophan metabolism, noradrenergic and purinergic system dysfunction as trait factors in schizophrenia spectrum and bipolar disorders. Of special interest is XANU, a metabolite previously not found to be associated with bipolar disorders.

Although the relationship between positive and negative symptoms of psychosis and dyslipidemia has been thoroughly investigated in recent studies, the potential link between depression and lipid status is still under-investigated. We here examined the association between lipid levels and depressive symptomatology in patients with psychotic disorders, in addition to their possible inflammatory associations. Participants (n = 652) with the following distribution: schizophrenia, schizophreniform and schizoaffective disorder (schizophrenia group, n = 344); bipolar I, II, NOS, and psychosis NOS (non-schizophrenia group, n = 308) were recruited consecutively from the Norwegian Thematically Organized Psychosis (TOP) Study. Clinical data were obtained by Positive and Negative Syndrome Scale (PANSS), and Calgary Depression Scale for Schizophrenia (CDSS). Blood samples were analyzed for total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (TG), C-reactive protein (CRP), soluble tumor necrosis factor receptor 1(sTNF-R1), osteoprotegerin (OPG), and interleukin 1 receptor antagonist (IL-1Ra). After adjusting for age, gender, BMI, smoking, and dyslipidemia-inducing antipsychotics, TC and LDL scores showed significant associations with depression [β = 0.13, p = 0.007; β = 0.14, p = 0.007], and with two inflammatory markers: CRP [β = 0.14, p = 0.007; β = 0.16, p = 0.007] and OPG [β = 0.14, p = 0.007; β = 0.11, p = 0.007]. Total model variance was 17% for both analyses [F(12, 433) = 8.42, p < 0.001; F(12, 433) = 8.64, p < 0.001]. Current findings highlight a potential independent role of depression and inflammatory markers, CRP and OPG in specific, in the pathophysiology of dyslipidemia in psychotic disorders.

Background: Inflammation and immune activation have been implicated in the pathogenesis of severe mental disorders and cardiovascular disease (CVD). Despite high level of comorbidity, many studies of the immune system in severe mental disorders have not systematically taken cardiometabolic risk factors into account., Methods: We investigated if inflammatory markers were increased in schizophrenia (SCZ) and affective (AFF) disorders independently of comorbid CVD risk factors. Cardiometabolic risk factors (blood lipids, body mass index and glucose) and CVD-related inflammatory markers CXCL16, soluble interleukin-2 receptor (sIL-2R), soluble CD14 (sCD14), macrophage inhibitory factor and activated leukocyte cell adhesion molecule (ALCAM) were measured in n = 992 patients (SCZ, AFF), and n = 647 healthy controls. We analyzed the inflammatory markers before and after controlling for comorbid cardiometabolic risk factors, and tested for association with psychotropic medication and symptom levels., Results: CXCL16 (p = 0.03) and sIL-2R (p = 7.8 × 10-5) were higher, while sCD14 (p = 0.05) were lower in patients compared to controls after controlling for confounders, with significant differences in SCZ for CXCL16 (p = 0.04) and sIL-2R (p = 1.1 × 10-5). After adjustment for cardiometabolic risk factors higher levels of sIL-2R (p = 0.001) and lower sCD14 (p = 0.002) remained, also in SCZ (sIL-2R, p = 3.0 × 10-4 and sCD14, p = 0.01). The adjustment revealed lower ALCAM levels (p = 0.03) in patients. We found no significant associations with psychotropic medication or symptom levels., Conclusion: The results indicate that inflammation, in particular enhanced T cell activation and impaired monocyte activation, are associated with severe mental disorders independent of comorbid cardiometabolic risk factors. This suggests a role of novel pathophysiological mechanisms in severe mental disorders, particularly SCZ.

