Immune-based Machine learning Prediction of Diagnosis and Illness State in Schizophrenia and Bipolar Disorder.

BACKGROUND: Schizophrenia and bipolar disorder frequently face significant delay in diagnosis, leading to being missed or misdiagnosed in early stages. Both disorders have also been associated with trait and state immune abnormalities. Recent machine learning-based studies have shown encouraging results using diagnostic biomarkers in predictive models, but few have focused on immune-based markers. Our main objective was to develop supervised machine learning models to predict diagnosis and illness state in schizophrenia and bipolar disorder using only a panel of peripheral kynurenine metabolites and cytokines. METHODS: The cross-sectional I-GIVE cohort included hospitalized acute bipolar patients (n = 205), stable bipolar outpatients (n = 116), hospitalized acute schizophrenia patients (n = 111), stable schizophrenia outpatients (n = 75) and healthy controls (n = 185). Serum kynurenine metabolites, namely tryptophan (TRP), kynurenine (KYN), kynurenic acid (KA), quinaldic acid (QUINA), xanthurenic acid (XA), quinolinic acid (QUINO) and picolinic acid (PICO) were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS), while V-plex Human Cytokine Assays were used to measure cytokines (interleukin-6 (IL-6), IL-8, IL-17, IL-12/IL23-P40, tumor necrosis factor-alpha (TNF-ɑ), interferon-gamma (IFN-γ)). Supervised machine learning models were performed using JMP Pro 17.0.0. We compared a primary analysis using nested cross-validation to a split set as sensitivity analysis. Post-hoc, we re-ran the models using only the significant features to obtain the key markers. RESULTS: The models yielded a good Area Under the Curve (AUC) (0.804, Positive Prediction Value (PPV) = 86.95; Negative Prediction Value (NPV) = 54.61) for distinguishing all patients from controls. This implies that a positive test is highly accurate in identifying the patients, but a negative test is inconclusive. Both schizophrenia patients and bipolar patients could each be separated from controls with a good accuracy (SCZ AUC 0.824; BD AUC 0.802). Overall, increased levels of IL-6, TNF-ɑ and PICO and decreased levels of IFN-γ and QUINO were predictive for an individual being classified as a patient. Classification of acute versus stable patients reached a fair AUC of 0.713. The differentiation between schizophrenia and bipolar disorder yielded a poor AUC of 0.627. CONCLUSIONS: This study highlights the potential of using immune-based measures to build predictive classification models in schizophrenia and bipolar disorder, with IL-6, TNF-ɑ, IFN-γ, QUINO and PICO as key candidates. While machine learning models successfully distinguished schizophrenia and bipolar disorder from controls, the challenges in differentiating schizophrenic from bipolar patients likely reflect shared immunological pathways by the both disorders and confounding by a larger state-specific effect. Larger multi-centric studies and multi-domain models are needed to enhance reliability and translation into clinic.

Low-dose interleukin-2 in patients with bipolar depression: A phase 2 randomised double-blind placebo-controlled trial.

Immune abnormalities including an insufficiency of regulatory T cells (Treg) and increased blood-based inflammatory markers have been observed in bipolar disorders (BD), particularly during depression. As Tregs are pivotal to control inflammation, Treg stimulation by low-dose IL-2 (IL-2LD) could have a therapeutic impact on bipolar depression. We performed a randomized, double-blind, placebo-controlled (2 active: 1 placebo) proof-of-concept trial of add-on IL-2LD in patients with bipolar depression. Patients received a placebo or IL-2LD (1MIU) once a day for 5 days, and then once a week for 4 weeks starting on week 2. The primary objective was to demonstrate a biological Treg response to IL-2LD assessed by fold increase in Treg percentage of CD4 + cells from baseline to day 5. Secondary objectives included safety assessment and mood improvement throughout the study period. This trial is registered with ClinicalTrials.gov, number NCT04133233. Fourteen patients with bipolar depression were included, with 4 receiving placebo and 10 IL-2LD. Baseline clinical and biological characteristics were balanced between groups. The primary evaluation criterion was met, with IL-2LD expanding 1.17 [95 % CI 1.01-1.34] vs 1.01 [95 % CI 0.90-1.12] (p = 0.0421) and activating Tregs. Secondary evaluation criteria were also met with significant improvements of depressive symptoms and global functioning from day-15 onwards in the IL-2LD treated patients. The treatment was well-tolerated, with no serious adverse events related to treatment. This proof-of-concept trial shows that stimulating Tregs in patients with bipolar depression is safe and associated with clinical improvements. This supports a pathophysiological role of inflammation in BD and warrants pursuing the evaluation of IL-2LD as an adjunct treatment of major mood disorders.

