Is reduced heart rate variability associated with functional somatic disorders? A cross-sectional population-based study; DanFunD.

OBJECTIVES: It has been hypothesised that functional somatic disorders (FSD) could be initiated by sympathetic predominance in the autonomic nervous system as measured by low heart rate variability (HRV). Earlier studies on the association between HRV and FSD are small case-control studies hampered by selection bias and do not consider the great overlap between the various FSDs. The aim of the present study is to assess any associations between HRV and various FSDs and whether chronic stress confounds such an association. DESIGN: A cross-sectional general population-based study. SETTING: The Danish Study of Functional Somatic Disorders conducted 2013-2015 in 10 municipalities in the western part of Greater Copenhagen, Denmark. PARTICIPANTS: A total of 6891 men and women aged 18-72 years were included in the analyses after exclusion of 602 persons with missing HRV data. Various delimitations of FSD (chronic fatigue, chronic widespread pain, irritable bowel and bodily distress syndrome) were identified by validated questionnaires and diagnostic interviews. HRV parameters in time and frequency domains were calculated from successive beat-to-beat heart rate (HR) data using the 'E-motion' HR monitor device during 7 min of supine rest. Chronic stress was assessed by Cohen's self-perceived stress scale. OUTCOME MEASURES: Logistic regression analyses were used to calculate possible associations between the various delimitations of FSD and HRV adjusting for chronic stress. RESULTS: Persons with FSD had a slightly higher mean HR and lower HRV as measured by time domain parameters, whereas associations with frequency domain parameters were not consistent. Adjusting for chronic stress attenuated associations slightly. CONCLUSION: The study supports a sympathetic predominance in persons with FSD, which could not be entirely explained by chronic stress. However, it is not possible to conclude whether the association is a causal factor to or a consequence of FSD.

Lipid metabolism and functional somatic disorders in the general population. The DanFunD study.

OBJECTIVES: Earlier studies on the association between plasma lipid profiles and functional somatic disorders (FSD) are mainly small case control studies hampered by selection bias and do not consider the great overlap between the various FSDs. The aim of the present study was to investigate the associations between various FSDs and plasma lipid profiles (total cholesterol, HDL cholesterol, non-HDL cholesterol and triglycerides) in a large, unselected population. DESIGN: A cross-sectional general population-based study. SETTING: The Danish Study of Functional Somatic Disorders (DanFunD) conducted in 2011-2015 in 10 municipalities in the western part of greater Copenhagen, Denmark. PARTICIPANTS: A total of 8,608 men and women aged 18-76 years were included in the analyses. Various delimitations of FSD such as chronic fatigue, chronic widespread pain, irritable bowel, and bodily distress syndrome were measured using validated self-administrated questionnaires. Lipid parameters were measured from fasting plasma samples using colorimetric slide methods with Vitros 4600/5600 Ortho Clinical Diagnostics. OUTCOME MEASURES: Logistic regression analyses were used to calculate possible associations between plasma lipids and the various delimitations of FSD. Associations are presented by OR (95% CI) and shown in boxplots. RESULTS: We found a positive association between bodily distress syndrome and triglycerides and non-HDL cholesterol and a negative association with HDL-cholesterol, but no consistent association with total cholesterol. A similar pattern was observed for persons with chronic fatigue, and to some degree for persons with chronic widespread pain, whereas persons with irritable bowel did not show a clear association with the lipid profiles. CONCLUSION: This is the first major study on plasma lipid profiles and FSD indicating an association between some delimitations of FSD and an unfavorable lipid profile. Due to the cross-sectional design, it cannot be determined whether the findings are consequences or determinants of FSD. Further studies-preferable prospective studies-are needed.

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.

Brain Health After COVID-19, Pneumonia, Myocardial Infarction, or Critical Illness.