Background: The prevalence of obesity, metabolic syndrome and type 2 diabetes mellitus is increased among patients with severe mental disorders, and particularly use of second generation antipsychotic drugs is associated with metabolic side effects. Antipsychotics have been found to alter levels of adipokines which regulate insulin sensitivity, but their role in antipsychotic-associated insulin resistance is not established, and it is unclear whether adipokines affect insulin resistance independently of body mass index (BMI)., Methods: We included 1050 patients with severe mental disorders and 112 healthy controls aged 18-65 years from the Oslo area, Norway. Clinical variables, BMI and use of medication were assessed, fasting blood samples were obtained for calculation of the leptin/adiponectin ratio (L/A ratio) and estimate of insulin resistance using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Case-control analyses were followed by mediation analyses to evaluate the possible direct effect of antipsychotics on HOMA-IR and indirect effect mediated via the L/A ratio. This was performed both with and without adjustment for BMI, in the total sample and in an antipsychotic monotherapy subsample (N = 387)., Results: BMI, L/A ratio and HOMA-IR were significantly higher in patients than controls (p < 0.001-p = 0.01). There was a significant direct effect from use of antipsychotics in general on HOMA-IR both without (b = 0.03, p = 0.007) and with adjustment for BMI (b = 0.03, p = 0.013), as well as a significant mediating effect via L/A ratio both without (b = 0.03, p < 0.001) and with adjustment for BMI (b = 0.01, p = 0.041). Use of olanzapine (b = 0.03, p < 0.001) or aripiprazole (b = 0.04, p < 0.001) in monotherapy showed significant effects on HOMA-IR mediated via L/A ratio., Conclusions: The study suggests that use of antipsychotics may alter adipokine levels, and that increased L/A ratio may play a role in the development of insulin resistance associated with use of antipsychotics also independently of BMI., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Although several studies have found reduced plasma BDNF levels in patients with severe mental disorders, the sample sizes have been small and have exhibited variation and heterogeneity. Furthermore, long-term neurobiological changes following childhood trauma and clinical severity have been linked to a reduction in BDNF levels. Accordingly, we aim to clarify, using the largest sample size to date, the role of plasma BDNF in individuals with severe mental disorders in relation to the number of episodes, current remission status, and childhood trauma experiences., Methods: The study sample comprised 1446 individuals (schizophrenia: SZ [n = 589]; bipolar disorder: BD [n = 254]; and healthy control: HC [n = 603]) all recruited from the same catchment area. A subsample (N = 629) of this larger group had a history of childhood trauma, and some (N = 195) participated in a one-year follow-up study. The level of BDNF in plasma was measured, and childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Diagnoses and episodes were obtained using the Structured Clinical Interview (SCID)., Results: Patients with SZ or BD had lower levels of plasma BDNF than did the HC group (p = 0.002, p = 0.003, respectively). Within patients, reduced plasma BDNF levels were associated with more depressive episodes (p = 0.04). Longer time in remission after depressive episodes was associated with higher plasma BDNF levels (p = 0.02), and patients reporting childhood sexual abuse exhibited lower plasma BDNF levels (p = 0.049) than patients without sexual abuse., Conclusion: Our study confirms that patients with a severe mental disorder exhibit reduced BDNF levels. While the strongest reduction in BDNF was observed in patients reporting childhood sexual abuse, reduced BDNF levels were also associated with more depressive episodes. Accordingly, further studies are warranted to determine whether treatment that increases BDNF levels may be beneficial to these individuals., (Copyright © 2018. Published by Elsevier B.V.)

Oxytocin is a neuropeptide involved in animal and human reproductive and social behavior. Three oxytocin signaling genes have been frequently implicated in human social behavior: OXT (structural gene for oxytocin), OXTR (oxytocin receptor), and CD38 (oxytocin secretion). Here, we characterized the distribution of OXT, OXTR, and CD38 mRNA across the human brain by creating voxel-by-voxel volumetric expression maps, and identified putative gene pathway interactions by comparing gene expression patterns across 20,737 genes. Expression of the three selected oxytocin pathway genes was enriched in subcortical and olfactory regions and there was high co-expression with several dopaminergic and muscarinic acetylcholine genes, reflecting an anatomical basis for critical gene pathway interactions. fMRI meta-analysis revealed that the oxytocin pathway gene maps correspond with the processing of anticipatory, appetitive, and aversive cognitive states. The oxytocin signaling system may interact with dopaminergic and muscarinic acetylcholine signaling to modulate cognitive state processes involved in complex human behaviors.

