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.

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.

Immune cell composition in unipolar depression: a comprehensive systematic review and meta-analysis.

Depression has been associated with inflammatory pathophysiological mechanisms, including alterations in amount of circulating immune cells. However, no meta-analysis within the past 20 years have reevaluated the circulating immune cells in blood and cerebrospinal fluid (CSF) from patients with depression compared to healthy controls. The aim of this study was to systematically evaluate the circulating immune cells in blood and CSF from patients with unipolar depression compared to healthy controls. Databases were searched up until February 12, 2021. Data-extraction was performed by two independent reviewers. 104 studies were included in the meta-analysis using fixed and random-effects models. Patients with depression had a significantly higher overall leukocyte count (35 studies; SMD, 0.46; 95% CI: 0.31-0.60, I2 = 68%), higher neutrophil count (24 studies; SMD, 0.52; 95% CI: 0.33-0.71, I2 = 77%) and higher monocyte count (27 studies; SMD, 0.32; 95% CI: 0.11-0.53, I2 = 77%) compared to healthy controls. Leukocyte counts were higher in inpatients, indicating a relation to depression severity. Furthermore, there were significant alterations in several lymphocyte subsets, including higher natural killer cells and T cell subsets. Higher neutrophil/lymphocyte ratio (11 studies; SMD = 0.24; 95% CI: 0.06-0.42, I2 = 73%), CD4/CD8 cell-ratio (26 studies; SMD = 0.14; 95% CI: 0.01-0.28, I2 = 42%) and T helper 17/T regulatory ratio (2 studies; SMD = 1.05; 95% CI: 0.15-1.95, I2 = 86%) were found in patients compared to healthy controls. CSF white cell count was higher in patients compared to controls (3 studies; SMD = 0.20; 95% CI: 0.01-0.38, I2 = 0%). There were no data for CSF cell subsets. This study suggests that there are several blood immune cell alterations in patients with unipolar depression compared to healthy controls, both in major leukocyte subsets and more specialized immune cell subsets.

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.

Effect of mode of birth on development of mental disorders in the offspring.

OBJECTIVE: Increasing rates of caesarean sections has led to concerns about long-term effects on the offspring's health, and it has been hypothesised that caesarean section induced differences in the child's microbiota could potentially increase the risk of mental disorders. METHODS: Nationwide Danish cohort study of 2,196,687 births was conducted between 1980 and 2015, with 38.5 million observation-years. Exposure was 'Caesarean Section' and outcome was the child's risk of any mental disorder. Absolute and relative risks (RRs) were estimated using inverse probability weighting to adjust for age, calendar time and confounding variables while accounting for the competing risk of death. RESULTS: Caesarean section (n = 364,908, 16.6%), compared to vaginal birth, was associated with a small RR increase of 8% (RR, 1.08; 95% CI, 1.04-1.13; n = 44,352) for the development of any in-patient psychiatric admission at age 36 for the offspring and with a small absolute risk difference of 0.47% (95% CI, 0.23-0.76). When looking at all in-patient, out-patient and emergency room psychiatric contacts among people born after 1995, the effect was diminished (RR, 1.04; 95% CI, 0.99-1.09; n = 15,211). The risk was comparable when comparing prelabour versus intrapartum caesarean section (RR, 0.98; 95% CI, 0.90-1.08) and acute versus planned caesarean section (RR, 1.00; 95% CI, 0.80-1.29). CONCLUSION: Birth by caesarean section was associated with only a very slightly increased risk of any in-patient psychiatric admission for the offspring and diminished even further when including all psychiatric contacts. The very small associations observed may be explained by unmeasured confounding and is unlikely to be of substantial clinical relevance.

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.

Genetic and psychosocial influence on the association between early childhood infections and later psychiatric disorders.