Importance: Brain health is most likely compromised after hospitalization for COVID-19; however, long-term prospective investigations with matched control cohorts and face-to-face assessments are lacking. Objective: To assess whether long-term cognitive, psychiatric, or neurological complications among patients hospitalized for COVID-19 differ from those among patients hospitalized for other medical conditions of similar severity and from healthy controls. Design, Setting, and Participants: This prospective cohort study with matched controls was conducted at 2 academic hospitals in Copenhagen, Denmark. The case cohort comprised patients with COVID-19 hospitalized between March 1, 2020, and March 31, 2021. Control cohorts consisted of patients hospitalized for pneumonia, myocardial infarction, or non-COVID-19 intensive care-requiring illness between March 1, 2020, and June 30, 2021, and healthy age- and sex-matched individuals. The follow-up period was 18 months; participants were evaluated between November 1, 2021, and February 28, 2023. Exposures: Hospitalization for COVID-19. Main Outcomes and Measures: The primary outcome was overall cognition, assessed by the Screen for Cognitive Impairment in Psychiatry (SCIP) and the Montreal Cognitive Assessment (MoCA). Secondary outcomes were executive function, anxiety, depressive symptoms, and neurological deficits. Results: The study included 345 participants, including 120 patients with COVID-19 (mean [SD] age, 60.8 [14.4] years; 70 men [58.3%]), 125 hospitalized controls (mean [SD] age, 66.0 [12.0] years; 73 men [58.4%]), and 100 healthy controls (mean [SD] age, 62.9 [15.3] years; 46 men [46.0%]). Patients with COVID-19 had worse cognitive status than healthy controls (estimated mean SCIP score, 59.0 [95% CI, 56.9-61.2] vs 68.8 [95% CI, 66.2-71.5]; estimated mean MoCA score, 26.5 [95% CI, 26.0-27.0] vs 28.2 [95% CI, 27.8-28.6]), but not hospitalized controls (mean SCIP score, 61.6 [95% CI, 59.1-64.1]; mean MoCA score, 27.2 [95% CI, 26.8-27.7]). Patients with COVID-19 also performed worse than healthy controls during all other psychiatric and neurological assessments. However, except for executive dysfunction (Trail Making Test Part B; relative mean difference, 1.15 [95% CI, 1.01-1.31]), the brain health of patients with COVID-19 was not more impaired than among hospitalized control patients. These results remained consistent across various sensitivity analyses. Conclusions and Relevance: This prospective cohort study suggests that post-COVID-19 brain health was impaired but, overall, no more than the brain health of patients from 3 non-COVID-19 cohorts of comparable disease severity. Long-term associations with brain health might not be specific to COVID-19 but associated with overall illness severity and hospitalization. This information is important for putting understandable concerns about brain health after COVID-19 into perspective.

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.

Adjunctive agents to antipsychotics in schizophrenia: a systematic umbrella review and recommendations for amino acids, hormonal therapies and anti-inflammatory drugs.

QUESTION: This umbrella review and guidelines aimed to provide evidence to support the rational choice of selected adjunctive therapies for schizophrenia. STUDY SELECTION AND ANALYSIS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and World Federation of Societies of Biological Psychiatry (WFSBP)-grading recommendations, 63 randomised control trials (RCTs) (of which 4219 unique participants have completed the RCTs) and 29 meta-analyses were analysed. FINDINGS: Provisional recommendations (WFSBP-grade 1) could be made for two molecules in augmentation to antipsychotics: (1) N-acetyl-cysteine (NAC, 1200-3600 mg/day, for >12 consecutive weeks) in improving negative symptoms, general psychopathology (positive and negative syndrome scale for schizophrenia (PANSS) general psychopathology factor (G)-G subscale), with the RCTs with the longer duration showing the most robust findings; (2) polyunsaturated fatty acids (3000 mg/day of eicosapentaenoic acid, for >12 weeks) in improving general psychopathology. Weaker recommendations (ie, WFSBP-grade 2) could be drawn for sarcosine (2 g/day) and minocycline (200-300 mg/day) for improving negative symptoms in chronic schizophrenia (not early schizophrenia), and NAC for improving positive symptoms and cognition. Weak recommendations are not ready for clinical practice. There is provisional evidence that oestrogens and raloxifene are effective in some patients, but further research is needed to determine their benefit/risk ratio. CONCLUSIONS: The results of this umbrella review should be interpreted with caution as the number of RCTs included in the meta-analyses was generally small and the effect sizes were weak or medium. For NAC, two RCTs with low risk of bias have provided conflicting results and the WFSBP-grade recommendation included also the results of meta-analyses. These drugs could be provisionally prescribed for patients for whom no other treatments have been effective, but they should be discontinued if they prove ineffective.