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.

Background: Disturbances in thyroid function have been associated with use of psychotropic drugs, including antipsychotics. Still, the thyroid function in relation to commonly prescribed antipsychotic drugs and polypharmacy is not fully known. We investigated thyroid function associated with use of antipsychotics in patients with psychotic disorders compared with healthy controls., Methods: We included 1345 patients and 989 healthy controls from the Thematically Organized Psychosis (TOP) study, recruiting participants between 18 and 65 years of age in the Oslo-area. All patients underwent a thorough clinical investigation and assessment of medication data. Thyroid function was determined from plasma levels of free thyroxin (fT4) and thyroid-stimulating hormone (TSH). Multiple linear regression analyses were performed to evaluate the association between thyroid parameters and use of antipsychotics, and monotherapy users of olanzapine, quetiapine, aripiprazole or risperidone (N = 473) were investigated separately., Results: We found lower levels of fT4 (median 13.70 vs 14.00, p < 0.001) in patients compared to healthy controls, and a prevalence of 12.9% of previously undiagnosed deviant thyroid states in the patient group. Lower fT4 levels was associated with use of antipsychotics in general (p = 0.001), and quetiapine (p = 0.003) and olanzapine (p = 0.018) in particular, while the associations with TSH were non-significant. Using antipsychotics in combination with other psychotropic drugs, and with antidepressants in particular, was associated with lower fT4 level (p < 0.001) than use of antipsychotics alone., Conclusions: Our findings indicate an association between use of antipsychotics and lower fT4. Clinicians should be aware that patients using quetiapine, olanzapine or antipsychotics in psychotropic polypharmacy are especially at risk., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Negative symptoms have traditionally been assessed based on clinicians' observations. The subjective experience of negative symptoms in people with psychosis may bring new insight. The Apathy Evaluation Scale (AES) is commonly used to study apathy in psychosis and has corresponding self-rated (AES-S) and clinician-rated (AES-C) versions. The aim of the present study was to determine the validity and reliability of the AES-S by investigating its concordance with the AES-C. Eighty-four first-episode (FEP) patients completed the shortened 12-item AES-S and AES-C at baseline (T1) and 12 months (T2). Concordance was studied by degree of correlation, comparison of mean scores, and change and difference between diagnostic groups. The Positive and Negative Symptom Scale (PANSS) was used to study convergent and discriminative properties. High concordance was found between AES-S and AES-C at both T1 and T2 regarding mean values, change from T1 to T2, and the proportion with high levels of apathy. Both versions indicated high levels of apathy in FEP, while associations with PANSS negative symptoms were weaker for AES-S than AES-C. Controlling for depression did not significantly alter results. We concluded that self-rated apathy in FEP patients is in concordance with clinician ratings, but in need of further study., (Copyright © 2018. Published by Elsevier B.V.)

