White blood cell counts, ratios, and C-reactive protein among individuals with schizophrenia spectrum disorder and associations with long-term outcomes: a population-based study.

BACKGROUND: Immune mechanisms are associated with adverse outcomes in schizophrenia; however, the predictive value of various peripheral immune biomarkers has not been collectively investigated in a large cohort before. OBJECTIVE: To investigate how white blood cell (WBC) counts, ratios, and C-Reactive Protein (CRP) levels influence the long-term outcomes of individuals with schizophrenia spectrum disorder (SSD). METHODS: We identified all adults in the Central Denmark Region during 1994-2013 with a measurement of WBC counts and/or CRP at first diagnosis of SSD. WBC ratios were calculated, and both WBC counts and ratios were quartile-categorized (Q4 upper quartile). We followed these individuals from first diagnosis until outcome of interest (death, treatment resistance and psychiatric readmissions), emigration or December 31, 2016, using Cox regression analysis to estimate adjusted hazard ratios (aHRs). RESULTS: Among 6,845 participants, 375 (5.5 %) died, 477 (6.9 %) exhibited treatment resistance, and 1470 (21.5 %) were readmitted during follow-up. Elevated baseline levels of leukocytes, neutrophils, monocytes, LLR, NLR, MLR, and CRP increased the risk of death, whereas higher levels of lymphocytes, platelets, and PLR were associated with lower risk. ROC analysis identified CRP as the strongest predictor for mortality (AUC=0.84). Moreover, elevated levels of leukocytes, neutrophils, monocytes, LLR, NLR and MLR were associated with treatment resistance. Lastly, higher platelet counts decreased the risk of psychiatric readmissions, while elevated LLR increased this risk. CONCLUSIONS: Elevated levels of WBC counts, ratios, and CRP at the initial diagnosis of SSD are associated with mortality, with CRP demonstrating the highest predictive value. Additionally, certain WBC counts and ratios are associated with treatment resistance and psychiatric readmissions.

Traumatic brain injury and long-term associations with work, divorce and academic achievement.

OBJECTIVE: Traumatic brain injuries (TBI), irrespective of severity, may have long-term social implications. This study explores the relationships between TBI severity and outcomes related to work stability, divorce, and academic achievement. METHODS: Using a Danish nationwide sample of persons with and without TBI, we employed case-control and longitudinal cohort designs. The case-control design utilized individuals aged 18 to 60 years and examined work stability. Each case, employed at time of TBI, was compared with 10 matched controls. The cohort design utilized individuals alive from 1980 to 2016 with and without TBI and assessed the likelihood of 1) divorce and 2) higher-level education. TBI exposures included concussion, skull fractures, or confirmed TBI. RESULTS: TBI cases exhibited higher odds ratios (OR) for work instability at all follow-ups compared to controls. Increased TBI severity was associated with a higher risk of work instability at 2-year follow-up (concussion: OR = 1.83; skull fracture: OR = 2.22; confirmed TBI: OR = 4.55), and with a higher risk of not working at 10-year follow-up (confirmed TBI: OR = 2.82; concussion: OR = 1.63). The divorce incidence rate ratio (IRR) was elevated in individuals with TBI (males: IRR = 1.52; females: IRR = 1.48) compared to those without TBI. Individuals with childhood TBI had reduced chances of attaining high school degree or higher (males: IRR = 0.79; females: IRR = 0.85) compared to those without TBI. CONCLUSION: TBI is associated with an increased long-term risk of social consequences, including work instability, divorce, and diminished chances of higher education, even in cases with concussion.

Brain network changes and cognitive function after cardiac arrest.