B Cell-activating factor (BAFF): A promising trans-nosographic biomarker of inflammation and autoimmunity in bipolar disorder and schizophrenia.

Immune dysregulation is an important aspect of schizophrenia (SZ) and bipolar disorders (BD) pathophysiology, including not only inflammatory but also autoimmune process reflective of abnormal humoral immune responses. Given that B cell-activating factor (BAFF) is an integral aspect of B lymphocyte regulation, the current study investigated BAFF in SZ and BD. 255 SZ patients, 407 BD patients and 185 healthy controls (HC) were investigated across three aspects of soluble BAFF (sBAFF) by (i) comparing sBAFF circulatory levels across SZ, BD and HC, (ii) determining potential correlations between the circulating levels of sBAFF and the genotype distribution of a functionally relevant polymorphism, namely the TNFSF13B 3'UTR insertion-deletion polymorphism (GCTGT>A), (iii) analyzing relationships between both sBAFF levels and 3'UTR insertion-deletion genotypes and disease risk, patients clinical characteristics and circulating levels of potent inflammatory molecules. In addition, in subsets of patients, we also searched for possible correlations between sBAFF levels and stigma of past infectious events as well as positivity for circulating systemic autoantibodies or those directed against central nervous system (CNS) structures. Studying blood derived serum and DNA, weobserved that circulating sBAFF levels were significantly higher in SZ and BD patients, versus HC (p = 5.3*10-10and p = 4.4*10-09). Patients experiencing acute episodes, versus stable patients, in between acute episodes, exhibited higher sBAFF levels (p = 0.017).In SZ patients, positive correlations were observed between elevated sBAFF levels and: (i) elevated positive psychotic symptoms (PANSS pos), (ii) history of childhood trauma (physical abuse), and (iii) low scores on global functioning (GAF) (p = 0.024, p = 0.024, and p = 0.041).We also found that the distribution of the BAFF Ins/Del genotypes was significantly correlated with circulating sBAFF levels in SZ and BD patients (p = 0.0004). Elevated sBAFF levels were also correlated with increased levels of pro-inflammatory markers in both SZ and BD cohorts (p < 0.001). Regarding infectious stigma, only patients seropositive, versus seronegative, for herpes simplex virus (HSV)1 immunoglobulin (Ig)G antibodies exhibited a significant association with high sBAFF levels (p = 0.013). In contrast, positivity for systemic or CNS autoantibodies was significantly associated with reduced sBAFF levels, compared to patients without autoantibodies (p = 0.0017). Overall, our findings indicate that BAFF may be a promising trans-nosographic biomarker of inflammation that is likely to offer predictive, diagnostic, and prognostic tools for the management of SZ and BD. The results therefore have practicable clinical utility given the availability of immunotherapeutic treatment options including targeted monoclonal antibodies against BAFF.

Season of birth and schizotypy in a sample of undergraduate students.

PURPOSE: In line with the psychotic continuum theory, the study of psychometric schizotypy in non-clinical samples has been proposed as a convenient yet powerful method for studying the etiology of psychosis. Based on this paradigm, several studies explored the association between season of birth (SoB) and schizotypy but led to inconsistent results. Building on the analysis of the previous studies, in the present study, we aimed to advance our understanding by improving the methodology (using a homogeneous group, eliminating unreliable respondents, taking into account potential confounders) and the reporting. METHODS: Subjects were recruited among undergraduate students from 3 Romanian Universities. To limit the potential influence of invalid response, we applied methods for detecting unreliable and/or biased questionnaires and excluded subjects with unreliable/ biased answers from the analyses. Schizotypal dimensions were measured using the Romanian translation of the 22-items Schizotypal Personality Questionnaire-Brief (SPQ-B). The association between schizotypy scores and season of birth was explored using linear regression. RESULTS: In a sample of 484 undergraduate students from Romania, we found that being born in late winter/early spring (February and March) was associated to higher total schizotypy score and disorganization. Furthermore, we found that restricting the sample to subjects born in an urban environment increased the strength of the association. CONCLUSION: This study is consistent with an association between SoB and the risk of psychotic disorders.