Background: A potential link between increase in total cholesterol and triglycerides and clinical improvement has been observed during antipsychotic drug treatment in chronic schizophrenia patients, possibly due to drug related effects on lipid biosynthesis. We examined whether changes in serum lipids are associated with alleviation of psychosis symptoms after one year of antipsychotic drug treatment in a cohort of first-episode psychosis (FEP) patients., Methods: A total of 132 non-affective antipsychotic-treated FEP patients were included through the Norwegian Thematically Organized Psychosis (TOP) project. Data on antipsychotic usage, serum lipids (total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides (TG)), body mass index (BMI) and clinical state were obtained at baseline and after 12months. The Positive and Negative Syndrome Scale (PANSS) was used to assess psychotic symptoms. Mixed-effects models were employed to examine the relationship between serum lipids and psychotic symptoms while controlling for potential confounders including BMI., Results: An increase in HDL during one year of antipsychotic treatment was associated with reduction in PANSS negative subscores (B=-0.48, p=0.03). This relationship was not affected by concurrent change in BMI (adjusted HDL: B=-0.54, p=0.02). No significant associations were found between serum lipids, BMI and PANSS positive subscores., Conclusion: We found that an increase in HDL level during antipsychotic treatment is associated with improvement in negative symptoms in FEP. These findings warrant further investigation to clarify the interaction between lipid pathways and psychosis., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

The Notch signaling pathway plays a crucial role in neurodevelopment and in adult brain homeostasis. We aimed to further investigate Notch pathway activity in bipolar disorder (BD) and schizophrenia (SCZ) by conducting a pathway analysis. We measured plasma levels of Notch ligands (DLL1 and DLK1) using enzyme immunoassays in a large sample of patients (SCZ n = 551, BD n = 246) and healthy controls (HC n = 639). We also determined Notch pathway related gene expression levels by microarray analyses from whole blood in a subsample (SCZ n = 338, BD n = 241 and HC n = 263). We found significantly elevated Notch ligand levels in plasma in both SCZ and BD compared to HC. Significant gene expression findings included increased levels of RFNG and KAT2B (p < 0.001), and decreased levels of PSEN1 and CREBBP in both patient groups (p < 0.001). RBPJ was significantly lower in SCZ vs HC (p < 0.001), and patients using lithium had higher levels of RBPJ (p < 0.001). We provide evidence of altered Notch signaling in both SCZ and BD compared to HC, and suggest that Notch signaling pathway may be disturbed in these disorders. Lithium may ameliorate aberrant Notch signaling. We propose that drugs targeting Notch pathway could be relevant in the treatment of psychotic disorders.

The Wnt signaling pathway plays a crucial role in neurodevelopment and in regulating the function and structure of the adult nervous system. Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders with evidence of subtle neurodevelopmental, structural and functional neuronal abnormalities. We aimed to elucidate the role of aberrant regulation of the Wnt system in these disorders by evaluating plasma levels of secreted Wnt modulators in patients (SCZ = 551 and BD = 246) and healthy controls (HCs = 639) using enzyme immune-assay. We also investigated the expression of 141 Wnt-related genes in whole blood in a subsample (SCZ = 338, BD = 241, and HCs = 263) using microarray analysis. Both SCZ and BD had dysregulated mRNA expression of Wnt-related genes favoring attenuated canonical (beta-catenin-dependent) signaling, and there were also indices of enhanced non-canonical Wnt signaling. In particular, FZD7, which may activate all Wnt pathways, but favors non-canonical signaling, and NFATc3, a downstream transcription factor and readout of the non-canonical Wnt/Ca 2+ pathway, were significantly increased in SCZ and BD (p < 3 × 10 -4 ). Furthermore, patients had lower plasma levels of soluble dickkopf 1 and sclerostin (p < 0.01) compared with HC. Our findings suggest that SCZ and BD are characterized by abnormal Wnt gene expression and plasma protein levels, and we propose that drugs targeting the Wnt pathway may have a role in the treatment of severe mental disorders.