Survival rates after out-of-hospital cardiac arrest have improved over the past two decades. Despite this progress, long-term cognitive impairment remains prevalent even in those with early recovery of consciousness after out-of-hospital cardiac arrest; however, little is known about the determinants and underlying mechanisms. We utilized the REcovery after cardiac arrest surVIVAL cohort of out-of-hospital cardiac arrest survivors who fully regained consciousness to correlate cognition measurements with brain network changes using resting-state functional MRI and the Montreal Cognitive Assessment at hospital discharge and a comprehensive neuropsychological assessment at three-month follow-up. About half of out-of-hospital cardiac arrest survivors displayed cognitive impairments at discharge, and in most, cognitive deficits persisted at three-month follow-up, particularly in the executive and visuospatial functions. Compared to healthy controls, out-of-hospital cardiac arrest survivors exhibited increased connectivity between resting-state networks, particularly involving the frontoparietal network. The increased connectivity between the frontoparietal and visual networks was associated with less favourable cognitive outcomes (ß = 14.0, P = 0.01), while higher education seemed to confer some cognitive protection (ß = -2.06, P = 0.03). In sum, the data highlight the importance of subtle cognitive impairment, also in out-of-hospital cardiac arrest survivors who are eligible for home discharge, and the potential of functional MRI to identify alterations in brain networks correlating with cognitive outcomes.

Trends in Incidence of Hospitalization for Hypoglycemia and Diabetic Ketoacidosis in Individuals With Type 1 or Type 2 Diabetes With and Without Severe Mental Illness in Denmark From 1996 to 2020: A Nationwide Study.

OBJECTIVE: To examine trends in incidence of acute diabetes complications in individuals with type 1 or type 2 diabetes with and without severe mental illness (SMI) in Denmark by age and calendar year. RESEARCH DESIGN AND METHODS: We conducted a cohort study using nationwide registers from 1996 to 2020 to identify individuals with diabetes, ascertain SMI status (namely, schizophrenia, bipolar disorder, or major depression) and identify the outcomes: hospitalization for hypoglycemia and diabetic ketoacidosis (DKA). We used Poisson regression to estimate incidence rates (IRs) and incidence rate ratios (IRRs) of recurrent hypoglycemia and DKA events by SMI, age, and calendar year, accounting for sex, diabetes duration, education, and country of origin. RESULTS: Among 433,609 individuals with diabetes, 8% had SMI. Risk of (first and subsequent) hypoglycemia events was higher for individuals with SMI than for those without SMI (for first hypoglycemia event, IRR: type 1 diabetes, 1.77 [95% CI 1.56-2.00]; type 2 diabetes, 1.64 [95% CI 1.55-1.74]). Individuals with schizophrenia were particularly at risk for recurrent hypoglycemia events. The risk of first DKA event was higher in individuals with SMI (for first DKA event, IRR: type 1 diabetes, 1.78 [95% CI 1.50-2.11]; type 2 diabetes, 1.85 [95% CI 1.64-2.09]). Except for DKA in the type 2 diabetes group, IR differences between individuals with and without SMI were highest in younger individuals (<50 years old) but stable across the calendar year. CONCLUSIONS: SMI is an important risk factor for acute diabetes complication and effective prevention is needed in this population, especially among the younger population and those with schizophrenia.

Association of symptom severity and cerebrospinal fluid alterations in recent onset psychosis in schizophrenia-spectrum disorders - An individual patient data meta-analysis.

Neuroinflammation and blood-cerebrospinal fluid barrier (BCB) disruption could be key elements in schizophrenia-spectrum disorders(SSDs) etiology and symptom modulation. We present the largest two-stage individual patient data (IPD) meta-analysis, investigating the association of BCB disruption and cerebrospinal fluid (CSF) alterations with symptom severity in first-episode psychosis (FEP) and recent onset psychotic disorder (ROP) individuals, with a focus on sex-related differences. Data was collected from PubMed and EMBASE databases. FEP, ROP and high-risk syndromes for psychosis IPD were included if routine basic CSF-diagnostics were reported. Risk of bias of the included studies was evaluated. Random-effects meta-analyses and mixed-effects linear regression models were employed to assess the impact of BCB alterations on symptom severity. Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses. CSF was altered in 38.8 % of individuals. No significant differences in symptom severity were found between individuals with and without CSF alterations (SMD = -0.17, 95 %CI -0.55-0.22, p = 0.341). However, males with elevated CSF/serum albumin ratios or any CSF alteration had significantly higher positive symptom scores than those without alterations (SMD = 0.34, 95 %CI 0.05-0.64, p = 0.037 and SMD = 0.29, 95 %CI 0.17-0.41p = 0.005, respectively). Mixed-effects and simple regression models showed no association (p > 0.1) between CSF parameters and symptomatic outcomes. No interaction between sex and CSF parameters was found (p > 0.1). BCB disruption appears highly prevalent in early psychosis and could be involved in positive symptoms severity in males, indicating potential difficult-to-treat states. This work highlights the need for considering BCB breakdownand sex-related differences in SSDs clinical trials and treatment strategies.

