Levels of cytokines in the cerebrospinal fluid of patients with psychotic disorders compared to individually matched healthy controls.

BACKGROUND: Increased peripheral cytokine levels have been observed in patients with psychotic disorders; however, large high-quality studies with individually matched healthy controls have been lacking regarding cytokines in cerebrospinal fluid (CSF) of individuals with psychotic disorders. METHODS: Patients diagnosed with a non-organic, non-affective psychotic disorder (ICD-10: F20/22-29) within a year prior to inclusion and individually age- and sex-matched healthy controls were included by identical in- and exclusion criteria's except for the psychiatric diagnoses. All participants were aged 18-50 years and individuals with neurological or immunological disorders were excluded. CSF cytokines were analyzed with MesoScale V-PLEX neuroinflammation panel. Co-primary outcomes were CSF interleukin-6 (IL-6) and IL-8. RESULTS: We included 104 patients and 104 healthy controls, matching on age, sex and BMI. No significant differences were found for the primary outcomes IL-6 (relative mean difference (MD): 0.97, 95 %CI: 0.84-1.11, p = 0.637) or IL-8 (MD: 1.01, 95 %CI: 0.93-1.09, p = 0.895). Secondary analyses found patients to have higher IL-4 (MD: 1.30, 95 %CI: 1.04-1.61, p = 0.018), a trend towards higher IFN-γ (MD: 1.26, 95 %CI: 0.99-1.59, p = 0.056), and lower IL-16 (MD: 0.83, 95 %CI: 0.74-0.94, p = 0.004) than healthy controls, though not significant after correction for multiple testing. IL-8 and IL-16 were found positively associated with CSF white blood cells and CSF/serum albumin ratio. The study was limited by 77.9 % of the patients being on antipsychotic treatment at time of intervention, and that levels of nine of the 26 cytokines were below lower limit of detection (LLOD) in >50 % of samples; however, for the primary outcomes IL-6 and IL-8 more than 99.5 % of the samples were above LLOD and for IL-8 all samples exceeded the lower limit of quantification (LLOQ). CONCLUSIONS: We found no evidence of increased IL-6 and IL-8 in patients with recent-onset psychotic disorders in contrary to previous findings in meta-analyses of CSF cytokines. Secondary analyses found indication of higher IL-4, decreased IL-16, and borderline increased IFN-γ in patients, neither of which have previously been reported on in CSF analyses of individuals with psychotic disorders.

Antineuronal Autoantibodies in the Cerebrospinal Fluid and Serum From 106 Patients With Recent-Onset Depression Compared With 106 Individually Matched Healthy Control Subjects.

No large studies have investigated the prevalence of cerebrospinal fluid antineuronal autoantibodies in isolated depression. In this case-control study comparing 106 patients with isolated depression (ICD-10 code F32) with 106 healthy control subjects, cerebrospinal fluid and serum samples were tested for 7 immunoglobulin G autoantibodies using commercial fixed cell-based assays. To explore validity of methods, positive samples were retested twice by cell-based assays and once by tissue-based assays (monkey cerebellum). The prevalence of any of the antineuronal autoantibodies in cerebrospinal fluid was 0.0% in both groups and the seroprevalence was 0.9% in both groups, based on consistent findings in cell-based assays. However, all samples were negative by the tissue-based assay. Evaluation of antineuronal autoantibodies in cerebrospinal fluid cannot be recommended routinely for patients with isolated depression of moderate severity. Future studies of isolated depression should consider much larger sample sizes and evaluation of antineuronal autoantibodies using modalities other than commercial kits.

Biomarkers in the cerebrospinal fluid of patients with psychotic disorders compared to healthy controls: a systematic review and meta-analysis.