Background: Antipsychotic-associated side effects are well known and represent a significant treatment challenge. Still, few large studies have investigated the overall side effect burden of antipsychotics in real-life settings., Objective: To describe the occurrence of side effects and perceived burden of antipsychotics in a large naturalistic sample, taking polypharmacy and patient characteristics into account., Method: Patients (n=1087) with psychotic disorders were assessed for side effects using the Udvalg for Kliniske Undersøgelser (UKU) side effect rating scale in addition to assessment of clinical and pharmacological data. Statistical analyses were performed controlling for possible confounding factors., Results: Use of antipsychotics showed significant associations to neurologic and sexual symptoms, sedation and weight gain, and >75% of antipsychotics-users reported side effects. More side effects were observed in patients using several antipsychotics (p=0.002), with increasing total dose (p=0.021) and with antipsychotics in combinations with other psychotropic drugs. Patients and investigators evaluated the side effect burden differently, particularly related to severity, gender and antipsychotics dose. Twice as many females described side effect burden as severe (p=0.004)., Conclusion: Patients with psychotic disorders have a high occurrence of symptoms associated with use of antipsychotics, and polypharmacy and female gender are seemingly risk factors for reporting a severe side effect burden. Due to the cross-sectional design evaluation of causality is tentative, and these findings should be further investigated in prospective studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

Background: Several studies have described an association between childhood maltreatment and inflammatory markers in the psychotic disorders (schizophrenia [SZ] and bipolar disorder [BD]). Previous studies have been relatively small (<50 participants), and the severity of abuse and the putative influence of body mass index (BMI) have not been properly investigated., Methods: The combined effects of childhood abuse severity and clinical diagnosis on inflammatory markers were investigated in a large sample (n=483) of patients with a disorder on the psychosis spectrum and in healthy controls (HCs). Plasma levels of inflammatory markers (high-sensitivity C-reactive protein [hs-CRP], soluble tumor necrosis factor receptor type 1 [TNFR-R1], glycoprotein 130 [gp130]) were analyzed, and BMI and data on childhood trauma events, on the basis of the Childhood Trauma Questionnaire (CTQ), were obtained from all participants., Results: Patients had increased levels of hs-CRP (P<0.001, Cohens d=0.4), lower levels of gp130 (P<0.001, Cohens d=0.5), higher BMI (P<0.001, Cohens d=0.5) and reported more childhood maltreatment experiences (P<0.001, Cohens d=1.2) than the HC group. The severity of childhood abuse (up to three types of abuse: sexual abuse, physical abuse, and emotional abuse) was associated with elevated BMI (f=8.46, P<0.001, Cohen's d=0.5) and hs-CRP (f=5.47, P=0.001, Cohen's d=0.3). Combined effects of patient status and severity of childhood abuse were found for elevated hs-CRP (f=4.76, P<0.001, Cohen's d=0.4). Differences among the groups disappeared when BMI was added to the model., Discussion: Trauma-altered immune activation via elevated hs-CRP in patients with SZ and BD may be mediated by higher BMI; however, the direction of this association needs further clarification., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Antipsychotics are effective in treating psychosis and mood episodes; however, the effect on cognition is less known. We investigated the association between serum levels of second-generation antipsychotics (SGAs) and cognitive performance in psychosis spectrum disorders in a naturalistic setting., Methods: A total of 495 patients with a DSM-IV Schizophrenia and Other Psychotic Disorders (SCZ, n = 373) or Bipolar Disorder (BD, n = 122) diagnosis treated with olanzapine, quetiapine, aripiprazole or risperidone were tested neuropsychologically with concurrent measurement of the serum concentration of the drug. Linear regression was used for association analyses., Results: Attention was positively associated with the olanzapine concentration (standardised beta (β) coefficient = 0.19, P = .006), and short-term verbal memory and verbal fluency were negatively associated with the quetiapine (β = -0.24, P = .004) and risperidone (β = -0.37, P = .007) concentrations respectively., Conclusions: The present results suggest that SGA serum concentration is associated with better attention (small effect size), and worse verbal memory (small effect size) and verbal fluency (medium effect size). These findings are in line with the notion that SGAs affect aspects of cognitive function, and suggest careful dosing in patients with severe memory and executive problems.