A replication study of sHLA-E influence on schizophrenia and bipolar disorder.

OBJECTIVES: Schizophrenia (SZ) and bipolar disorders (BP) are chronic and severe neuropsychiatric diseases. These disorders are tightly related to immune deregulations. In the current study, we intended to replicate the previously reported involvement of the soluble HLA-E isoforms (sHLA-E) in the risk of developing the two conditions along with disease severity in a Tunisian population group. PATIENTS AND METHODS: One hundred and twenty-four patients with schizophrenia and 121 with bipolar disorder meeting the DSM-IV criteria along 111 healthy controls were included in this present case-control study. The soluble HLA-E isoforms circulating levels were measured using the ELISA method. The statistical analyses were performed using Kruskal-Wallis and Wilcoxon rank sum tests by R software and GraphPad prism 9. RESULTS: We found that the sHLA-E circulating levels were significantly higher in BP patients as compared to healthy controls (P<0.0001) and that such increases were mainly observed in patients during an acute phase of their disease (P<0.0001). In SZ patients, while we failed to observe an association with the levels of sHLA-E in the entire SZ sample, we found that high sHLA-E levels characterized stabilized patients in comparison with those during an acute episode (P=0.022). Finally, we did not observe any association between sHLA-E circulating levels and symptoms assessed by the classical clinical scales either in BP or SZ patients. CONCLUSION: Overall, the present findings replicate in a Tunisian population group the previously demonstrated implication of sHLA-E circulating levels in the risk of developing BP or SZ in a French patient cohort. Such replication allows to consider HLA-E as a potent and true inflammatory marker in the context of the two disorders.

Immune cell subsets in patients with bipolar disorder or schizophrenia with history of childhood maltreatment.

A history of Childhood Maltreatment (CM) has been repeatedly associated with an increased risk of developing bipolar disorders (BD) or schizophrenia (SZ). The impact of severe stress induced by CM has been proposed to be mediated by elevated inflammation reflected by dysregulated inflammatory processes. Little is known about the potential impact of CM on lymphocyte subpopulations or the role of pre-existing infections on CM physiological consequences. This study therefore explored the role of CM and past infection exposure impact on lymphocyte subpopulations to give an indication of their relevance as stressors in the pathoetiology of major mood and psychotic disorders. 118 adult patients with SZ, and 152 with BD were included in the analysis. CM history was assessed by the Childhood Trauma Questionnaire (CTQ), with current and past psychiatric symptomatology also evaluated. Circulating immune cell subsets were analyzed using flow cytometry-based analysis. Past exposure to common infectious stigma including toxoplasma, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) were measured by solid phase-enzyme microplate and ELISA immunoassays. The relationship between CM, biological phenotypes (including immune cell subsets distribution and past infectious status) and clinical phenotypes were analyzed using univariate and multivariate analyses. BD patients with, versus without, CM had higher levels of CD3+CD8+ cytotoxic T cells and CMV antibodies along with decreased levels of CD45RA+CCR7+CD8+ naïve CD8+ T cells, and a more severe clinical profile. CMV antibody levels were inversely associated with the CD3 + CD8 + lymphocyte subset level. SZ patients with, versus without, CM, showed lower levels of CD14 + monocytes and no specific clinical characteristics. The accumulation of different types of maltreatment associated with increased body mass index and CMV autoantibodies as well as decreased levels of CD14 + monocytes. In both BD and SZ, further analysis according to the type and the number of CM subtypes showed association with specific changes in lymphocyte cell subsets, clinical profile, and infectious stigma. Adults with BD or SZ exposed to CM exhibit specific immune cell subset profiles, clinical features, and stigma of past infections. In BD, our data indicate an interplay between CM and CMV infections, which may possibly contribute to premature aging and cellular senescence, both of which have previously been shown to associate with mood disorders. Longitudinal studies of CM-exposed patients are required to clarify the interactions of CM and viral infections, including as to the pathophysiological processes driving patient symptomatology.