Immunological Biomarkers as Predictors of Treatment Response in Psychotic Disorders.

Psychotic disorders, notably schizophrenia, impose a detrimental burden on both an individual and a societal level. The mechanisms leading to psychotic disorders are multifaceted, with genetics and environmental factors playing major roles. Increasing evidence additionally implicates neuro-inflammatory processes within at least a subgroup of patients with psychosis. While numerous studies have investigated anti-inflammatory add-on treatments to current antipsychotics, the exploration of immunological biomarkers as a predictor of treatment response remains limited. This review outlines the current evidence from trials exploring the potential of baseline inflammatory biomarkers as predictors of the treatment effect of anti-inflammatory drugs as add-ons to antipsychotics and of antipsychotics alone. Several of the studies have found correlations between baseline immunological biomarkers and treatment response; however, only a few studies incorporated baseline biomarkers as a primary endpoint, and the findings thus need to be interpreted with caution. Our review emphasizes the need for additional research on the potential of repurposing anti-inflammatory drugs while utilizing baseline inflammatory biomarkers as a predictor of treatment response and to identify subgroups of individuals with psychotic disorders where add-on treatment with immunomodulating agents would be warranted. Future studies investigating the correlation between baseline inflammatory markers and treatment responses can pave the way for personalized medicine approaches in psychiatry centred around biomarkers such as specific baseline inflammatory biomarkers in 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.

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.

Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models.

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug-omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug-drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.

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.

The Immune System and Depression: From Epidemiological to Clinical Evidence.

Depression is a frequent mental disorder with a substantial contribution to years lived with disability worldwide. In the search for new treatment targets, the immune system's contribution to the pathogenesis of depression has received increased attention as immune activation has been associated with depression in various epidemiological and case-control studies. Epidemiological studies have shown that immune exposures such as severe infections and autoimmune disorders increase the risk of depression. Furthermore, immune system activation has been indicated in case-control studies of depression revealing higher levels of key pro-inflammatory cytokines among patients with depression than healthy controls, particularly in blood and to some extent in the cerebrospinal fluid. Moreover, brain imaging studies indicate increased microglial activity during depression, and gut microbiota studies have documented alterations of gut microbiota composition to be associated with depression. Based on findings from animal and human studies, several immune-mediated molecular mechanisms have been suggested to underlie the association between increased immunological activity and depression. However, the research is challenged by the heterogeneity of the depression diagnosis and - to some extent - the precision of currently available technology for immune biomarker quantification, particularly regarding the assessment of low-grade neuroinflammation. Nonetheless, an enhanced understanding of the complex interactions between the immune system and the brain in the context of depression could pave the way for precision medicine approaches with immune-modulating treatment as a promising additional option in the treatment of depression.

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.

Deep Learning for Cross-Diagnostic Prediction of Mental Disorder Diagnosis and Prognosis Using Danish Nationwide Register and Genetic Data.