Genetic evidence for the causal effects of C-reactive protein on self-reported habitual sleep duration.

Inflammatory responses to acute stimuli are proposed to regulate sleep, but the relationship between chronic inflammation and habitual sleep duration is elusive. Here, we study this relation using genetically predicted level of chronic inflammation, indexed by CRP and IL6 signaling, and self-reported sleep duration. By Mendelian randomization analysis, we show that elevated CRP level within <10 mg/L has a homeostatic effect that facilitates maintaining 7-8 h sleep duration per day - making short-sleepers sleep longer (p = 2.42 × 10-2) and long-sleepers sleep shorter (1.87 × 10-7); but it is not associated with the overall sleep duration (p = 0.17). This homeostatic effect replicated in an independent CRP dataset. We observed causal effects of the soluble interleukin 6 receptor and gp130 on overall sleep duration (p = 1.62 × 10-8, p = 2.61 × 10-58, respectively), but these effects disappeared when CRP effects were accounted for in the model. Using polygenic score analysis, we found that the homeostatic effect of CRP on sleep duration stems primarily from the genetic variants within the CRP gene region: when genetic variants outside of this region were used to predict CRP levels, the opposite direction of effect was observed. In conclusion, we show that elevated CRP level may causally facilitate maintaining an optimal sleep duration that is beneficial to health, thus updating our current knowledge of immune regulation on sleep.

Possible temporal relationship between SARS-CoV-2 infection and anti-NMDA receptor encephalitis: a meta-analysis.

The global impact of SARS-CoV-2 infection has raised concerns about secondary diseases beyond acute illness. This review explores the significance and potential underlying mechanisms of how SARS-CoV-2 infection might elicit an immune response targeting N-methyl-D-aspartate (NMDA) receptors, and its implications for autoimmune-driven neuropsychiatric manifestations. We identified 19 published case reports of NMDA receptor encephalitis associated with SARS-CoV-2 infection or vaccination by a systematic literature search. The significance of these reports was limited since it is not clear if a coincidental or causal relationship exists between SARS-CoV-2 infection or vaccination and manifestation of NMDA receptor encephalitis. The included studies were hampered by difficulties in establishing if these patients had pre-existing NMDA receptor antibodies which entered the brain by infection- or vaccination-associated transient blood-brain barrier leakage. In addition, four cases had comorbid ovarian teratoma, which is a known trigger for development of NMDA receptor encephalitis. Considering that billions of people have contracted COVID-19 or have been vaccinated against this virus, the publication of only 19 case reports with a possible link to NMDA receptor encephalitis, indicates that it is rare. In conclusion, these findings do not support the case that SARS-CoV-2 infection or vaccination led to an increase of existing or de novo encephalitis mediated by an autoimmune response targeting NMDA receptor function. Nevertheless, this work underscores the importance of ongoing vigilance in monitoring viral outbreaks and their potential impact on the central nervous system through basic, epidemiological and translational research.

Immune Cell Alterations in Psychotic Disorders: A Comprehensive Systematic Review and Meta-Analysis.