OBJECTIVE: To evaluate the influence of extensive genetic and psychosocial confounding on the association between early childhood infection and five major psychiatric disorders METHODS: A case-cohort study including participants from the Danish iPSYCH2012 sample, a case-cohort sample where all cases born between May 1, 1981, and December 31, 2005, diagnosed with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar affective disorder (BIP), Major Depressive Disorder (MDD) or schizophrenia (SCZ), were identified and pooled with a representative sample (subcohort) of the Danish population. We used Cox proportional hazards regression customized to the case-cohort setup to calculate hazard ratios of outcome with 95% confidence intervals (CIs), following exposure to early childhood infection before the age of 5 years for ADHD and ASD, and before the age of 10 years for BIP, MDD, and SCZ. To evaluate psychosocial confounding we included sex, calendar period, sibling infections, urbanicity, parental socio-economic status, parental mental health information, and polygenic risk scores for all five disorders, as covariates. To estimate how liability for psychiatric disorders measured through the PRS influenced the risk of early childhood infection, we calculated odds ratios (ORs) with 95% CIs, using logistic regression RESULTS: Early childhood infection was associated with ADHD, ASD, MDD, and SCZ with number of childhood infections increasing the hazard. The HR was still significant in the model with full adjustments after 1 infection for ADHD (HR 1.29, 95% CI: 1.19-1.41), ASD (HR 1.28, 95% CI: 1.18-1.40), MDD (HR 1.23, 95% CI: 1.14-1.33), and SCZ (HR 1.21, 95% CI: 1.07-1.36), but not for BIP (HR1.17, 95% CI: 0.96-1.42). Probands exposed to sibling infections, but not own infection had an absolute risk of ADHD, BIP, MDD, and SCZ that closely approached the absolute risk for individuals exposed to own infections. We found evidence of gene-environment correlation with higher PRS of MDD and to some extent SCZ increasing the risk of infections and higher PRS of BIP associated with significantly decreased risk CONCLUSION: Early childhood infection is significantly associated with ADHD, ASD, MDD, and SCZ and not explained by genetic or psychosocial confounding. Although we found evidence of gene-environment correlation, it had minor impact on the results.

Neuroimmunological investigations of cerebrospinal fluid in patients with recent onset depression - a study protocol.

BACKGROUND: A proinflammatory response has been suggested to be involved in the pathophysiology of depression in a subgroup of patients. However, comprehensive largescale studies on neuroimmunological investigations of the cerebrospinal fluid (CSF) are lacking and no largescale longitudinal CSF studies comparing patients with depression to healthy controls currently exist. METHODS: A longitudinal case-control study including at least 100 patients with first time depression (ICD-10: F32) within the past year with ongoing symptoms and at least 100 sex and age matched healthy controls with collection of CSF, blood, and fecal samples. All individuals will be evaluated by neurological examination including neurological soft signs, interviewed for psychopathology assessment and have symptomatology evaluated by relevant rating scales. Level of functioning and quality of life will be evaluated by a panel of interview questions and rating scales, and cognitive function assessed by a relevant test battery. In addition, a large number of potential confounders will be registered (BMI, smoking status, current medication etc.). Primary outcomes: CSF white cell count, CSF/serum albumin ratio, CSF total protein levels, IgG index, CSF levels of IL-6 and IL-8, and the prevalence of any CNS-reactive autoantibody in CSF and/or blood. SECONDARY OUTCOMES: exploratory analyses of a wide range of neuroimmunological markers and specific autoantibodies. Power calculations are computed for all primary outcomes based on previous CSF studies including patients with depression and healthy controls. DISCUSSION: This study will represent the hitherto largest investigation of CSF in patients with recent onset depression compared to healthy controls. We expect to elucidate neuroimmunological alterations in individuals with depression and characterize an immunological profile paving the way for the development of effective treatments based on biomarkers. 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).

Examine the public health impacts of functional somatic disorders using the DanFunD study.

Background: Persistent physical symptoms (e.g. pain, fatigue) are prevalent in the population and some persons may develop a functional somatic disorder (FSD). We still need to explore the limits between general bodily sensations and FSD, and great controversies exist as regard delimitation, occurrence, risk factors, prognosis, and costs of FSD in the general population. This is mainly due to the lack of focused, sufficient powered, population-based epidemiological studies. Material and Methods: The DanFunD study is the largest focused population-based study on FSD and has the potential to answer these crucial questions regarding the FSD disorders. DanFunD has its origin in the Copenhagen area of Denmark and was initiated in 2009 by an interdisciplinary team of researchers including basic scientists, clinical researchers, epidemiologists, and public health researchers. A population-based cohort of nearly 10,000 people have filled in detailed questionnaires, gone through a thorough health examination, and a biobank is established. The cohort was re-examined after five years. Results:The prevalence of FSD in the Danish population is about 10-15% and is twice as common in women as in men. Persons with FSD report impaired daily activities and low self-perceived health, which qualifies FSD as a major public health problem. The research plan to unravel the risk factors for FSD employs a bio-psycho-social approach according to a detailed plan. Preliminary results are presented, and work is in progress. Likewise, plans for assessing prognosis and health care costs are provided. Conclusion: We invite researchers in the field to collaborate on this unique data material.