Psychotic disorders are severe mental disorders with poorly understood etiology. Biomarkers in the cerebrospinal fluid (CSF) could provide etiological clues and diagnostic tools for psychosis; however, an unbiased overview of CSF alterations in individuals with psychotic disorders is lacking. The objective of this study was to summarize all quantifiable findings in CSF from individuals with psychotic disorders compared to healthy controls (HC). Studies published before January 25th, 2023 were identified searching PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, and PsycINFO. Screening, full-text review, data extraction, and risk of bias assessments were performed by two independent reviewers following PRISMA guidelines. Findings in patients and healthy controls were compared and summarized using random-effects analyses and assessment of publication bias, subgroup and sensitivity analyses were performed. 145 studies, covering 197 biomarkers, were included, of which 163 biomarkers have not previously been investigated in meta-analyses. All studies showed some degree of bias. 55 biomarkers measured in CSF were associated with psychosis and of these were 15 biomarkers measured in ≥2 studies. Patients showed increased levels of noradrenaline (standardized mean difference/SMD, 0.53; 95% confidence interval/CI, 0.16 to 0.90) and its metabolite 3-methoxy-4-hydroxyphenylglycol (SMD, 0.30; 95% CI: 0.05 to 0.55), the serotonin metabolite 5-hydroxyindoleacetic acid (SMD, 0.11; 95% CI: 0.01 to 0.21), the pro-inflammatory neurotransmitter kynurenic acid (SMD, 1.58; 95% CI: 0.34 to 2.81), its precursor kynurenine (SMD,0.99; 95% CI: 0.60 to 1.38), the cytokines interleukin-6 (SMD, 0.58; 95% CI: 0.39 to 0.77) and interleukin-8 (SMD, 0.43; 95% CI: 0.24 to 0.62), the endocannabinoid anandamide (SMD, 0.78; 95% CI: 0.53 to 1.02), albumin ratio (SMD, 0.40; 95% CI: 0.08 to 0.72), total protein (SMD, 0.29; 95% CI: 0.16 to 0.43), immunoglobulin ratio (SMD, 0.45; 95% CI: 0.06 to 0.85) and glucose (SMD, 0.48; 95% CI: 0.01 to 0.94). Neurotensin (SMD, -0.67; 95% CI: -0.89 to -0.46) and γ-aminobutyric acid (SMD, -0.29; 95% CI: -0.50 to -0.09) were decreased. Most biomarkers showed no significant differences, including the dopamine metabolites homovanillic acid and 3,4-dihydroxyphenylacetic acid. These findings suggest that dysregulation of the immune and adrenergic system as well as blood-brain barrier dysfunction are implicated in the pathophysiology of psychotic disorders.

Comparisons of 25 cerebrospinal fluid cytokines in a case-control study of 106 patients with recent-onset depression and 106 individually matched healthy subjects.

BACKGROUND: Neuroinflammation has been suggested as a contributor to the pathophysiology of depression; however, large case-control studies investigating cytokine levels in the cerebrospinal fluid (CSF) from patients with recent-onset depression by multiplex analyses are missing. METHODS: An individually matched (sex and age) prospective case-control study comparing patients with recent-onset depression to healthy controls. CSF was analyzed with the Mesoscale V-PLEX Neuroinflammation Panel 1. OUTCOMES: comparisons of analyte levels in the CSF between groups with interleukin (IL)-6 and IL-8 as primary outcomes and 23 other cytokines as secondary outcomes. RESULTS: We included 106 patients (84.0% outpatients) with recent-onset depression and 106 healthy controls. There were no significant differences in the primary outcomes IL-6 (relative mean difference (MD): 1.10; 95% confidence interval (CI) 0.93-1.30; p = 0.276) or IL-8 levels (MD: 1.05; 95% CI 0.96-1.16; p = 0.249) relative to healthy controls. IL-4 was 40% higher (MD: 1.40; 95% CI 1.14-1.72; p = 0.001), monocyte chemoattractant protein (MCP)-1 was 25% higher (MD: 1.25; 95% CI 1.06-1.47; p = 0.009) and macrophage inflammatory protein (MIP)-1ß was 16% higher (MD: 1.16; 95% CI 1.02-1.33; p = 0.025) in patients with depression relative to healthy controls. However, only IL-4 was significantly elevated after correction for multiple testing of secondary outcomes (p = 0.025). CONCLUSION: We found no significant differences in CSF levels of the co-primary outcomes IL-6 and IL-8, however, the higher CSF levels of IL-4, MCP-1 and MIP-1ß among patients with recent-onset depression compared to healthy controls indicate a potential role of these cytokines in the neuroinflammatory response to depression.

Antineuronal antibodies in cerebrospinal fluid and serum of 104 patients with psychotic disorders compared to 104 individually matched healthy controls.