Importance: Diagnoses and treatment of mental disorders are hampered by the current lack of objective markers needed to provide a more precise diagnosis and treatment strategy. Objective: To develop deep learning models to predict mental disorder diagnosis and severity spanning multiple diagnoses using nationwide register data, family and patient-specific diagnostic history, birth-related measurement, and genetics. Design, Setting, and Participants: This study was conducted from May 1, 1981, to December 31, 2016. For the analysis, which used a Danish population-based case-cohort sample of individuals born between 1981 and 2005, genotype data and matched longitudinal health register data were taken from the longitudinal Danish population-based Integrative Psychiatric Research Consortium 2012 case-cohort study. Included were individuals with mental disorders (attention-deficit/hyperactivity disorder [ADHD]), autism spectrum disorder (ASD), major depressive disorder (MDD), bipolar disorder (BD), schizophrenia spectrum disorders (SCZ), and population controls. Data were analyzed from February 1, 2021, to January 24, 2022. Exposure: At least 1 hospital contact with diagnosis of ADHD, ASD, MDD, BD, or SCZ. Main Outcomes and Measures: The predictability of (1) mental disorder diagnosis and (2) severity trajectories (measured by future outpatient hospital contacts, admissions, and suicide attempts) were investigated using both a cross-diagnostic and single-disorder setup. Predictive power was measured by AUC, accuracy, and Matthews correlation coefficient (MCC), including an estimate of feature importance. Results: A total of 63 535 individuals (mean [SD] age, 23 [7] years; 34 944 male [55%]; 28 591 female [45%]) were included in the model. Based on data prior to diagnosis, the specific diagnosis was predicted in a multidiagnostic prediction model including the background population with an overall area under the curve (AUC) of 0.81 and MCC of 0.28, whereas the single-disorder models gave AUCs/MCCs of 0.84/0.54 for SCZ, 0.79/0.41 for BD, 0.77/0.39 for ASD, 0.74/0.38, for ADHD, and 0.74/0.38 for MDD. The most important data sets for multidiagnostic prediction were previous mental disorders and age (11%-23% reduction in prediction accuracy when removed) followed by family diagnoses, birth-related measurements, and genetic data (3%-5% reduction in prediction accuracy when removed). Furthermore, when predicting subsequent disease trajectories of the disorder, the most severe cases were the most easily predictable, with an AUC of 0.72. Conclusions and Relevance: Results of this diagnostic study suggest the possibility of combining genetics and registry data to predict both mental disorder diagnosis and disorder progression in a clinically relevant, cross-diagnostic setting prior to clinical assessment.

Association between infections and functional somatic disorders: a cross-sectional population-based cohort study.

OBJECTIVES: It has been suggested that infections can trigger functional somatic disorders (FSD). However, current evidence is limited by inconsistent findings in smaller studies conducted in clinical settings within selected populations and short follow-up times. We aimed to test the hypothesis that former infections are associated with FSD using data from nationwide registries and a large population-based cohort study, the Danish Study of Functional Disorders study. DESIGN: FSD cases were identified in a cross-sectional population-based cohort and linked retrospectively to former hospital contacts with infections identified in the Danish National Patient Registry. The associations between FSD and former infections within 17 years were analysed using logistic regressions to calculate ORs and 95% CIs adjusted for age, sex and subjective social status. SETTING: A population-based cohort in Denmark examined between 2011 and 2015. PARTICIPANTS: A total of 9656 men and women aged 18-76 years. MAIN OUTCOME MEASURES: FSD measured by various delimitations, including bodily distress syndrome (BDS), irritable bowel (IB), chronic fatigue (CF), chronic widespread pain (CWP), and multiple chemical sensitivity (MCS). RESULTS: Overall, infections were associated with increased risk of all delimitations of FSD. The associations were more pronounced for multisystemic FSD. The number of prior infections increased the risk in a dose-response manner (p<0.0001). Bacterial but not viral infections were significantly associated with BDS (OR 1.69 (95% CI 1.46 to 1.96)), IB (OR 1.41 (95% CI 1.06 to 1.88)), CWP (OR 1.47 (95% CI 1.13 to 1.90)) and CF (OR 1.62 (95% CI 1.34 to 1.96)), but not MCS. CONCLUSION: Former infections leading to hospital contacts were associated with a higher risk of having FSD. These associations were more pronounced for bacterial than viral infections, and more infections increased the risk in a dose-response manner. These results tend to support the idea that severe infections could play a role in FSD.