Infectious mononucleosis as a risk factor for depression: A nationwide cohort study.

BACKGROUND: Infectious mononucleosis is a clinical diagnosis characterized by fever, sore throat, lymph node enlargement and often prolonged fatigue, most commonly caused by Epstein-Barr virus infection. Previous studies have indicated that infectious mononucleosis can be followed by depression; however, large-scale studies are lacking. We used nationwide registry data to investigate the association between infectious mononucleosis and subsequent depression in this first large-scale study. METHODS: Prospective cohort study using nationwide Danish registers covering all 1,440,590 singletons born (1977-2005) in Denmark by Danish born parents (21,830,542 person-years' follow-up until 2016); where 12,510 individuals had a hospital contact with infectious mononucleosis. The main outcome measures were a diagnosis of major depressive disorder (ICD-8: 296.09, 298.09, 300.4; ICD-10: F32) requiring hospital contact. RESULTS: Infectious mononucleosis was associated with a 40% increased hazard ratio (HR) for a subsequent depression diagnosis in the fully adjusted model (HR: 1.40, 95% CI: 1.26-1.56;n = 358), when compared to unexposed individuals. The increased risk of being diagnosed with depression was significant to the periods one to four years after the infectious mononucleosis diagnosis (HR: 1.40, 95% CI: 1.17-1.67;n = 121) and ≥ five years (HR: 1.40, 95% CI: 1.22-1.61;n = 207). We did not find any differences according to age (p = 0.61) nor sex (p = 0.30). CONCLUSION: In this largest study to date, infectious mononucleosis in childhood or adolescence was associated with an increased risk of a subsequent depression. Our findings have important clinical implications and identifies youth with infectious mononucleosis as a group at high risk of later depression in young adulthood.

Cerebrospinal fluid test results and associations with subsequent mental disorders, neurological diseases, and CNS infections: A population-based cohort study.

BACKGROUND: Cerebrospinal fluid (CSF) immune alterations have been associated with mental disorders, neurological disease, and CNS infections; however, comprehensive large-scale longitudinal CSF studies are lacking. METHODS: By using the Clinical Laboratory Information System (LABKA) Research Database in the Central Denmark Region (1994-2012), we included 15,030 individuals tested for CSF WBC, CSF/serum albumin ratio, IgG index, total protein, albumin, or IgG with follow-up for the risk of mental disorders, psychotropic prescriptions, neurological diseases, or CNS infections, estimated by Cox regression. RESULTS: Among individuals receiving a mental disorder diagnosis (N = 1,147) after a CSF test, 30·0% had an abnormal CSF test result, while for those with a neurological disease (N = 3,201), 39·9% had abnormal test results, and among individuals with CNS infections (N = 1,276), 73·0% had abnormal test results. Individuals with abnormal CSF test results had an increased risk of mental disorders (HR = 3·20; 95%CI = 2·86-3·59), neurological diseases (HR = 12·40; 95%CI = 11·65-13·20), and CNS infections (HR = 338·59; 95%CI = 299·06-383·35) compared to individuals not registered with a CSF test. However, the risk of mental disorders was higher (P < 0·001) after CSF test results within the normal range (HR = 4·45; 95%CI = 4·08-4·86), whereas for neurological diseases (HR = 9·72; 95%CI = 9·19-10·29) and CNS infections (HR = 55·17; 95%CI = 47·12-64·60), the risk was highest after abnormal CSF test results (all P < 0·001). The risk of organic mental disorders tended to be highest in individuals with abnormal CSF test results (HR = 19·30; 95%CI = 13·44-27·71) even though not significantly different from the risk in the group of individuals with CSF test results in the normal range (HR = 13·55; 95%CI = 9·36-19·60) (P ≥ 0·05). Abnormal CSF test results were associated with an elevated risk of psychotropic prescriptions (HR = 3·91; 95%CI = 3·66-4·18), as were CSF test results within the normal range (HR = 4·26; 95%CI = 4·03-4·51) (P < 0·05). CONCLUSIONS: Immunological CSF abnormalities are associated with an increased risk of mental disorders, neurological disease, and particularly CNS infections; however, the included CSF parameters were not specific for mental disorders and the relevant CSF biomarkers in psychiatry are yet to be discovered.