BACKGROUND: Antineuronal antibodies can cause psychotic symptoms, particularly NMDAR antibodies; however, studies on the prevalence of antineuronal antibodies in cerebrospinal fluid (CSF) and serum of patients with psychotic disorders compared to matched healthy controls are sparse. METHODS: We included 104 patients with a first-time diagnosis of a psychotic disorder within one year prior to inclusion (50 % outpatients) and 104 individually matched healthy controls, all without any known immunological conditions. CSF and serum were tested for IgG antibodies (Abs) against NMDAR NR1-subunit, GAD65, LGI1, CASPR2, AMPAR1, AMPAR2 and GABAb-receptor B1/B2 using commercial fixed cell-based assays (CBAs) (Euroimmun). Positive samples were retested with CBA twice, and tested with tissue-based assays (TBA). Primary outcomes were the presence of any of the seven anti-neuronal antibodies in CSF or serum. Secondarily, we analyzed the prevalence of each autoantibody. RESULTS: No antineuronal IgG antibodies were consistently found in any CSF sample and NMDAR-antibodies were not consistently present in any of the 208 participants, neither in CSF nor serum. CASPR2-Abs were consistently found in the serum of one patient and one control, and one healthy control, without diabetes, was seropositive for GAD65-Abs. CASPR2 borderline seropositivity was additionally found in one patient and two controls. All samples positive on CBA were negative on TBA. CONCLUSIONS: We found no significant differences between patients and controls. Antineuronal IgG antibodies are very rare when screening a broad group of individuals with recent-onset psychotic disorders without other indications of autoimmune encephalitis. Thus, much larger studies are needed to conclude on potential contrasts in prevalence compared to healthy controls.

Cerebrospinal Fluid and Blood Biomarkers of Neuroinflammation and Blood-Brain Barrier in Psychotic Disorders and Individually Matched Healthy Controls.

BACKGROUND AND HYPOTHESIS: Neuroinflammation and blood-brain barrier (BBB) dysfunction have been observed in patients with psychotic disorders. However, previous studies have mainly focused on selected patients and broad screenings of cerebrospinal fluid (CSF) of patients with recent onset psychosis compared to healthy controls are lacking. STUDY DESIGN: We included 104 patients with recent onset psychotic disorder and 104 individually matched healthy controls. CSF and blood were analyzed for readily available markers assessing neuroinflammation and BBB dysfunction. Primary outcomes were CSF white blood cell count (WBC), total protein, IgG Index, and CSF/serum albumin ratio. Secondary outcomes included additional markers of inflammation and BBB, and analyses of association with clinical variables. STUDY RESULTS: CSF/serum albumin ratio (Relative Mean Difference (MD): 1.11; 95%CI: 1.00-1.23; P = .044) and CSF/serum IgG ratio (MD: 1.17; 95%CI: 1.01-1.36; P = .036) was increased in patients compared to controls. A higher number of patients than controls had CSF WBC >3 cells/µl (seven vs. one, OR: 7.73, 95%CI: 1.33-146.49, P = .020), while WBC>5 cells/µl was found in two patients (1.9%) and no controls. Inpatients had higher serum WBC and neutrophil/lymphocyte ratio (all p-values for effect heterogeneity < .011). Mean CSF WBC (MD: 1.10; 95%CI: 0.97-1.26), protein (MD: 1.06; 95%CI: 0.98-1.15) and IgG index (MD: 1.05; 95%CI: 0.96-1.15) were not significantly elevated. CONCLUSIONS: When comparing a broad group of patients with psychotic disorders with healthy controls, patients had increased BBB permeability, more patients had high CSF WBC levels, and inpatients had increased peripheral inflammation, consistent with the hypothesis of a subgroup of patients with increased activation of the immune system.

Neuroinflammatory Biomarkers in Cerebrospinal Fluid From 106 Patients With Recent-Onset Depression Compared With 106 Individually Matched Healthy Control Subjects.