Natural killer cells in first-episode psychosis: an innate immune signature?

Accumulating evidence majorly implicates immune dysfunction in the etiology of psychotic disorders. In particular, altered numbers and functions of natural killer (NK) cells have been described in psychosis, but interpretation has often been confounded by a number of biases, including treatment. Eighty-one first-episode psychosis (FEP) patients who subsequently received a diagnosis of either schizophrenia (SZ; n = 30) or bipolar disorder (BP; n = 31) over a five-year follow-up period were investigated for their NK cell phenotype and compared to 61 healthy controls (HCs). We found a similar proportion of CD3-CD56+ NK cells in FEP patients and HCs. The frequency of NK cells expressing the late cell activation marker HLA-DR was significantly increased in FEP patients compared to HCs, especially in patients with BP (p < 0.0001) and, to a lesser degree, in patients with SZ (p = 0.0128). Interestingly, the expression of the activating NKG2C receptor, known to be associated with infections, was higher in patients with SZ and BP than in HCs (p < 0.0001) and correlated with HLA-DR expression, altogether defining adaptive NK cells. In terms of NK cell function, we observed a suppressed capacity of SZ-derived NK cells to mount cytotoxic responses in the presence of target cells, while NK cells from patients with BP show an inability to produce IFN-γ, a cytokine pivotal to NK function. This study strongly suggests major dysfunction of NK cells in FEP with functioning impairment correlated with psychotic, manic, and depressive symptoms in subsequently diagnosed patients with SZ and BP.

Low peripheral mitochondrial DNA copy number during manic episodes of bipolar disorders is associated with disease severity and inflammation.

Mitochondria (Mt) are intra-cellular components essential for cellular energy processes whose dysfunction may induce premature cellular senescence and/or inflammation, both observed in bipolar disorders (BD). We investigated mitochondrial DNA copy number (mtDNAcn) levels in patients with BD being in manic, depressive or euthymic phase and in healthy controls (HC) both characterized for the levels of blood-based inflammatory markers and stigma of pathogens. 312 patients with BD were compared to 180 HC. mtDNAcn were measured using a digital droplet PCR. Serum levels of 14 inflammatory molecules and 3 anti-infectious IgG stigma were respectively evaluated by electro-chemiluminescence, ELISA and dedicated immunoassays. The statistical analyses were performed using Spearman's correlation, Wilcoxon signed-rank and Kruskal-Wallis rank sum tests. P-values were adjusted for multiple testing with Benjamini-Hochberg method. We found low levels of mtDNAcn in BD patients as compared to HC (P = 0.008) especially during manic episodes (P = 0.0002). We also observed that low levels of mtDNAcn are negatively correlated with mood and psychotic scales (PANSS, YMRS and CGI) (adjusted P (Adj P) = 0.02, 0.003 and 0.05 respectively) and positively with the GAF severity scale (Adj P = 0.002). They were also correlated with high levels of both intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 (Adj P = 0.003 and 0.001) along with a trend toward increased IL-2, IL-10 and B2M circulating levels (Adj P = 0.05). Here, we report correlations between marker of mitochondria functioning and both clinical scales and inflammatory markers in BD patients experiencing manic episodes. If replicated, these finding might allow to predict transition between disease phases and to design accurate therapeutic options.

Immunoglobulin sub-class distribution in bipolar disorder and schizophrenia: potential relationship with latent Toxoplasma Gondii infection.