BACKGROUND: A comprehensive meta-analysis on the composition of circulating immune cells from both the myeloid and the lymphoid lines including specialized subsets in blood and cerebrospinal fluid (CSF) of patients with psychotic disorders compared with healthy control participants has been lacking. METHODS: Multiple databases (PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, and PsycINFO) were searched for eligible studies up until October 18, 2022. All studies investigating circulating immune cells in the blood and CSF from patients with psychotic disorders (ICD-10: F20 and F22-29) compared with healthy control participants were included. RESULTS: A total of 86 studies were included in the meta-analysis. In the blood, the following categories of immune cells were elevated: leukocyte count (31 studies, standardized mean difference [SMD] = 0.35; 95% CI, 0.24 to 0.46), granulocyte count (4 studies, SMD = 0.57; 95% CI, 0.12 to 1.01), neutrophil granulocyte count (21 studies, SMD = 0.32; 95% CI, 0.11 to 0.54), monocyte count (23 studies, SMD = 0.40; 95% CI, 0.23 to 0.56), and B lymphocyte count (10 studies, SMD = 0.26; 95% CI, 0.04 to 0.48). Additionally, the neutrophil/lymphocyte ratio (23 studies, SMD = 0.40; 95% CI, 0.19 to 0.60), the monocyte/lymphocyte ratio (9 studies, SMD = 0.31; 95% CI, 0.04 to 0.57), and the platelet/lymphocyte ratio (10 studies, SMD = 0.23; 95% CI, 0.03 to 0.43) were elevated. The CSF cell count showed a similar tendency but was not significantly elevated (3 studies, SMD = 0.14; 95% CI, -0.04 to 0.32). CONCLUSIONS: The results indicate a broad activation of the immune system in psychotic disorders, with cells from both the myeloid and the lymphoid line being elevated. However, CSF analyses were lacking in most of the studies, and many studies were hampered by insufficient adjustment for confounding factors such as body mass index and smoking.

The correlates of neonatal complement component 3 and 4 protein concentrations with a focus on psychiatric and autoimmune disorders.

Complement components have been linked to schizophrenia and autoimmune disorders. We examined the association between neonatal circulating C3 and C4 protein concentrations in 68,768 neonates and the risk of six mental disorders. We completed genome-wide association studies (GWASs) for C3 and C4 and applied the summary statistics in Mendelian randomization and phenome-wide association studies related to mental and autoimmune disorders. The GWASs for C3 and C4 protein concentrations identified 15 and 36 independent loci, respectively. We found no associations between neonatal C3 and C4 concentrations and mental disorders in the total sample (both sexes combined); however, post-hoc analyses found that a higher C3 concentration was associated with a reduced risk of schizophrenia in females. Mendelian randomization based on C4 summary statistics found an altered risk of five types of autoimmune disorders. Our study adds to our understanding of the associations between C3 and C4 concentrations and subsequent mental and autoimmune disorders.

SARS-CoV-2 and autoantibodies in the cerebrospinal fluid of COVID-19 patients: prospective multicentre cohort study.

Disease mechanisms underlying neurological and neuropsychiatric symptoms after coronavirus disease 2019 (COVID-19), termed neuro-COVID, are poorly understood. Investigations of the cerebrospinal fluid (CSF) for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antibodies, as well as autoantibodies against neuronal surface antigens, could improve our understanding in that regard. We prospectively collected CSF and blood from patients investigated by lumbar puncture for neurological or neuropsychiatric symptoms during or after COVID-19. Primary outcomes were the presence of (i) SARS-CoV-2 RNA in CSF via polymerase chain reaction (PCR), (ii) SARS-CoV-2 immunoglobulin G (IgG) anti-S receptor-binding-domain antibodies via the Euroimmun and Wantai assays and (iii) IgG autoantibodies against neuronal surface antigens using commercial cell- and tissue-based assays (Euroimmun). Secondary outcomes were (i) routine CSF investigations and (ii) correlation between SARS-CoV-2 antibody levels in CSF with serum levels, blood-brain barrier permeability and peripheral inflammation. We obtained CSF from 38 COVID-19 patients (mean age 56.5 ± 19.2 years, 53% women) who developed neurological and neuropsychiatric symptoms. CSF pleocytosis (>5 cells) was observed in 9/38 patients (23.7%), elevated CSF protein (>0.50 g/L) in 13/38 (34.2%) and elevated CSF/serum albumin ratio in 12/35 (34.3%). PCR for SARS-CoV-2 RNA in CSF was negative in all. SARS-CoV-2 CSF antibodies were detected in 15/34 (44.1%; Euroimmun assay) and 7/31 (22.6%; Wantai assay) individuals, but there were no signs of intrathecal SARS-CoV-2 IgG production. SARS-CoV-2 CSF antibodies were positively correlated with serum levels (R = 0.93, P < 0.001), blood-brain barrier permeability (R = 0.47, P = 0.006), peripheral inflammation (R = 0.51, P = 0.002) and admission to the intensive care unit [odds ratio (OR) 17.65; 95% confidence interval (CI) 1.18-264.96; P = 0.04; n = 15]. Cell-based assays detected weakly positive NMDAR, LGI1 and CASPR2 antibodies in serum of 4/34 (11.8%) patients but not in CSF. The tissue-based assay showed anti-neuronal fluorescence in CSF from one individual, staining for Purkinje cells. In summary, whereas we did not detect active SARS-CoV-2 infection in the CSF, SARS-CoV-2 antibodies were prevalent. The absence of intrathecal antibody production points towards blood-brain barrier impairment as the origin of CSF SARS-CoV-2 antibodies. In contrast, CSF autoantibodies against neuronal surface antigens were rare. There was no evidence for a clinical correlate of these antibodies. We conclude that, rather than specific autoimmune neuronal injury, non-specific effects of critical illness including an impaired blood-brain barrier are more likely to contribute to neuro-COVID.