BACKGROUND: Neuroinflammation has been linked to depression; however, neuroinflammatory biomarkers in the cerebrospinal fluid (CSF) have not previously been thoroughly investigated in a large group of patients with recent-onset depression compared with healthy control subjects. METHODS: We conducted an individually matched case-control study comparing patients with recent-onset depression (ICD-10: F32) to control subjects. Primary outcomes were CSF white cell count (WCC), CSF-to-serum albumin ratio, CSF total protein, and immunoglobulin G (IgG) index. Secondary outcomes were CSF WCC differential count and CSF neutrophil-to-lymphocyte, CSF-to-serum IgG, and CSF-to-plasma glucose ratios. Linear models adjusting for sex and age were applied. RESULTS: We included 106 patients with recent-onset depression (84.0% outpatients) and 106 healthy control subjects. Patients had 18% higher CSF WCC relative to control subjects (relative mean difference [MD]: 1.18; 95% CI: 1.02-1.40; p = .025). CSF WCC differed with depression symptomatology (p = .034), and patients with severe depression (n = 29) had 43% higher CSF WCC relative to control subjects (MD: 1.43; 95% CI: 1.13-1.80, p = .003). Two (1.9%) patients and no controls (0.0%) had CSF WCC above the normal range (>5 × 106/L). No significant differences between groups were observed regarding CSF-to-serum albumin ratio (MD: 1.07; 95% CI: 0.97-1.18; p = .191), CSF total protein (MD: 1.01; 95% CI: 0.94-1.09; p = .775), or IgG index (MD: 1.05; 95% CI: 0.97-1.15; p = .235). Regarding secondary outcomes, the proportion of CSF neutrophils was lower among patients (MD: 0.22; 95% CI: 0.08-0.59; p = .003) relative to control subjects, whereas the remaining outcomes were not significantly different (all p > .06). CONCLUSIONS: Patients had higher CSF WCC relative to control subjects, indicating increased neuroimmunologic activation, particularly for severe depression.

Effectiveness of medical treatment for bipolar disorder regarding suicide, self-harm and psychiatric hospital admission: between- and within-individual study on Danish national data.

BACKGROUND: Mood stabilisers are the main treatment for bipolar disorder. However, it is uncertain which drugs have the best outcomes. AIMS: To investigate whether rates of suicide, self-harm and psychiatric hospital admission in individuals with bipolar disorder differ between mood stabilisers. METHOD: A cohort design was applied to people aged ≥15 years who were diagnosed with bipolar disorder and living in Denmark during 1995-2016. Treatment with lithium, valproate, other mood stabilisers and antipsychotics were compared in between- and within-individual analyses, and adjusted for sociodemographic characteristics and previous self-harm. RESULTS: A total of 33 337 individuals with bipolar disorder were included (266 900 person-years). When compared with individuals not receiving treatment, those receiving lithium had a lower rate of suicide (hazard ratio 0.40, 95% CI 0.31-0.51). When comparing treatment and non-treatment periods in the same individuals, lower rates of self-harm were found for lithium (hazard ratio 0.74, 95% CI 0.61-0.91). Lower rates of psychiatric hospital admission were found for all drug categories compared with non-treatment periods in within-individual analyses (P<0.001). The low rates of self-harm and hospital admission for lithium in within-individual analyses were supported by results of between-individual analyses. CONCLUSIONS: Lithium was associated with lower rates of suicide, self-harm and psychiatric hospital readmission in all analyses. With respect to suicide, lithium was superior to no treatment. Although confounding by indication cannot be excluded, lithium seems to have better outcomes in the treatment of bipolar disorder than other mood stabilisers.

Immunological investigations of the cerebrospinal fluid in patients with recent onset psychotic disorders: A study protocol.