BACKGROUND: Immune dysfunction could play a significant role in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ), conditions with an underlying pro-inflammatory state. Studies on humoral immune responses (which reflects antibody mediated fight against pathogens) in schizophrenia and bipolar disorder are sparse and often providing contradictory results. The aim of this study was to assess humoral immunity in a group of stable bipolar disorder and schizophrenia patients compared to controls by determining total Immunoglobulins and IgG subclasses and to assess their association with latent Toxoplasma gondii and/or CMV infection. METHODS: 334 subjects (124 BD, 75 SZ and 135 Healthy Controls [HC]) were included and tested for humoral immunity by determining the total immunoglobulins (IgG,A and M) and IgG subclasses (IgG1, IgG2, IgG3, IgG4) and their relationship with latent Toxoplasma gondii infection, an established risk factor for BD and SZ. RESULTS: Although lower levels of IgG, IgG1, IgG2, IgG4 and IgA were found among BD as compared to HC and/or SZ, after adjustment for confounding variables, only low levels of IgG and IgG1 in BD remai- ned significant. Strikingly highest levels of antibodies to T. gondii (but not CMV) infection in BD and SZ were associated with lowest levels of IgG3 and IgG4 levels as compared to controls. CONCLUSIONS: Schizophrenia and bipolar disorder patients with latent T. gondii specific infection may be more vulnerable to changes in immuno-inflammatory processes than controls with similar latent infectious state. Simultaneous sequential immunological monitoring both in steady state and active disease phases in the same BD and SZ patients are warranted to understand the role of Toxoplasma gondii latency in these disorders.

Small area-level variation in the incidence of psychotic disorders in an urban area in France: an ecological study.

PURPOSE: We sought to determine whether significant variation in the incidence of clinically relevant psychoses existed at an ecological level in an urban French setting, and to examine possible factors associated with this variation. We aimed to advance the literature by testing this hypothesis in a novel population setting and by comparing a variety of spatial models. METHODS: We sought to identify all first episode cases of non-affective and affective psychotic disorders presenting in a defined urban catchment area over a 4 years period, over more than half a million person-years at-risk. Because data from geographic close neighbourhoods usually show spatial autocorrelation, we used for our analyses Bayesian modelling. We included small area neighbourhood measures of deprivation, migrants' density and social fragmentation as putative explanatory variables in the models. RESULTS: Incidence of broad psychotic disorders shows spatial patterning with the best fit for models that included both strong autocorrelation between neighbouring areas and weak autocorrelation between areas further apart. Affective psychotic disorders showed similar spatial patterning and were associated with the proportion of migrants/foreigners in the area (inverse correlation). In contrast, non-affective psychoses did not show spatial patterning. CONCLUSIONS: At ecological level, the variation in the number of cases and the factors that influence this variation are different for non-affective and affective psychotic disorders. Important differences in results-compared with previous studies in different settings-point to the importance of the context and the necessity of further studies to understand these differences.

Prevalence of psychotic disorders in an urban area of France.

BACKGROUND: Most data on the prevalence of psychotic disorders is limited to global estimates or restricted to schizophrenia. Consequently, there is limited information available about the prevalence of psychotic disorders more widely and outwith age and sex - specific prevalence values. The objective of this study is to provide period prevalence estimates, detailed by gender and age groups, for treated psychotic disorders in an adult population (aged 18 years and over) from an urban area in France. METHODS: Prospective reporting of cases treated over an 8-week period complemented by several methods estimating the number of potentially missed cases, including a leakage study. The study took place in an urban, well defined catchment area, with a population of 67 430 at risk subjects living in the east of a Paris suburb. RESULTS: The observed prevalence was of 3.72 per 1000 subjects at risk; after adjustment for potentially lost cases the estimate was of 4.60 per 1000 subjects at risk. Observed prevalence was higher in men (4.71 per 1000, Relative Risk = 1.68) and in the 35-45 age-band (6.05 per 1000, Relative Risk = 1.93). CONCLUSION: Global prevalence estimates of psychotic disorders in this study are in line with expected values based on studies conducted in other countries. Careful consideration of the causes of missed cases and gathering of complementary data are essential and could result in significant changes in prevalence estimates. Detailed estimates (by age) suggest that treated psychosis might not be a lifelong condition.

Rural-urban variation in incidence of psychosis in France: a prospective epidemiologic study in two contrasted catchment areas.

BACKGROUND: The aim of our study is to provide data on the incidence of psychotic disorders in France and compare the incidence rates in populations with different levels of urbanization. METHODS: We prospectively included the incident cases of psychotic disorders from two catchment areas with contrasted levels of urbanization. In the more rural area, we also calculated incidence rates in three different groups of population defined by the size of towns in which they live (small, medium and large towns). RESULTS: The annual incidence of psychosis was greater in the urban area (36.02/100000 person-year at risk) than in the rural area (17.2/100000 person-year at risk).Non-affective psychoses were the majority of cases and their incidence was greater in males and younger subjects. The affective psychoses were slightly more frequent in women and showed less variation with age. In the rural centre, greater levels of urbanicity were associated with an increase in the incidence of all psychoses (affective and non-affective). CONCLUSIONS: Our study confirms previous observations of increased incidence rates for non-affective psychoses in the more urbanized areas and suggests that a similar pattern might be present for affective psychoses.