Prediction models of suicide and non-fatal suicide attempt after discharge from a psychiatric inpatient stay: A machine learning approach on nationwide Danish registers.

INTRODUCTION: To develop machine learning models capable of predicting suicide and non-fatal suicide attempt as separate outcomes in the first 30 days after discharge from a psychiatric inpatient stay. METHODS: Prospective cohort study using nationwide Danish registry data. We included individuals who were 18 years or older, and all discharges from psychiatric hospitalizations in Denmark from 1995 to 2018. We trained predictive models using 10-fold cross validation on 80% of the data and did testing on the remaining 20%. RESULTS: The best model for predicting non-fatal suicide attempt was an ensemble of predictions from gradient boosting (XGBoost) and categorical boosting (catBoost). The ROC-AUC for predicting suicide attempt was 0.85 (95% CI: 0.84-0.85). At a risk threshold of 4.36%, positive predictive value (PPV) was 11.0% and sensitivity was 47.2%. The best model for predicting suicide was an ensemble of predictions from random forest, XGBoost and catBoost. For suicide, the ROC-AUC was 0.71 (95% CI: 0.70-0.73). At a risk threshold of 0.15%, PPV was 0.34% and sensitivity was 56.0%. The most contributing predictors differed when predicting suicide and suicide attempt, indicating that separate models are needed. The ensemble model was fair across sex and age, and more so than the penalized logistic regression model. CONCLUSIONS: We achieved good performance for predicting suicide attempts and demonstrated a clinical application of ensemble models. Our results indicate a difference in predictive performance for models predicting suicide and suicide attempt, respectively. Thus, we recommend that suicide and suicide attempt are treated as two separate endpoints, in particular for clinical application. We demonstrated that the ensemble model is fairer across sex and age compared with a penalized logistic regression, and therefore we recommend the use of well-tested ensembles despite a more complex explainability.

Long-term neurological outcome after COVID-19 using all SARS-CoV-2 test results and hospitalisations in Denmark with 22-month follow-up.

Hospitalisation with COVID-19 is associated with an increased risk of neurological sequelae; however, representative nationwide studies comparing to other infections with similar severity and also including milder SARS-CoV-2 infections have been lacking. Using the nationwide Danish registers including all SARS-CoV-2 PCR test results and hospitalisations between March 1, 2020, and December 31, 2021, we estimate the risk of any first neurological disorder diagnosed in inpatient, outpatient, or emergency room settings. We show that positive tests increase the rate of neurological disorders by a hazard ratio of 1.96 (95% confidence interval: 1.88-2.05) compared to individuals not tested and by a hazard ratio of 1.11 (95% confidence interval: 1.07-1.16) compared to individuals with negative tests only. However, there is no evidence that the risk of neurological disorders is higher for individuals who test positive compared to non-COVID-19 infections treated with anti-infective medication. The risk of neurological disorders is increased after COVID-19-hospitalisation compared to no COVID-19 hospital admission; however, these risks are comparable to hospitalisation with other respiratory infections (P value 0.328). In conclusion, COVID-19 is associated with an increased risk of neurological disorders, but no more than that observed after other infections of similar severity.

An international research agenda for clozapine-resistant schizophrenia.