BACKGROUND: Though many previous studies have indicated immunological alterations in psychotic disorders, the role and prevalence of neuroinflammation is still unknown. Studies previously investigating immune related biomarkers in the cerebrospinal fluid (CSF) of these patients are mainly small studies on few markers, and many have not compared patients to healthy controls. METHODS: We will conduct a large case-control study including at least 100 patients with recent onset psychotic disorders and 100 sex- and age matched healthy controls. The cases will include patients diagnosed with a psychotic disorder according to ICD-10 (F20/F22-29) within a year prior to inclusion. We will collect both CSF, blood and fecal samples, to gain insight into possible immunological alterations. The psychopathology of all participants will thoroughly be evaluated using the SCAN interview, and multiple rating scales covering different symptom groups. All participants will partake in a detailed neurological examination, including the Neurological Evaluation Scale assessing neurological soft signs. Additionally, we will assess cognitive functioning, evaluate quality of life and level of functioning, and collect data on a broad array of possible confounders. Our primary outcomes will include CSF leucocytes, CSF/serum albumin ratio, CSF total protein, IgG index, CSF levels of IL-6 and IL-8, and presence of antineuronal autoantibodies in CSF and blood. For our secondary outcomes, exploratory analyses will be performed on a broader panel of neuroimmunological markers. All participants will be invited for a follow-up visit to assess longitudinal changes. The current study is part of a larger CSF biobank build-up for severe mental disorders (PSYCH-FLAME). DISCUSSION: This study will represent the largest investigation of CSF in patients with psychotic disorders compared to healthy controls to date. We expect the study to contribute with new, important knowledge on pathophysiological mechanisms, and to help pave the way for future investigations of individualized treatment options. TRIAL REGISTRATION: The study is approved by The Regional Committee on Health Research Ethics (Capital Region, j.no: H-16030985) and The Danish Data Protection Agency (j.no: RHP-2016-020, I-Suite no.: 04945).

Psychiatric Admissions, Referrals, and Suicidal Behavior Before and During the COVID-19 Pandemic in Denmark: A Time-Trend Study.

OBJECTIVE: To assess the patterns in psychiatric admissions, referrals, and suicidal behavior before and during the COVID-19 pandemic. METHODS: This study utilized health records from hospitals and Emergency Medical Services (EMS) covering 46% of the Danish population (n = 2,693,924). In a time-trend study, we compared the number of psychiatric in-patients, referrals to mental health services and suicidal behavior in years prior to the COVID-19 pandemic to levels during the first lockdown (March 11 - May 17, 2020), inter-lockdown period (May 18 - December 15, 2020), and second lockdown (December 16, 2020 - February 28, 2021). RESULTS: During the pandemic, the rate of psychiatric in-patients declined compared to pre-pandemic levels (RR = 0.95, 95% CI = 0.94 - 0.96, p < 0.01), with the largest decrease of 19% observed three weeks into the first lockdown. Referrals to mental health services were not significantly different (RR = 1.01, 95% CI = 0.92 - 1.10, p = 0.91) during the pandemic; neither was suicidal behavior among hospital contacts (RR = 1.04, 95% CI = 0.94 - 1.14, p = 0.48) nor EMS contacts (RR = 1.08, 95% CI = 1.00 - 1.18, p = 0.06). Similar trends were observed across nearly all age groups, sexes, and types of mental disorders examined. In the age group <18, an increase in the rate of psychiatric in-patients (RR = 1.11, 95% CI = 1.07 - 1.15, p < 0.01) was observed during the pandemic; however, this did not exceed the pre-pandemic, upwards trend in psychiatric hospitalizations in the age group <18 (p = 0.78). CONCLUSION: The COVID-19 pandemic has been associated with a decrease in psychiatric hospitalizations, while no significant change was observed in referrals to mental health services and suicidal behavior. Psychiatric hospitalizations among children and adolescents increased during the pandemic; however, this appears to be a continuation of a pre-pandemic trend.

What does a threatened saproxylic beetle look like? Modelling extinction risk using a new morphological trait database.

The extinction of species is a non-random process, and understanding why some species are more likely to go extinct than others is critical for conservation efforts. Functional trait-based approaches offer a promising tool to achieve this goal. In forests, deadwood-dependent (saproxylic) beetles comprise a major part of threatened species, but analyses of their extinction risk have been hindered by the availability of suitable morphological traits. To better understand the mechanisms underlying extinction in insects, we investigated the relationships between morphological features and the extinction risk of saproxylic beetles. Specifically, we hypothesised that species darker in colour, with a larger and rounder body, a lower mobility, lower sensory perception and more robust mandibles are at higher risk. We first developed a protocol for morphological trait measurements and present a database of 37 traits for 1,157 European saproxylic beetle species. Based on 13 selected, independent traits characterising aspects of colour, body shape, locomotion, sensory perception and foraging, we used a proportional-odds multiple linear mixed-effects model to model the German Red List categories of 744 species as an ordinal index of extinction risk. Six out of 13 traits correlated significantly with extinction risk. Larger species as well as species with a broad and round body had a higher extinction risk than small, slim and flattened species. Species with short wings had a higher extinction risk than those with long wings. On the contrary, extinction risk increased with decreasing wing load and with higher mandibular aspect ratio (shorter and more robust mandibles). Our study provides new insights into how morphological traits, beyond the widely used body size, determine the extinction risk of saproxylic beetles. Moreover, our approach shows that the morphological characteristics of beetles can be comprehensively represented by a selection of 13 traits. We recommend them as a starting point for functional analyses in the rapidly growing field of ecological and conservation studies of deadwood.