Serum autoantibodies against α7-nicotinic receptors in subgroups of patients with bipolar disorder or schizophrenia: clinical features and link with peripheral inflammation.

There is growing evidence that autoantibodies (AAbs) against proteins expressed in the brain are playing an important role in neurological and psychiatric disorders. Here, we explore the presence and the role of peripheral AAbs to the α7-nicotinic acetylcholine receptor (nAChR) in inflammatory subgroups of psychiatric patients with bipolar disorder (BD) or schizophrenia (SCZ) and healthy controls. We have identified a continuum of AAb levels in serum when employing a novel ELISA technique, with a significant elevation in patients compared to controls. Using unsupervised two-step clustering to stratify all the subjects according to their immuno-inflammatory background, we delineate one subgroup consisting solely of psychiatric patients with severe symptoms, high inflammatory profile, and significantly increased levels of anti-nAChR AAbs. In this context, we have used monoclonal mouse anti-human α7-nAChR antibodies (α7-nAChR-mAbs) and shown that TNF-α release was enhanced upon LPS stimulation in macrophages pre-incubated with α7-nAChR-mAbs compared to the use of an isotype control. These findings provide a basis for further study of circulating nicotinic AAbs, and the inflammatory profile observed in patients with major mood and psychotic disorders.

Mitochondrial Biomarkers and Metabolic Syndrome in Bipolar Disorder.

The object of this study is test whether mitochondrial blood-based biomarkers are associated with markers of metabolic syndrome in bipolar disorder, hypothesizing higher lactate but unchanged cell-free circulating mitochondrial DNA levels in bipolar disorder patients with metabolic syndrome. In a cohort study, primary testing from the FondaMental Advanced Centers of Expertise for bipolar disorder (FACE-BD) was conducted, including 837 stable bipolar disorder patients. The I-GIVE validation cohort consists of 237 participants: stable and acute bipolar patients, non-psychiatric controls, and acute schizophrenia patients. Multivariable regression analyses show significant lactate association with triglycerides, fasting glucose and systolic and diastolic blood pressure. Significantly higher levels of lactate were associated with presence of metabolic syndrome after adjusting for potential confounding factors. Mitochondrial-targeted metabolomics identified distinct metabolite profiles in patients with lactate presence and metabolic syndrome, differing from those without lactate changes but with metabolic syndrome. Circulating cell-free mitochondrial DNA was not associated with metabolic syndrome. This thorough analysis mitochondrial biomarkers indicate the associations with lactate and metabolic syndrome, while showing the mitochondrial metabolites can further stratify metabolic profiles in patients with BD. This study is relevant to improve the identification and stratification of bipolar patients with metabolic syndrome and provide potential personalized-therapeutic opportunities.

Diet quality and associations with lactate and metabolic syndrome in bipolar disorder.

BACKGROUND: Nutrition is largely affected in bipolar disorder (BD), however, there is a lack of understanding on the relationship between dietary categories, BD, and the prevalence of metabolic syndrome. The objective of this study is to examine dietary trends in BD and it is hypothesized that diets with increased consumption of seafood and high-fiber carbohydrates will be correlated to improved patient outcomes, and a lower frequency of metabolic syndrome. METHODS: This retrospective cohort study includes two French cohorts. The primary cohort, FACE-BD, includes 268 stable BD patients. The second cohort, I-GIVE, includes healthy controls, both stable and acute BD and schizophrenia patients. Four dietary categories were assessed: meat, seafood, low-fiber and high-fiber carbohydrates. Dietary data from two food frequency questionnaires were normalized using min-max scaling and assessed using various statistical analyses. RESULTS: In our primary cohort, the increased high-fiber carbohydrate consumption was correlated to lower prevalence of metabolic syndrome and improved mood. Low-fiber carbohydrate consumption is associated with higher BMI, while higher seafood consumption was correlated to improved mood and delayed age of onset. Results were not replicated in our secondary cohort. LIMITATIONS: Our populations were small and two different dietary questionnaires were used; thus, results were used to examine similarities in trends. CONCLUSIONS: Overall, various dietary trends were associated with metabolic syndrome, BMI, lactate, mood and age of onset. Improving our understanding of nutrition in BD can provide mechanistic insight, clinically relevant nutritional guidelines for precision medicine and ultimately improve the quality of lives for those with BD.