Treatment-resistant symptoms occur in about a third of patients with schizophrenia and are associated with a substantial reduction in their quality of life. The development of new treatment options for clozapine-resistant schizophrenia constitutes a crucial, unmet need in psychiatry. Additionally, an overview of past and possible future research avenues to optimise the early detection, diagnosis, and management of clozapine-resistant schizophrenia is unavailable. In this Health Policy, we discuss the ongoing challenges associated with clozapine-resistant schizophrenia faced by patients and health-care providers worldwide to improve the understanding of this condition. We then revisit several clozapine guidelines, the diagnostic tests and treatment options for clozapine-resistant schizophrenia, and currently applied research approaches in clozapine-resistant schizophrenia. We also suggest methodologies and targets for future research, divided into innovative nosology-oriented field trials (eg, examining dimensional symptom staging), translational approaches (eg, genetics), epidemiological research (eg, real-world studies), and interventional studies (eg, non-traditional trial designs incorporating lived experiences and caregivers' perspectives). Finally, we note that low-income and middle-income countries are under-represented in studies on clozapine-resistant schizophrenia and propose an agenda to guide multinational research on the cause and treatment of clozapine-resistant schizophrenia. We hope that this research agenda will empower better global representation of patients living with clozapine-resistant schizophrenia and ultimately improve their functional outcomes and quality of life.

Serum glial fibrillary acidic protein and neurofilament light chain in treatment-naïve patients with unipolar depression.

BACKGROUND: Unipolar depression has been associated with increased levels of glial dysfunction and neurodegeneration biomarkers, such as Glial Fibrillary Acidic Protein (GFAP) and Neurofilament light chain (NfL). However, previous studies were conducted on patients taking psychotropic medication and did not monitor longitudinal associations between disease status and GFAP/NfL. METHODS: Treatment-naïve patients with unipolar depression (n = 110) and healthy controls (n = 33) were included. GFAP/NfL serum levels were analyzed by Single Molecule Array at baseline and 3-month follow-up. The primary endpoint was GFAP/NfL levels in patients with depression compared with healthy controls. The secondary endpoint was the associations between GFAP/NfL with depression severity and cognitive function. RESULTS: The patients' mean HAM-D17 score was 18.9 (SD 3.9) at baseline and improved by 7.9 (SD 6.8) points during follow-up. GFAP/NfL was quantified in all individuals. At baseline, the adjusted GFAP levels were -16.8 % (95 % CI: -28.8 to -1.9, p = 0.03) lower among patients with depression compared to healthy controls, while NfL levels were comparable between the groups (p = 0.57). In patients with depression, mean NfL levels increased from baseline to follow-up (0.68 pg/ml, p = 0.03), while GFAP levels were unchanged (p = 0.24). We did not find consistent associations between NfL/GFAP with depression scores or cognitive function. CONCLUSION: This largest study of serum NfL/GFAP levels in patients with depression did not support previous findings of elevated GFAP/NfL in patients with depression or positive associations with depression severity. Although limited by a small control group, our study may support the presence of glial dysfunction but not damage to neurons in depression.

Alteration of Gut Microbiome in Patients With Schizophrenia Indicates Links Between Bacterial Tyrosine Biosynthesis and Cognitive Dysfunction.

Background: Schizophrenia (SCZ) is a heterogeneous neuropsychiatric disorder for which current treatment has insufficient efficacy and severe adverse effects. The modifiable gut microbiome might be a potential target for intervention to improve neurobiological functions through the gut-microbiome-brain axis. Methods: In this case-control study, gut microbiota of 132 patients with SCZ and increased waist circumference were compared with gut microbiota of two age- and sex-matched control groups, composed of 132 healthy individuals and 132 individuals with metabolic syndrome. Shotgun sequencing was used to characterize fecal samples at the taxonomic and functional levels. Cognition of the patients with SCZ was evaluated using the Brief Assessment of Cognition instrument. Results: SCZ gut microbiota differed significantly from those of healthy control subjects and individuals with metabolic syndrome in terms of richness and global composition. SCZ gut microbiota were notably enriched in Flavonifractor plautii, Collinsella aerofaciens, Bilophila wadsworthia, and Sellimonas intestinalis, while depleted in Faecalibacterium prausnitzii, Ruminococcus lactaris, Ruminococcus bicirculans, and Veillonella rogosae. Functional potential of the gut microbiota accounted for 11% of cognition variability. In particular, the bacterial functional module for synthesizing tyrosine, a precursor for dopamine, was in SCZ cases positively associated with cognitive score (ρ = 0.34, q ≤ .1). Conclusions: Overall, this study shows that the gut microbiome of patients with SCZ differs greatly from that of healthy control subjects or individuals with metabolic syndrome. Cognitive function of patients with SCZ is associated with the potential for gut bacterial biosynthesis of tyrosine, a precursor for dopamine, suggesting that gut microbiota might be an intervention target for alleviation of cognitive dysfunction in SCZ.

