Cellular adhesion molecules in drug-naïve and previously medicated patients with schizophrenia-spectrum disorders.

BACKGROUND: Endothelial inflammation may be involved in the pathogenesis of schizophrenia, and cellular adhesion molecules (CAMs) on endothelial cells may facilitate leukocyte binding and transendothelial migration of cells and inflammatory factors. The aim of the present study was to assess levels of soluble cellular adhesion molecules, including intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD) in patients with schizophrenia compared to healthy controls. METHODS: The study population consists of 138 patients with schizophrenia-spectrum disorder, of whom 54 were drug-naïve, compared to 317 general population controls. The potential confounders age, gender, smoking and body mass index (BMI) were adjusted for in linear regression models. RESULTS: The total patient group showed significantly higher levels of ICAM-1 (p < 0.001) and VCAM-1 (p < 0.001) compared to controls. Previously medicated patients showed higher ICAM-1 levels compared to drug-naïve patients (p = 0.042) and controls (p < 0.001), and elevated VCAM-1 levels compared to controls (p < 0.001). Drug-naive patients had elevated levels of VCAM-1 (p = 0.031) compared to controls. CONCLUSIONS: In our study, patients with schizophrenia - including the drug-naïve - have higher levels of soluble CAMs compared to healthy controls. These findings suggest activation of the endothelial system as in inflammation.

Toxoplasma gondii infection associated with inflammasome activation and neuronal injury.

Toxoplasma gondii (TOXO) infection typically results in chronic latency due to its ability to form cysts in the brain and other organs. Latent toxoplasmosis could promote innate immune responses and impact brain function. A large body of evidence has linked TOXO infection to severe mental illness (SMI). We hypothesized that TOXO immunoglobulin G (IgG) seropositivity, reflecting previous infection and current latency, is associated with increased circulating neuron-specific enolase (NSE), a marker of brain damage, and interleukin-18 (IL-18), an innate immune marker, mainly in SMI. We included 735 patients with SMI (schizophrenia or bipolar spectrum) (mean age 32 years, 47% women), and 518 healthy controls (HC) (mean age 33 years, 43% women). TOXO IgG, expressed as seropositivity/seronegativity, NSE and IL-18 were measured with immunoassays. We searched for main and interaction effects of TOXO, patient/control status and sex on NSE and IL-18. In the whole sample as well as among patients and HC separately, IL-18 and NSE concentrations were positively correlated (p < 0.001). TOXO seropositive participants had significantly higher NSE (3713 vs. 2200 pg/ml, p < 0.001) and IL-18 levels (1068 vs. 674 pg/ml, p < 0.001) than seronegative participants, and evaluation within patients and HC separately showed similar results. Post-hoc analysis on cytomegalovirus and herpes simplex virus 1 IgG status showed no associations with NSE or IL-18 which may suggest TOXO specificity. These results may indicate ongoing inflammasome activation and neuronal injury in people with TOXO infections unrelated to diagnosis.

Polygenic liability for antipsychotic dosage and polypharmacy - a real-world registry and biobank study.

Genomic prediction of antipsychotic dose and polypharmacy has been difficult, mainly due to limited access to large cohorts with genetic and drug prescription data. In this proof of principle study, we investigated if genetic liability for schizophrenia is associated with high dose requirements of antipsychotics and antipsychotic polypharmacy, using real-world registry and biobank data from five independent Nordic cohorts of a total of N = 21,572 individuals with psychotic disorders (schizophrenia, bipolar disorder, and other psychosis). Within regression models, a polygenic risk score (PRS) for schizophrenia was studied in relation to standardized antipsychotic dose as well as antipsychotic polypharmacy, defined based on longitudinal prescription registry data as well as health records and self-reported data. Meta-analyses across the five cohorts showed that PRS for schizophrenia was significantly positively associated with prescribed (standardized) antipsychotic dose (beta(SE) = 0.0435(0.009), p = 0.0006) and antipsychotic polypharmacy defined as taking ≥2 antipsychotics (OR = 1.10, CI = 1.05-1.21, p = 0.0073). The direction of effect was similar in all five independent cohorts. These findings indicate that genotypes may aid clinically relevant decisions on individual patients´ antipsychotic treatment. Further, the findings illustrate how real-world data have the potential to generate results needed for future precision medicine approaches in psychiatry.