Validation of boar taint detection by sensory quality control: relationship between sample size and uncertainty of performance indicators.

To prevent impaired consumer acceptance due to insensitive sensory quality control, it is of primary importance to periodically validate the performance of the assessors. This communication show cases how the uncertainty of sensitivity and specificity estimates is influenced by the total number of assessed samples and the prevalence of positive (here: boar tainted) samples. Furthermore, a statistically sound approach to determining the sample size that is necessary for performance validation is provided. Results show that a small sample size is associated with large uncertainty, i.e., confidence intervals and thus compromising the point estimates for assessor sensitivity. In turn, to reliably identify sensitive assessors with sufficient test power, a large sample size is needed given a certain level of confidence. Easy-to-use tables for sample size estimations are provided.

What's (in) a real smoothie. A division of linguistic labour in consumers' acceptance of name-product combinations?

Is being, say, a macaroon or a smoothie a matter of what these products look and taste like and how they feel in the mouth? Or is it a matter of which ingredients have been used and how they have been processed? Will ordinary consumers always rely on their own judgment in such matters, or delegate the final judgment to experts of some sort? The present experimental study addressed these issues in combination by testing the limits for consumers' acceptance of three different name-product combinations when exposed to taste samples alone (sensory product attributes), taste samples in combination with ingredients lists and nutrition facts (adding factual information), and both, in combination with authoritative definitions (adding experts' final judgments). The examples were modelled around authentic cases from the Danish food market which have been subject to vast legal as well as public concern. The results provide new insights into the socio-cognitive dynamics behind consumers' acceptance or rejection of specific name-product combinations and new leads for supporting the fairness of food naming practices with a view also to the product type, the stage it has reached in its life-cycle, and its degree of familiarity on the market.

Higher total serum cholesterol levels are associated with less severe strokes and lower all-cause mortality: ten-year follow-up of ischemic strokes in the Copenhagen Stroke Study.

BACKGROUND AND PURPOSE: Evidence of a causal relation between serum cholesterol and stroke is inconsistent. We investigated the relation between total serum cholesterol and both stroke severity and poststroke mortality to test the hypothesis that hypercholesterolemia is primarily associated with minor stroke. METHODS: In the study, 652 unselected patients with ischemic stroke arrived at the hospital within 24 hours of stroke onset. A measure of total serum cholesterol was obtained in 513 (79%) within the 24-hour time window. Stroke severity was measured with the Scandinavian Stroke Scale (0=worst, 58=best); a full cardiovascular risk profile was established for all. Death within 10 years after stroke onset was obtained from the Danish Registry of Persons. RESULTS: Mean+/-SD age of the 513 patients was 75+/-10 years, 54% were women, and the mean+/-SD Scandinavian Stroke Scale score was 39+/-17. Serum cholesterol was inversely and almost linearly related to stroke severity: an increase of 1 mmol/L in total serum cholesterol resulted in an increase in the Scandinavian Stroke Scale score of 1.32 (95% CI, 0.28 to 2.36, P=0.013), meaning that higher cholesterol levels are associated with less severe strokes. A survival analysis revealed an inverse linear relation between serum cholesterol and mortality, meaning that an increase of 1 mmol/L in cholesterol results in a hazard ratio of 0.89 (95% CI, 0.82 to 0.97, P=0.01). CONCLUSIONS: The results of our study support the hypothesis that a higher cholesterol level favors development of minor strokes. Because of selection, therefore, major strokes are more often seen in patients with lower cholesterol levels. Poststroke mortality, therefore, is inversely related to cholesterol.