Genetic and epidemiological analyses of infection load and its relationship with psychiatric disorders.

Severe infections and psychiatric disorders have a large impact on both society and the individual. Studies investigating these conditions and the links between them are therefore important. Most past studies have focused on binary phenotypes of particular infections or overall infection, thereby losing some information regarding susceptibility to infection as reflected in the number of specific infection types, or sites, which we term infection load. In this study we found that infection load was associated with increased risk for attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, depression, schizophrenia and overall psychiatric diagnosis. We obtained a modest but significant heritability for infection load (h2 = 0.0221), and a high degree of genetic correlation between it and overall psychiatric diagnosis (rg = 0.4298). We also found evidence supporting a genetic causality for overall infection on overall psychiatric diagnosis. Our genome-wide association study for infection load identified 138 suggestive associations. Our study provides further evidence for genetic links between susceptibility to infection and psychiatric disorders, and suggests that a higher infection load may have a cumulative association with psychiatric disorders, beyond what has been described for individual infections.

COVID-19 and Risk for Mental Disorders Among Adults in Denmark.

Importance: Psychiatric outcomes after COVID-19 have been of high concern during the pandemic; however, studies on a nationwide level are lacking. Objective: To estimate the risk of mental disorders and use of psychotropic medication among individuals with COVID-19 compared with individuals not tested, individuals with SARS-CoV-2-negative test results, and those hospitalized for non-COVID-19 infections. Design, Setting, and Participants: This nationwide cohort study used Danish registries to identify all individuals who were alive, 18 years or older, and residing in Denmark between January 1 and March 1, 2020 (N = 4 152 792), excluding individuals with a mental disorder history (n = 616 546), with follow-up until December 31, 2021. Exposures: Results of SARS-CoV-2 polymerase chain reaction (PCR) testing (negative, positive, and never tested) and COVID-19 hospitalization. Main Outcomes and Measures: Risk of new-onset mental disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F00-F99) and redeemed psychotropic medication (Anatomical Therapeutic Chemical classification codes N05-N06) was estimated through survival analysis using a Cox proportional hazards model, with a hierarchical time-varying exposure, reporting hazard rate ratios (HRR) with 95% CIs. All outcomes were adjusted for age, sex, parental history of mental illness, Charlson Comorbidity Index, educational level, income, and job status. Results: A total of 526 749 individuals had positive test results for SARS-CoV-2 (50.2% men; mean [SD] age, 41.18 [17.06] years), while 3 124 933 had negative test results (50.6% women; mean [SD] age, 49.36 [19.00] years), and 501 110 had no tests performed (54.6% men; mean [SD] age, 60.71 [19.78] years). Follow-up time was 1.83 years for 93.4% of the population. The risk of mental disorders was increased in individuals with positive (HRR, 1.24 [95% CI, 1.17-1.31]) and negative (HRR, 1.42 [95% CI, 1.38-1.46]) test results for SARS-CoV-2 compared with those never tested. Compared with individuals with negative test results, the risk of new-onset mental disorders in SARS-CoV-2-positive individuals was lower in the group aged 18 to 29 years (HRR, 0.75 [95% CI, 0.69-0.81]), whereas individuals 70 years or older had an increased risk (HRR, 1.25 [95% CI, 1.05-1.50]). A similar pattern was seen regarding psychotropic medication use, with a decreased risk in the group aged 18 to 29 years (HRR, 0.81 [95% CI, 0.76-0.85]) and elevated risk in those 70 years or older (HRR, 1.57 [95% CI, 1.45-1.70]). The risk for new-onset mental disorders was substantially elevated in hospitalized patients with COVID-19 compared with the general population (HRR, 2.54 [95% CI, 2.06-3.14]); however, no significant difference in risk was seen when compared with hospitalization for non-COVID-19 respiratory tract infections (HRR, 1.03 [95% CI, 0.82-1.29]). Conclusion and Relevance: In this Danish nationwide cohort study, overall risk of new-onset mental disorders in SARS-CoV-2-positive individuals did not exceed the risk among individuals with negative test results (except for those aged ≥70 years). However, when hospitalized, patients with COVID-19 had markedly increased risk compared with the general population, but comparable to risk among patients hospitalized for non-COVID-19 infections. Future studies should include even longer follow-up time and preferentially include immunological biomarkers to further investigate the impact of infection severity on postinfectious mental disorder sequelae.