Sex differences in autonomic adverse effects related to antipsychotic treatment and associated hormone profiles.

Autonomic adverse effects of antipsychotic drugs (APs) cause clinical challenges, but few studies have investigated sex differences and their underlying biological pathways. Sex-specific regulation of relevant hormones could be involved. We investigated sex differences in autonomic adverse effects related to olanzapine, quetiapine, risperidone, and aripiprazole, and the role of hormones related to APs. Patients with severe mental disorders (N = 1318) were included and grouped based on AP monotherapy: olanzapine (N = 364), quetiapine (N = 211), risperidone (N = 102), aripiprazole (N = 138), and no AP (N = 503). Autonomic symptoms from the Udvalg for Kliniske Undersøgelser (UKU) side effect scale was analyzed with logistic regression, adjusting for age, diagnosis, and polypharmacy. Further, we analyzed associations between autonomic symptoms and hormones related to APs. We found associations between autonomic adverse effects and APs, with sex-specific risk for palpitations/tachycardia associated with hormonal changes related to APs. Results showed increased salivation associated with aripiprazole, reduced salivation with quetiapine, and nausea/vomiting and palpitations/tachycardia with olanzapine, and higher risk of nausea/vomiting, diarrhea, constipation, polyuria/polydipsia, and palpitations/tachycardia in females. Significant sex x AP interaction was found for palpitations/tachycardia, with higher risk in risperidone-treated males, which was associated with different hormone profiles of prolactin, cortisol, and insulin. Our findings implicate a role of several hormones in the sex-specific autonomic adverse effects related to APs.

Tobacco smoking related to childhood trauma mediated by cognitive control and impulsiveness in severe mental disorders.

BACKGROUND: People with severe mental disorders (SMDs) show an increased prevalence of tobacco smoking compared to the general population. Tobacco smoking and other adult adverse health behaviors have been associated with traumatic experiences in childhood. In the present study we investigated the relationship between childhood trauma and tobacco smoking in people with SMDs, including the possible mediating role of cognitive- and personality characteristics, i.e. cognitive control, impulsiveness, affective lability and self-esteem. METHODS: Enrolled in the study were 871 participants with schizophrenia (SCZ, N = 484) and bipolar (BD, N = 387) spectrum disorders. We assessed tobacco smoking behavior (yes/no and amount), and history of childhood trauma with the Childhood Trauma Questionnaire. Data on cognitive control, impulsiveness, affective lability, and self-esteem were available in subsamples. We performed linear and logistic regressions, and conducted mediation analyses in PROCESS. All analyses were as standard adjusted for age, sex, and diagnostic group. RESULTS: Experience of one or more subtypes of childhood trauma was significantly associated with smoking tobacco in SMDs (p = 0.002). There were no significant associations between childhood trauma and amount of tobacco smoking. Cognitive control and impulsiveness were significant mediators between childhood trauma and tobacco smoking. CONCLUSIONS: These findings indicate the experience of childhood trauma as a predisposing factor for tobacco smoking in SMDs. Cognitive control and impulsiveness were suggested as mediating mechanisms, indicating the importance of considering inhibition related self-regulatory aspects in efforts to improve health behavior in individuals with SMDs and childhood trauma.

Impulsivity across severe mental disorders: a cross-sectional study of immune markers and psychopharmacotherapy.