Objective: A proinflammatory imbalance in the tumor necrosis factor (TNF) system may contribute to the pathogenesis of schizophrenia (SCZ) and bipolar disorders (BDs) and related comorbidities. We investigated the relative distribution of TNF-related molecules in blood and dorsolateral prefrontal cortex (DLPFC) in these disorders., Method: We measured plasma levels of TNF, soluble TNF receptor 1 (sTNFR1), soluble TNF receptor 2 (sTNFR2), and a disintegrin and metalloprotease-17 (ADAM17) using enzyme immunoassays and calculated the TNF/sTNFRs ratio (TNF/sTNFR1+sTNFR2) in a sample of 816 SCZ and BD spectrum patients and 624 healthy controls (HCs). TNF, TNFRSF1A (TNFR1), TNFRSF1B (TNFR2), and ADAM17 mRNA levels were determined in whole blood, and postmortem DLPFC obtained from an independent cohort (n = 80 SCZ, n = 44 BD, and n = 86 HC)., Results: In peripheral blood, we show increased TNF-related measures in patients compared to HC, with an increased TNF/sTNFRs ratio (p = 6.00 × 10-5), but decreased TNF mRNA expression (p = 1 × 10-4), with no differences between SCZ and BD. Whole blood ADAM17 mRNA expression was markedly higher in BD vs SCZ patients (p = 1.40 × 10-14) and vs HC (p = 1.22 × 10-8). In postmortem DLPFC, we found no significant differences in mRNA expression of TNF pathway genes between any groups., Conclusions: SCZ and BD patients have increased plasma TNF pathway markers without corresponding increase in blood cell gene expression. ADAM17 expression in leukocytes is markedly different between the two disorders, while alterations in TNF-related gene expression in DLPFC are uncertain. Further studies are necessary to elucidate the aberrant regulation of the TNF pathway in severe mental disorders., (© The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com)

There is growing interest in using intranasal oxytocin (OT) to treat social dysfunction in schizophrenia and bipolar disorders (i.e., psychotic disorders). While OT treatment results have been mixed, emerging evidence suggests that OT system dysfunction may also play a role in the etiology of metabolic syndrome (MetS), which appears in one-third of individuals with psychotic disorders and associated with increased mortality. Here we examine the evidence for a potential role of the OT system in the shared risk for MetS and psychotic disorders, and its prospects for ameliorating MetS. Using several studies to demonstrate the overlapping neurobiological profiles of metabolic risk factors and psychiatric symptoms, we show that OT system dysfunction may be one common mechanism underlying MetS and psychotic disorders. Given the critical need to better understand metabolic dysregulation in these disorders, future OT trials assessing behavioural and cognitive outcomes should additionally include metabolic risk factor parameters., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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 R 2 =0.113, F(6,357)=8.58, p<0.001) and with depression (adjusted R 2 =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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: The aim of the present study was to examine the effect of selective serotonin reuptake inhibitors (SSRIs) on cardiovascular risk factors in patients with schizophrenia or bipolar disorder., Method: We used data from a cross-sectional study on 1301 patients with schizophrenia or bipolar disorder, of whom 280 were treated with SSRIs. The primary outcome variable was the serum concentration of total cholesterol. Secondary outcome variables were low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, triglyceride and glucose levels, body mass index, waist circumference, and systolic and diastolic blood pressure., Results: After adjusting for potential confounders, an SSRI serum concentration in the middle of the reference interval was associated with an increase of the total cholesterol level by 14.56 mg/dL (95% confidence interval (CI) 5.27-23.85 mg/dL, P = 0.002), the LDL cholesterol level by 8.50 mg/dL (CI 0.22-16.77 mg/dL, P = 0.044), the triglyceride level by 46.49 mg/dL (CI 26.53-66.46 mg/dL, P < 0.001) and the occurrence of the metabolic syndrome by a factor of 2.10 (CI 1.21-3.62, P = 0.008). There were also significant associations between the SSRI dose and total cholesterol and LDL cholesterol levels., Conclusions: This study is the first to reveal significant associations between SSRI use and metabolic abnormalities in patients with schizophrenia or bipolar disorder. Although the effects were statistically significant, alterations were small. Thus, the clinical impact of the findings is most likely limited.