Number of traumatic brain injuries and temporal associations with depression: A register-based cohort study.

OBJECTIVE: To explore the association of the number of traumatic brain injuries (TBIs) and temporal associations with the subsequent risk of depression in the population. METHODS: National register-based cohort study on all individuals registered with TBI (ICD-10: S06, ICD-8: 85.0-85.5) from 1977 to 2015 in Denmark (n = 494,216) and a sex- and age-matched reference population (n = 499,505). The associations with the number of TBIs and time to depression (0-6, 7-12 and more than 12 months following TBI) were analyzed using Cox proportional hazard regression. RESULTS: During a follow-up of mean 14.5 (SD 11.3) years, a total of 27,873 (5.6%) individuals who had at least one TBI and 15,195 (3.0%) in the reference population were diagnosed with a depression. First-time TBI was associated with a higher risk of depression in both men (HR = 1.73 [95% CI:1.67-1.79]) and women (HR = 1.66 [95% CI:1.61-1.70]) after multiple adjustments for educational status and comorbidities including previous depression, and the association became stronger in a dose-response association with the number of TBIs (test for trend p < 0.01). The HRs for depression were highest the first 6 months after the TBI in both men (HR = 5.69 [95% CI:4.66-6.94]) and women (HR = 4.55 [95% CI:3.93-5.26]) and decreased gradually the following year but remained elevated from one year after TBI until end of follow-up independent of the number of TBIs (p < 0.01). The associations did not vary with age or calendar time. CONCLUSION: Traumatic brain injury is associated with a higher risk of depression, especially in the first months after TBI and the risk increases with the number of TBIs.

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.

The impact of the Covid-19 pandemic on mental and physical health in Denmark - a longitudinal population-based study before and during the first wave.

BACKGROUND: In the continuation of the first wave of the Covid-19 outbreak in Denmark, unprecedented restrictions with great impact on the citizen's everyday life were implemented. The objectives of this study were to investigate the influence of the Covid-19 pandemic on mental and physical health in the Danish population during the spring 2020 first wave outbreak and lockdown. METHODS: A sample from the adult Danish population (n = 2190) were included. Self-reported measures of illness worry (Whiteley-6-R), emotional distress (SCL-90), and physical symptom load (SLC-90) were obtained before and during the first wave of the pandemic and compared with Wilcoxon signed-rank tests. Impact of covariates on physical and mental health was evaluated with ordinal regression analyses. Results from a tailored questionnaire regarding the Covid-19 pandemic were presented to explore the direct impact of the pandemic. RESULTS: We only found minor increases in illness worry, emotional distress and physical symptom load (0-1 points difference, p ≤ 0.007) during the Covid-19 pandemic compared to before the pandemic. Sex, age, education, and physical disease were not associated with illness worry, emotional distress, or physical symptom load. Overall, the participants were trustful in the authorities' recommendations and felt that they managed the pandemic and the restrictions to a great extent despite that some expected great/major future consequences of the pandemic. CONCLUSIONS: This study suggested that the first wave of the Covid-19 pandemic only had minor impact on mental and physical health in the Danish general population. Future studies should address the impact of the second wave of the pandemic and the renewed implementation of the concomitant restrictions.

COVID-19 pandemic and mental health consequences: Systematic review of the current evidence.