BACKGROUND: Impulsivity is a transdiagnostic feature linked to severe clinical expression and a potential target for psychopharmacological strategies. Biological underpinnings are largely unknown, but involvement of immune dysregulation has been indicated, and the effects of psychopharmacological agents vary. We investigated if impulsivity was associated with circulating immune marker levels and with a range of psychopharmacological treatment regimens in severe mental disorders. METHODS: Impulsivity was assessed in a sample (N = 657) of patients with schizophrenia or schizophreniform disorder (SCZ) (N = 116) or bipolar disorder (BD) (N = 159) and healthy participants (N = 382) using the Barratt Impulsiveness Scale (BIS-11) questionnaire. Plasma levels of systemic immune markers (RANTES, IL-1RA, IL-18, IL-18BP, sTNFR-1) were measured by enzyme immunoassays. Patients underwent thorough clinical assessment, including evaluation of psychotropic medication. Associations were assessed using linear regressions. RESULTS: Impulsivity  was positively associated with SCZ (p < 0.001) and BD (p < 0.001) diagnosis and negatively associated with age (p < 0.05), but not significantly associated with any of the circulating immune markers independently of diagnostic status. Among patients, impulsivity was negatively associated with lithium treatment (p = 0.003) and positively associated with antidepressant treatment (p = 0.011) after controlling for diagnosis, psychotropic co-medications, manic symptoms, and depressive symptoms. CONCLUSIONS: We report elevated impulsivity across SCZ and BD but no associations to systemic immune dysregulation based on the current immune marker selection. The present study reveals associations between impulsivity in severe mental disorders and treatment with lithium and antidepressants, with opposite directions. Future studies are warranted to determine the causal directionality of the observed associations with psychopharmacotherapy.

Characterizing the Shared Genetic Underpinnings of Schizophrenia and Cardiovascular Disease Risk Factors.

OBJECTIVE: Schizophrenia is associated with increased risk of cardiovascular disease (CVD), although there is variation in risk among individuals. There are indications of shared genetic etiology between schizophrenia and CVD, but the nature of the overlap remains unclear. The aim of this study was to fill this gap in knowledge. METHODS: Overlapping genetic architectures between schizophrenia and CVD risk factors were assessed by analyzing recent genome-wide association study (GWAS) results. The bivariate causal mixture model (MiXeR) was applied to estimate the number of shared variants and the conjunctional false discovery rate (conjFDR) approach was used to pinpoint specific shared loci. RESULTS: Extensive genetic overlap was found between schizophrenia and CVD risk factors, particularly smoking initiation (N=8.6K variants) and body mass index (BMI) (N=8.1K variants). Several specific shared loci were detected between schizophrenia and BMI (N=304), waist-to-hip ratio (N=193), smoking initiation (N=293), systolic (N=294) and diastolic (N=259) blood pressure, type 2 diabetes (N=147), lipids (N=471), and coronary artery disease (N=35). The schizophrenia risk loci shared with smoking initiation had mainly concordant effect directions, and the risk loci shared with BMI had mainly opposite effect directions. The overlapping loci with lipids, blood pressure, waist-to-hip ratio, type 2 diabetes, and coronary artery disease had mixed effect directions. Functional analyses implicated mapped genes that are expressed in brain tissue and immune cells. CONCLUSIONS: These findings indicate a genetic propensity to smoking and a reduced genetic risk of obesity among individuals with schizophrenia. The bidirectional effects of the shared loci with the other CVD risk factors may imply differences in genetic liability to CVD across schizophrenia subgroups, possibly underlying the variation in CVD comorbidity.

Patients with schizophrenia and bipolar disorder display a similar global gene expression signature in whole blood that reflects elevated proportion of immature neutrophil cells with association to lipid changes.

