Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation

Background Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients. Methods We tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n = 1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n = 1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers. Results We report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA, IL-18R1), and increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol types and the expression of inflammasome system elements in SMI. Conclusions Based on these results, we suggest a role for inflammasome activation/dysregulation in SMI. Our findings further the understanding of possible underlying inflammatory mechanisms and may expose important therapeutic targets in SMI.publishedVersio

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6–11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Background: Alzheimer's disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer's Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR=0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR=0.022, opposite direction of effect). Conclusions: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP

Fylkesvise forskjeller i forskrivning av klozapin

BAKGRUNN Nasjonale retningslinjer anbefaler å tilby klozapin til pasienter med schizofreni etter to mislykkede forsøk med andre antipsykotiske legemidler. En av hovedmålsettingene med innføringen av pakkeforløp i psykisk helsevern er å gi et likeverdig tilbud til pasienter uavhengig av hvor i landet de bor. Vi ønsket å undersøke forskrivningen av klozapin i ulike fylker i Norge. MATERIALE OG METODE Vi hentet aggregerte data fra Reseptregisteret, Norsk pasientregister og Statistisk sentralbyrå på forskrivning av klozapin, antall pasienter i kontakt med spesialisthelsetjenesten under diagnosen schizofreni og befolkningstall for året 2016. RESULTATER I 2016 var det på landsbasis 50 (95 % KI 48–52) brukere av klozapin per 100 000 innbyggere. Antallet var høyest i Troms (76 (95 % KI 63–89) per 100 000 innbyggere) og lavest i Akershus (38 (95 % KI 33–43) per 100 000 innbyggere). Vi fant ingen signifikant korrelasjon mellom forskrivningsraten av klozapin og andelen av befolkningen i fylket under behandling for schizofreni i spesialisthelsetjenesten. FORTOLKNING Forskrivningen av klozapin varierer mellom norske fylker og er ikke korrelert med andelen av befolkningen under behandling for schizofreni i spesialisthelsetjenesten. En mulig forklaring på de geografiske forskjellene er ulik grad av implementering av nasjonale retningslinjer

Mortality among patients discharged from an acute psychiatric department: A 5-year prospective study

The primary aim of the study was to explore the post discharge standardized mortality ratio of patients from an acute psychiatric department in Norway. The secondary aims were to explore if the standardized mortality ratio is still increasing and to examine the causes of death in the defined population. We conducted a 5-year prospective study among patients admitted to an acute psychiatric department with catchment area responsibilities. A total of 380 patients were included in the study, and the number and causes of deaths were obtained from the Norwegian Cause of Death Registry. Excess mortality was found for the patient group. The standardized mortality ratio for all causes of death was 6.7 (95% CI, 4.6–8.8). The study finds an increased standardized mortality ratio relative to a previous corresponding study in Norway, and the suicide risk was especially elevated the first 2 years after discharge

Clinical characteristics of patients with bipolar disorder and premorbid traumatic brain injury: a cross-sectional study

Background About one in ten diagnosed with bipolar disorder (BD) has experienced a premorbid traumatic brain injury (TBI), while not fulfilling the criteria of bipolar and related disorder due to another medical condition (BD due to TBI). We investigated whether these patients have similar clinical characteristics as previously described in BD due to TBI (i.e. more aggression and irritability and an increased hypomania/mania:depression ratio) and other distinct clinical characteristics. Methods Five hundred five patients diagnosed with BD type I, type II, or not otherwise specified, or cyclothymia were interviewed about family, medical, and psychiatric history, and assessed with the Young Mania Rating Scale (YMRS) and the Inventory of Depressive Symptoms Clinician Rated 30 (IDS-C30). Principal component analyses of YMRS and IDS-C30 were conducted. Bivariate analyses and logistic regression analyses were used to compare clinical characteristics between patients with (n = 37) and without (n = 468) premorbid TBI. Results Premorbid TBI was associated with a higher YMRS disruptive component score (OR 1.7, 95% CI 1.1–2.4, p = 0.0077) and more comorbid migraine (OR 4.6, 95% CI 1.9–11, p = 0.00090) independently of several possible confounders. Items on disruptive/aggressive behaviour and irritability had the highest loadings on the YMRS disruptive component. Premorbid TBI was not associated with an increased hypomania/mania:depression ratio. Conclusions Disruptive symptoms and comorbid migraine characterize BD with premorbid TBI. Further studies should examine whether the partial phenomenological overlap with BD due to TBI could be explained by a continuum of pathophysiological effects of TBI across the diagnostic dichotomy

Epilepsy and other seizure disorders in acute psychiatric inpatients

Background: It is well known that patients with epilepsy have a high rate of psychiatric comorbidity. However, studies exploring epilepsy in psychiatric cohorts are scarce. The aim of this study was to examine the prevalence of seizure disorders in acute psychiatric inpatients. Methods: This is a cross-sectional study performed in a catchment-area based acute psychiatric department. All patients (age > 18) admitted during September 2011 - March 2012 were eligible for inclusion. Consenting patients were screened for a life-time history of epilepsy or seizures using self-reported questionnaire data and diagnostic codes for epilepsy in hospital and National registries. Patients scoring positive to one or more of these screening criteria underwent a thorough diagnostic validation (chart review), and the seizure disorders were classified as epilepsy, acute symptomatic seizures and/or psychogenic non-epileptic seizures according to current definitions. Results: A total of 380 out of 591 (64.3%) consecutively admitted patients consented to participate in the study. Eighty-nine patients (23.4%) scored positive to one or more screening criteria. Fifteen (3.9%) were classified with epilepsy, 21 (5.5%) with acute symptomatic seizures and 9 (2.4%) with psychogenic non-epileptic seizures. Conclusions: This is the first study to report on the prevalence of seizure disorders in acute psychiatric inpatients. The life-time prevalence of epilepsy in this cohort of patients is five - six times as high as reports in the general population. These findings underscore the need for the clinical psychiatrist to have comprehensive knowledge on the interface between epileptology and psychiatry. Trials registration: ClinicalTrials.gov identifier NCT01415323