BACKGROUND: During the COVID-19 pandemic general medical complications have received the most attention, whereas only few studies address the potential direct effect on mental health of SARS-CoV-2 and the neurotropic potential. Furthermore, the indirect effects of the pandemic on general mental health are of increasing concern, particularly since the SARS-CoV-1 epidemic (2002-2003) was associated with psychiatric complications. METHODS: We systematically searched the database Pubmed including studies measuring psychiatric symptoms or morbidities associated with COVID-19 among infected patients and among none infected groups the latter divided in psychiatric patients, health care workers and non-health care workers. RESULTS: A total of 43 studies were included. Out of these, only two studies evaluated patients with confirmed COVID-19 infection, whereas 41 evaluated the indirect effect of the pandemic (2 on patients with preexisting psychiatric disorders, 20 on medical health care workers, and 19 on the general public). 18 of the studies were case-control studies/compared to norm, while 25 of the studies had no control groups. The two studies investigating COVID-19 patients found a high level of post-traumatic stress symptoms (PTSS) (96.2%) and significantly higher level of depressive symptoms (p = 0.016). Patients with preexisting psychiatric disorders reported worsening of psychiatric symptoms. Studies investigating health care workers found increased depression/depressive symptoms, anxiety, psychological distress and poor sleep quality. Studies of the general public revealed lower psychological well-being and higher scores of anxiety and depression compared to before COVID-19, while no difference when comparing these symptoms in the initial phase of the outbreak to four weeks later. A variety of factors were associated with higher risk of psychiatric symptoms and/or low psychological well-being including female gender, poor-self-related health and relatives with COVID-19. CONCLUSION: Research evaluating the direct neuropsychiatric consequences and the indirect effects on mental health is highly needed to improve treatment, mental health care planning and for preventive measures during potential subsequent pandemics.

Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis.

Infections and inflammatory processes have been associated with the development of schizophrenia and affective disorders; however, no study has yet systematically reviewed all available studies on cerebrospinal fluid (CSF) immune alterations. We aimed to systematically review the CSF immunological findings in schizophrenia spectrum and affective disorders. We identified all studies investigating CSF inflammatory markers in persons with schizophrenia or affective disorders published prior to March 23, 2017 searching PubMed, CENTRAL, EMBASE, Psychinfo, and LILACS. Literature search, data extraction and bias assessment were performed by two independent reviewers. Meta-analyses with standardized mean difference (SMD) including 95% confidence intervals (CI) were performed on case-healthy control studies. We identified 112 CSF studies published between 1942-2016, and 32 case-healthy control studies could be included in meta-analyses. Studies varied regarding gender distribution, age, disease duration, treatment, investigated biomarkers, and whether recruitment happened consecutively or based on clinical indication. The CSF/serum albumin ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.71; 95% CI 0.33-1.09) and affective disorders (4 studies [298 patients]; SMD = 0.41; 95% CI 0.23-0.60, I2 = 0%), compared to healthy controls. Total CSF protein was elevated in both schizophrenia (3 studies [97 patients]; SMD = 0.41; 95% CI 0.15-0.67, I2 = 0%) and affective disorders (2 studies [53 patients]; SMD = 0.80; 95% CI 0.39-1.21, I2 = 0%). The IgG ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.68; 95% CI 0.30-1.06), whereas the IgG Albumin ratio was decreased (1 study [32 patients]; SMD = -0.62; 95% CI -1.13 to -0.12). Interleukin-6 (IL-6) levels (7 studies [230 patients]; SMD = 0.55; 95% CI 0.35-0.76; I2 = 1%) and IL-8 levels (3 studies [95 patients]; SMD = 0.46; 95% CI 0.17-0.75, I2 = 0%) were increased in schizophrenia but not significantly increased in affective disorders. Most of the remaining inflammatory markers were not significantly different compared to healthy controls in the meta-analyses. However, in the studies which did not include healthy controls, CSF abnormalities were more common, and two studies found CSF dependent re-diagnosis in 3.2-6%. Current findings suggest that schizophrenia and affective disorders may have CSF abnormalities including signs of blood-brain barrier impairment and inflammation. However, the available evidence does not allow any firm conclusion since all studies showed at least some degree of bias and vastly lacked inclusion of confounding factors. Moreover, only few studies investigated the same parameters with healthy controls and high-quality longitudinal CSF studies are lacking, including impact of psychotropic medications, lifestyle factors and potential benefits of anti-inflammatory treatment in subgroups with CSF inflammation.

Correction: Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis.

Following publication of this paper, the authors realised that there were some errors in the reporting of the results on IL-6. This article has now been updated to include the correct values, following re-running of all analyses. For details of the changes made, please see the associated correction. This article was also originally published under standard licence, but has now been made available under a [CC BY 4.0] licence. The PDF and HTML versions of the paper have been modified accordingly.