Schizophrenia (SCZ) and bipolar disorder (BD) share clinical characteristics, genetic susceptibility, and immune alterations. We aimed to identify differential transcriptional patterns in peripheral blood cells of patients with SCZ or BD versus healthy controls (HC). We analyzed microarray-based global gene expression data in whole blood from a cohort of SCZ (N = 329), BD (N = 203) and HC (N = 189). In total, 65 genes were significantly differentially expressed in SCZ and 125 in BD, as compared to HC, with similar ratio of up- and downregulated genes in both disorders. Among the top differentially expressed genes, we found an innate immunity signature that was shared between SCZ and BD, consisting of a cluster of upregulated genes (e.g., OLFM4, ELANE, BPI and MPO) that indicate an increased fraction of immature neutrophils. Several of these genes displayed sex differences in the expression pattern, and post-hoc analysis demonstrated a positive correlation with triglyceride and a negative correlation with HDL cholesterol. We found that many of the downregulated genes in SCZ and BD were associated with smoking. These findings of neutrophil granulocyte-associated transcriptome signatures in both SCZ and BD point at altered innate immunity pathways with association to lipid changes and potential for clinical translation.

Preventive Medication Patterns in Bipolar Disorder and Their Relationship With Comorbid Substance Use Disorders in a Cross-National Observational Study.

Objective: The potential role of sub-optimal pharmacological treatment in the poorer outcomes observed in bipolar disorder (BD) with vs. without comorbid substance use disorders (SUDs) is not known. Thus, we investigated whether patients with BD and comorbid SUD had different medication regimens than those with BD alone, in samples from France and Norway, focusing on compliance to international guidelines. Methods: Seven hundred and seventy patients from France and Norway with reliably ascertained BD I or II (68% BD-I) were included. Medication information was obtained from patients and hospital records, and preventive treatment was categorized according to compliance to guidelines. We used Bayesian and regression analyses to investigate associations between SUD comorbidity and medication. In the Norwegian subsample, we also investigated association with lack of medication. Results: Comorbid SUDs were as follows: current tobacco smoking, 26%, alcohol use disorder (AUD), 16%; cannabis use disorder (CUD), 10%; other SUDs, 5%. Compliance to guidelines for preventive medication was lacking in 8%, partial in 44%, and complete in 48% of the sample. Compliance to guidelines was not different in BD with and without SUD comorbidity, as was supported by Bayesian analyses (highest Bayes Factor = 0.16). Cross national differences in treatment regimens led us to conduct country-specific adjusted regression analyses, showing that (1) CUD was associated with increased antipsychotics use in France (OR = 2.4, 95% CI = 1.4-3.9, p = 0.001), (2) current tobacco smoking was associated with increased anti-epileptics use in Norway (OR = 4.4, 95% CI = 1.9-11, p < 0.001), and (3) AUD was associated with decreased likelihood of being medicated in Norway (OR = 1.2, 95% CI = 1.04-1.3, p = 0.038). Conclusion: SUD comorbidity in BD was overall not associated with different pharmacological treatment in our sample, and not related to the level of compliance to guidelines. We found country-specific associations between comorbid SUDs and specific medications that warrant further studies.

Lifetime Cannabis Use Is Not Associated With Negative Beliefs About Medication in Patients With First Treatment Psychosis.

Objective: Cannabis use is common among patients with psychosis, and along with negative beliefs about medication, it has been found to predict poor adherence to antipsychotic drug treatment. Such lack of adherence to antipsychotic drug treatment increases the risk of poor clinical outcomes and relapse in patients with first treatment for psychosis (FTP). However, to date, it is unclear whether cannabis use may be related to negative perceptions about antipsychotic drug treatment. Methods: A cross-sectional sample of 265 FTP patients with schizophrenia spectrum disorder underwent extensive clinical assessments. Three measures of cannabis use were obtained: lifetime, current and meeting diagnostic criteria for abuse or addiction. For the primary analyses we focused on lifetime cannabis use. The Beliefs about Medication Questionnaire (BMQ) was employed to assess the patients' specific concerns and perceptions of antipsychotic medications, as well as general beliefs about pharmacotherapy. The relationship between lifetime cannabis use and BMQ scores was investigated with general linear model (GLM) analyses, controlling for age and sex. Results: Patients with lifetime use of cannabis ≥10 times were more likely to be male, younger at the age of onset of psychosis and with higher levels of alcohol use and daily tobacco smoking, as compared to the non-users (p < 0.05). Neither lifetime use of cannabis, current use nor a cannabis abuse diagnosis was associated with negative beliefs about medicines as measured by the BMQ questionnaire. Conclusion: Use of cannabis is not linked to negative perceptions about antipsychotic medicines in patients with FTP. Other reasons for poor compliance to antipsychotic drug treatment in cannabis users need to be further investigated.