Circulating S100B levels at birth and risk of six major neuropsychiatric or neurological disorders: a two-sample Mendelian Randomization Study.

Circulating levels of the astrocytic marker S100B have been associated with risk of neuropsychiatric or neurological disorders. However, reported effects have been inconsistent, and no causal relations have yet been established. We applied two-sample Mendelian Randomization (MR) on the association statistics from genome-wide association studies (GWAS) for circulating S100B levels measured 5-7 days after birth (the iPSYCH sample) and in an older adult sample (mean age, 72.5 years; the Lothian sample), upon those derived from major depression disorder (MDD), schizophrenia (SCZ), bipolar disorder (BIP), autism spectral disorder (ASD), Alzheimer's disease (AD), and Parkinson's disease (PD). We studied the causal relations in the two S100B datasets for risk of these six neuropsychiatric disorders. MR suggested increased S100B levels 5-7 days after birth to causally increase the risk of MDD (OR = 1.014; 95%CI = 1.007-1.022; FDR-corrected p = 6.43×10-4). In older adults, MR suggested increased S100B levels to have a causal relation to the risk of BIP (OR = 1.075; 95%CI = 1.026-1.127; FDR-corrected p = 1.35×10-2). No significant causal relations were found for the other five disorders. We did not observe any evidence for reverse causality of these neuropsychiatric or neurological disorders on altered S100B levels. Sensitivity analyses using more stringent SNP-selection criteria and three alternative MR models suggested the results are robust. Altogether, our findings imply a small cause-effect relation for the previously reported associations of S100B and mood disorders. Such findings may provide a novel avenue for the diagnosis and management of disorders.

Influence of vaccination on adverse health outcomes after SARS-CoV-2 infection among individuals with alcohol use disorder: a population-based study.

BACKGROUND AND AIMS: Alcohol use disorders (AUD) have not been included in the priority groups for early vaccine against SARS-CoV-2. We aimed to determine adverse outcomes after SARS-CoV-2 infection among individuals with AUD and how this is modified by vaccination. DESIGN, SETTING AND PARTICIPANTS: This was a registry-based cohort study carried out in Denmark, 27 February 2020 to 15 October 2021, comprising 2157 individuals with AUD and 237 541 without AUD who had had a polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection during the study period. MEASUREMENTS: The association of AUD with the absolute and relative risk of hospitalization, intensive care and 60-day mortality after SARS-CoV-2 infection and of all-cause mortality throughout the follow-up period were measured. Potential interactions with SARS-CoV-2 vaccination, education and sex were explored in stratified analyses and tested by including interaction terms and using likelihood ratio tests. FINDINGS: Individuals with AUD had an increased absolute and relative risk of adverse outcomes, including hospitalization [incidence rate ratio (IRR) = 1.72, 95% confidence interval (CI) = 1.51-1.95], intensive care (IRR = 1.47, 95% CI = 1.07-2.02) and 60-day mortality [mortality rate ratio (MRR) = 2.35, 95% CI = 1.94-2.85] compared with SARS-CoV-2-positive individuals without AUD. Irrespective of AUD, highest risks of these adverse health outcomes were observed for individuals not vaccinated against SARS-CoV-2 infection, for individuals of low educational level and in males. However, for all-cause mortality throughout the follow-up period, SARS-CoV-2 infection showed a lower relative mortality risk increase, whereas being unvaccinated showed a higher relative mortality risk increase, in individuals with AUD than in the reference population without AUD (P of interaction tests < 0.0001). CONCLUSIONS: Both alcohol use disorder and being unvaccinated for SARS-CoV-2 appear to be independent risk factors for adverse health outcomes following SARS-CoV-2 infection.