Psychiatric comorbidity in individuals with bullous pemphigoid and all bullous disorders in the Danish national registers.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering skin disease that takes a profound physical and mental toll on those affected. The aim of the study was to investigate the bidirectional association between BP and all bullous disorders (ABD) with a broad array of psychiatric disorders, exploring the influence of prescribed medications. METHODS: This nationwide, register-based cohort study encompassed 6,470,450 individuals born in Denmark and alive from 1994 to 2016. The hazard ratios (HRs) of a subsequent psychiatric disorder in patients with BP/ABD and the reverse exposure and outcome were evaluated. RESULTS: Several psychiatric disorders were associated with increased risk of subsequent BP (4.18-fold for intellectual disorders, 2.32-fold for substance use disorders, 2.01-fold for schizophrenia and personality disorders, 1.92-1.85-1.49-fold increased risk for organic disorders, neurotic and mood disorders), independent of psychiatric medications. The association between BP and subsequent psychiatric disorders was not significant after adjusting for BP medications, except for organic disorders (HR 1.27, CI 1.04-1.54). Similar results emerged with ABD. CONCLUSION: Psychiatric disorders increase the risk of a subsequent diagnosis of BP/ABD independent of medications, whereas medications used for the treatment of BP/ABD appear to account for the subsequent onset of psychiatric disorders. Clinically, an integrated approach attending to both dermatological and psychiatric symptoms is recommended, and dermatologists should remain vigilant for early symptoms of psychiatric disorders to decrease mental health comorbidity.

Correction to: Psychiatric comorbidity in individuals with bullous pemphigoid and all bullous disorders in the Danish national registers.

An amendment to this paper has been published and can be accessed via the original article.

Association Between Neurological Disorders and Death by Suicide in Denmark.

Importance: Neurological disorders have been linked to suicide, but the risk across a broad spectrum of neurological disorders remains to be assessed. Objectives: To examine whether people with neurological disorders die by suicide more often than other people and to assess for temporal associations. Design, Setting, and Participants: Nationwide, retrospective cohort study on all persons 15 years or older living in Denmark, from 1980 through 2016 (N = 7 300 395). Exposures: Medical contact for head injury, stroke, epilepsy, polyneuropathy, diseases of myoneural junction, Parkinson disease, multiple sclerosis, central nervous system infections, meningitis, encephalitis, amyotrophic lateral sclerosis, Huntington disease, dementia, intellectual disability, and other brain diseases from 1977 through 2016 (n = 1 248 252). Main Outcomes and Measures: Death by suicide during 1980-2016. Adjusted incidence rate ratio (IRRs) were estimated using Poisson regressions, adjusted for sociodemographics, comorbidity, psychiatric diagnoses, and self-harm. Results: Of the more than 7.3 million individuals observed over 161 935 233 person-years (49.1% males), 35 483 died by suicide (median duration of follow-up, 23.6 years; interquartile range, 10.0-37.0 years; mean age, 51.9 years; SD, 17.9 years). Of those, 77.4% were males, and 14.7% (n = 5141) were diagnosed with a neurological disorder, equivalent to a suicide rate of 44.0 per 100 000 person-years compared with 20.1 per 100 000 person-years among individuals not diagnosed with a neurological disorder. People diagnosed with a neurological disorder had an adjusted IRR of 1.8 (95% CI, 1.7-1.8) compared with those not diagnosed. The excess adjusted IRRs were 4.9 (95% CI, 3.5-6.9) for amyotrophic lateral sclerosis, 4.9 (95% CI, 3.1-7.7) for Huntington disease, 2.2 (95% CI, 1.9-2.6) for multiple sclerosis, 1.7 (95% CI, 1.6-1.7) for head injury, 1.3 (95% CI, 1.2-1.3) for stroke, and 1.7 (95% CI, 1.6-1.8) for epilepsy. The association varied according to time since diagnosis with an adjusted IRR for 1 to 3 months of 3.1 (95% CI, 2.7-3.6) and for 10 or more years, 1.5 (95% CI, 1.4 to 1.6, P < .001). Compared with those who were not diagnosed with a neurological disorder, those with dementia had a lower overall adjusted IRR of 0.8 (95% CI, 0.7-0.9), which was elevated during the first month after diagnosis to 3.0 (95% CI, 1.9-4.6; P < .001). The absolute risk of suicide for people with Huntington disease was 1.6% (95% CI, 1.0%-2.5%). Conclusions and Relevance: In Denmark from 1980 through 2016, there was a significantly higher rate of suicide among those with a diagnosed neurological disorder than persons not diagnosed with a neurological disorder. However, the absolute risk difference was small.