Sex differences in antipsychotic-related triglyceride levels are associated with metabolic hormone differences in patients with severe mental disorders.

BACKGROUND: Adverse effects of antipsychotics (AP) contribute to cardiovascular disease (CVD) risk in patients with severe mental disorders (SMD). We investigated sex differences in AP-related CVD risk factors and the role of metabolic hormones. METHODS: Patients with SMD (N = 1791) receiving AP with different CVD risk were recruited and grouped into olanzapine and/or clozapine (N = 532), other APs (N = 744) or no use of APs (N = 515). Associations between CVD risk factor (total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), body mass index (BMI), glucose, blood pressure), sex and AP groups were tested in multiple linear regression with interactions, controlling for diagnostic group, lifestyle factors, polypharmacy, age and ethnicity. Next, we tested associations between sex differences in AP-related CVD risk factors and metabolic regulatory hormones. RESULTS: AP groups and male sex were significantly associated with higher levels of LDL-C, TG and BMI, and lower levels of HDL-C. Significant interaction between AP groups and sex were found for TG (p = 0.017), with larger increase in males. Serum adiponectin, insulin, cortisol, leptin, testosterone, free thyroxine and thyroid-stimulating hormone (TSH) were associated with TG levels (all p ≤ 0.001), and a significant interaction with sex for insulin (p = 0.005), cortisol (p = 0.016), leptin (p < 0.001) and TSH (p = 0.001). CONCLUSIONS: We found more severe AP-related CVD risk factors in male patients with SMD. The male-dependent increase in TG levels was associated with leptin, insulin, cortisol and TSH levels. Clinicians treating patients with SMD should be aware of increased vulnerability for AP-related lipid abnormalities in males.

Interleukin-18 signaling system links to agitation in severe mental disorders.

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 (ß = 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 (ß = 0.06, t = 1.27, p = 0.20), IL-18 (ß = 0.05, t = 1.25, p = 0.21), IL-18R1 (ß = 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.

Plasma Levels of the Cytokines B Cell-Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) in Schizophrenia, Bipolar, and Major Depressive Disorder: A Cross Sectional, Multisite Study.

BACKGROUND: Immune dysfunction has been implicated in the pathogenesis of schizophrenia and other nonaffective psychosis (SCZ), bipolar spectrum disorder (BIP) and major depressive disorder (MDD). The cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) super family and are essential in orchestrating immune responses. Abnormal levels of BAFF and APRIL have been found in autoimmune diseases with CNS affection. METHODS: We investigated if plasma levels of BAFF and APRIL differed between patients with SCZ, BIP, and MDD with psychotic symptoms (n = 2009) and healthy control subjects (HC, n = 1212), and tested for associations with psychotic symptom load, controlling for sociodemographic status, antipsychotic and other psychotropic medication, smoking, body-mass-index, and high sensitivity CRP. RESULTS: Plasma APRIL level was significantly lower across all patient groups compared to HC (P < .001; Cohen's d = 0.33), and in SCZ compared to HC (P < .001; d = 0.28) and in BIP compared to HC (P < .001; d = 0.37). Lower plasma APRIL was associated with higher psychotic symptom load with nominal significance (P = .017), but not with any other clinical characteristics. Plasma BAFF was not significantly different across patient groups vs HC, but significantly higher in BIP compared to HC (P = .040; d = 0.12) and SCZ (P = .027; d = 0.10). CONCLUSIONS: These results show aberrant levels of BAFF and APRIL and association with psychotic symptoms in patients with SCZ and BIP. This suggest that dysregulation of the TNF system, mediated by BAFF and APRIL, is involved in the pathophysiology of psychotic disorders.