Background: Mood stabilizers like lithium and anticonvulsants are used in bipolar and related psychotic disorders. There is a lack of knowledge of the relationship of these medications and cognition in the psychosis spectrum. We studied the association between serum concentration of mood stabilizers and cognitive performance in a well-characterized sample of bipolar and schizophrenia spectrum disorders., Methods: Serum concentrations of valproate, lamotrigine, and lithium were analyzed for associations to performance on neuropsychological tests in six cognitive domains in individuals with bipolar disorder (n = 167) and in a combined sample of individuals with bipolar or schizophrenia spectrum disorders (n = 217). Linear regression with adjustments for gender, age, and symptom levels of depression, mania, and psychosis were applied for the association analyses., Results: There were negative associations between serum levels of valproate and short term delayed recall (bipolar: p = 0.043; combined: p = 0.044) and working memory (bipolar: p = 0.043). A positive association was suggested between serum level of lithium and working memory (bipolar: p = 0.039). There were no other significant relationships between serum levels of valproate, lamotrigine, or lithium and neuropsychological test performance in neither the bipolar disorder nor the combined group., Conclusions: Serum levels of mood stabilizers were unrelated to cognitive performance in most domains, indicating that higher dose does not lead to broader cognitive impairments in bipolar and related psychotic disorder patients. However, worsened memory with increasing levels of valproate suggests cautious dosing of anticonvulsants, while increasing lithium level seems to be associated with improved memory. The findings should be interpreted with caution due to the explorative, naturalistic design.

Schizophrenia is associated with decreased life expectancy (15-25 y) compared to the general population, with comorbid somatic diseases and in particular cardiovascular diseases being a major cause. Life style and medication probably account for much of the increased mortality risk due to somatic diseases in schizophrenia, but the evidence implicating biological pathways potentially affecting both body and brain is increasing. This includes overlapping genes between schizophrenia and somatic diseases, prenatal risk factors such as hypoxia and infections, and increased cardiovascular disease risk in drug-naïve patients at illness onset. Although environmental bias increases throughout the disease course, there are also some studies on chronic schizophrenia and postmortem brain samples that warrant further attention. In the following, we will attempt to move beyond environmental impact and explore some of the shared pathophysiological mechanisms potentially underlying both schizophrenia and somatic diseases., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: 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., Methods: 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., Results: 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., Discussion: 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.

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., (© The Royal College of Psychiatrists 2016.)

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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Cognitive impairment is a core feature of psychosis spectrum disorders. Antipsychotics have at best small positive effects on cognitive performance. There is a lack of knowledge regarding the effects of antidepressants on cognitive functioning in these disorders. In the present study cognitive performance was investigated in relation to serum levels of antidepressants in persons with bipolar disorder and schizophrenia. Serum concentrations of escitalopram, citalopram and venlafaxine plus O-desmethylvenlafaxine were measured in a total of 187 participants with bipolar disorder (N=74) or schizophrenia spectrum disorders (N=113), and analyzed in relation to neuropsychological tests performance of verbal learning, verbal memory, attention, working memory, executive functioning and processing speed. Analyses were performed using linear regression adjusting for a range of confounders. There was a significant positive association between the serum level of venlafaxine plus O-desmethylvenlafaxine and verbal memory (immediate recall: Logical Memory Test immediate recall [p=0.015], and long term delayed recall: Logical Memory Test delayed recall [p=0.011]). No significant associations were seen between citalopram or escitalopram and verbal memory. There were no significant associations between the tested antidepressants and verbal learning, attention, working memory, executive functioning, or processing speed. Venlafaxine seem to be associated with better verbal memory in bipolar disorder and schizophrenia. This suggests a possible beneficial role of certain antidepressants on cognitive dysfunction, which may have clinical implications and provide insight into underlying pathophysiology. However, the current findings should be replicated in independent samples., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

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.