Cardiometabolic risk factors associated with brain age and accelerate brain ageing.

The structure and integrity of the ageing brain is interchangeably linked to physical health, and cardiometabolic risk factors (CMRs) are associated with dementia and other brain disorders. In this mixed cross-sectional and longitudinal study (interval mean = 19.7 months), including 790 healthy individuals (mean age = 46.7 years, 53% women), we investigated CMRs and health indicators including anthropometric measures, lifestyle factors, and blood biomarkers in relation to brain structure using MRI-based morphometry and diffusion tensor imaging (DTI). We performed tissue specific brain age prediction using machine learning and performed Bayesian multilevel modeling to assess changes in each CMR over time, their respective association with brain age gap (BAG), and their interaction effects with time and age on the tissue-specific BAGs. The results showed credible associations between DTI-based BAG and blood levels of phosphate and mean cell volume (MCV), and between T1-based BAG and systolic blood pressure, smoking, pulse, and C-reactive protein (CRP), indicating older-appearing brains in people with higher cardiometabolic risk (smoking, higher blood pressure and pulse, low-grade inflammation). Longitudinal evidence supported interactions between both BAGs and waist-to-hip ratio (WHR), and between DTI-based BAG and systolic blood pressure and smoking, indicating accelerated ageing in people with higher cardiometabolic risk (smoking, higher blood pressure, and WHR). The results demonstrate that cardiometabolic risk factors are associated with brain ageing. While randomized controlled trials are needed to establish causality, our results indicate that public health initiatives and treatment strategies targeting modifiable cardiometabolic risk factors may also improve risk trajectories and delay brain ageing.

Exploring low grade inflammation by soluble urokinase plasminogen activator receptor levels in schizophrenia: a sex-dependent association with depressive symptoms.

BACKGROUND: There is evidence of increased low grade inflammation (LGI) in schizophrenia patients. However, the inter-individual variation is large and the association with demographic, somatic and psychiatric factors remains unclear. Our aim was to explore whether levels of the novel LGI marker soluble urokinase plasminogen activator receptor (suPAR) were associated with clinical factors in schizophrenia and if such associations were sex-dependent. METHOD: In this observational study a total of 187 participants with schizophrenia (108 males, 79 females) underwent physical examination and assessment with clinical interviews (Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Alcohol Use Disorder Identification Test (AUDIT), and Drug Use Disorder Identification Test (DUDIT)). Blood levels of suPAR, glucose, lipids, and high sensitivity C-reactive protein (hsCRP) were determined and body mass index (BMI) calculated. Multivariable linear regression analyses were used adjusting for confounders, and sex interaction tested in significant variables. RESULTS: Adjusting for sex, age, current tobacco smoking and BMI, we found that levels of hsCRP and depressive symptoms (CDSS) were positively associated with levels of suPAR (p < 0.001). The association between suPAR and CDSS score was significant in females (p < 0.001) but not in males. Immune activation measured by hsCRP was not associated with depressive symptoms after adjusting for BMI. CONCLUSION: Our findings indicate that increased suPAR levels are associated with depressive symptoms in females with schizophrenia, suggesting aberrant immune activation in this subgroup. Our results warrant further studies, including longitudinal follow-up of suPAR levels in schizophrenia and experimental studies of mechanisms.

Characterising the shared genetic determinants of bipolar disorder, schizophrenia and risk-taking.

Increased risk-taking is a central component of bipolar disorder (BIP) and is implicated in schizophrenia (SCZ). Risky behaviours, including smoking and alcohol use, are overrepresented in both disorders and associated with poor health outcomes. Positive genetic correlations are reported but an improved understanding of the shared genetic architecture between risk phenotypes and psychiatric disorders may provide insights into underlying neurobiological mechanisms. We aimed to characterise the genetic overlap between risk phenotypes and SCZ, and BIP by estimating the total number of shared variants using the bivariate causal mixture model and identifying shared genomic loci using the conjunctional false discovery rate method. Summary statistics from genome wide association studies of SCZ, BIP, risk-taking and risky behaviours were acquired (n = 82,315-466,751). Genomic loci were functionally annotated using FUMA. Of 8.6-8.7 K variants predicted to influence BIP, 6.6 K and 7.4 K were predicted to influence risk-taking and risky behaviours, respectively. Similarly, of 10.2-10.3 K variants influencing SCZ, 9.6 and 8.8 K were predicted to influence risk-taking and risky behaviours, respectively. We identified 192 loci jointly associated with SCZ and risk phenotypes and 206 associated with BIP and risk phenotypes, of which 68 were common to both risk-taking and risky behaviours and 124 were novel to SCZ or BIP. Functional annotation implicated differential expression in multiple cortical and sub-cortical regions. In conclusion, we report extensive polygenic overlap between risk phenotypes and BIP and SCZ, identify specific loci contributing to this shared risk and highlight biologically plausible mechanisms that may underlie risk-taking in severe psychiatric disorders.

Shared Genetic Loci Between Body Mass Index and Major Psychiatric Disorders: A Genome-wide Association Study.

Importance: People with major psychiatric disorders (MPDs) have a 10- to 20-year shorter life span than the rest of the population, and this difference is mainly due to comorbid cardiovascular diseases. Genome-wide association studies have identified common variants involved in schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MD) and body mass index (BMI), a key cardiometabolic risk factor. However, genetic variants jointly influencing MPD and BMI remain largely unknown. Objective: To assess the extent of the overlap between the genetic architectures of MPDs and BMI and identify genetic loci shared between them. Design, Setting, and Participants: Using a conditional false discovery rate statistical framework, independent genome-wide association study data on individuals with SCZ (n = 82 315), BIP (n = 51 710), MD (n = 480 359), and BMI (n = 795 640) were analyzed. The UK Biobank cohort (n = 29 740) was excluded from the MD data set to avoid sample overlap. Data were collected from August 2017 to May 2018, and analysis began July 2018. Main Outcomes and Measures: The primary outcomes were a list of genetic loci shared between BMI and MPDs and their functional pathways. Results: Genome-wide association study data from 1 380 284 participants were analyzed, and the genetic correlation between BMI and MPDs varied (SCZ: r for genetic = -0.11, P = 2.1 × 10-10; BIP: r for genetic = -0.06, P = .0103; MD: r for genetic = 0.12, P = 6.7 × 10-10). Overall, 63, 17, and 32 loci shared between BMI and SCZ, BIP, and MD, respectively, were analyzed at conjunctional false discovery rate less than 0.01. Of the shared loci, 34% (73 of 213) in SCZ, 52% (36 of 69) in BIP, and 57% (56 of 99) in MD had risk alleles associated with higher BMI (conjunctional false discovery rate <0.05), while the rest had opposite directions of associations. Functional analyses indicated that the overlapping loci are involved in several pathways including neurodevelopment, neurotransmitter signaling, and intracellular processes, and the loci with concordant and opposite association directions pointed mostly to different pathways. Conclusions and Relevance: In this genome-wide association study, extensive polygenic overlap between BMI and SCZ, BIP, and MD were found, and 111 shared genetic loci were identified, implicating novel functional mechanisms. There was mixture of association directions in SCZ and BMI, albeit with a preponderance of discordant ones.

Association between serum lipid levels, osteoprotegerin and depressive symptomatology in psychotic 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 [ß = 0.13, p = 0.007; ß = 0.14, p = 0.007], and with two inflammatory markers: CRP [ß = 0.14, p = 0.007; ß = 0.16, p = 0.007] and OPG [ß = 0.14, p = 0.007; ß = 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.

Free thyroxine and thyroid-stimulating hormone in severe mental disorders: A naturalistic study with focus on antipsychotic medication.

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.

Side effect burden of antipsychotic drugs in real life - Impact of gender and polypharmacy.

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.