Patients with psychosis spectrum disorders hospitalized during the COVID-19 pandemic unravel overlooked SARS-CoV-2 past infection clustering with HERV-W ENV expression and chronic inflammation.

Epidemiology has repeatedly associated certain infections with a risk of further developing psychiatric diseases. Such infections can activate retro-transposable genetic elements (HERV) known to trigger immune receptors and impair synaptic plasticity of neuroreceptors. Since the HERV-W ENV protein was recently shown to co-cluster with pro-inflammatory cytokines in a subgroup of patients with schizophrenia or bipolar disorder, we questioned the influence of the COVID-19 pandemic on patients with psychosis spectrum disorders (PSD). Present results revealed that (i) SARS-CoV-2 serology shows high prevalence and titers of antibodies in PSD, (ii) HERV-W ENV is detected in seropositive individuals only and (iii) SARS-CoV-2 and HERV-W ENV positivity co-clustered with high serum levels of pro-inflammatory cytokines in psychotic patients. These results thus suggest that SARS-CoV-2 infection in many patients with psychotic disorders now admitted in the psychiatry department did not cause severe COVID-19. They also confirm the previously reported association of elevated serum pro-inflammatory cytokines and HERV-W ENV in a subgroup of psychotic patients. In the context of the COVID-19 pandemic, this cluster is only found in SARS-CoV-2 seropositive PSD cases, suggesting a dominant influence of this virus on HERV-W ENV and cytokine expression, and/or patients' greater susceptibility to SARS-CoV-2 infection. Further investigation on an interplay between this viral infection and the clinical evolution of such PSD patients is needed. However, this repeatedly defined subgroup of psychotic patients with a pro-inflammatory phenotype and HERV expression calls for a differential therapeutic approach in psychoses, therefore for further precision medicine development.

Kynurenine pathway abnormalities are state-specific but not diagnosis-specific in schizophrenia and bipolar disorder.

Schizophrenia (SCZ) and bipolar disorder (BD) are associated with immunological dysfunctions that have been hypothesized to lead to clinical symptomatology in particular through kynurenine pathway abnormalities. The aim of this study was thus to investigate the impact of serum kynurenine metabolite levels on diagnosis, clinical state, symptom severity and clinical course in a large French transdiagnostic cohort of SCZ and BD patients. Four patient groups (total n = 507) were included in a cross-sectional observational study: 1) hospitalized acute bipolar patients (n = 205); 2) stable bipolar outpatients (n = 116); 3) hospitalized acute schizophrenia patients (n = 111) and 4) stable schizophrenia outpatients (n = 75), in addition to healthy controls (HC) (n = 185). The quantitative determination of serum kynurenine metabolites was performed using liquid chromatography-tandem mass spectrometry. Kynurenine levels were lower in all patients combined compared to HC while ANCOVA analyses did not reveal inter-diagnostic difference between SCZ and BD. Interestingly, hospitalized patients of both diagnostic groups combined displayed significantly lower kynurenine levels than stabilized outpatients. Psychotic symptoms were associated with lower quinaldic acid (F = 9.18, p=<.001), which is KAT-driven, whereas a longer duration of illness contributed to abnormalities in tryptophan (F = 5.41, p = .023), kynurenine (F = 16.93, p=<.001), xanthurenic acid (F = 9.34, p = .002), quinolinic acid (F = 9.18, p = .003) and picolinic acid (F = 4.15, p = .043), metabolized through the KMO-branch. These data confirm illness state rather than diagnosis to drive KP alterations in SCZ and BD. Lower levels of KP metabolites can thus be viewed as a transdiagnostic feature of SCZ and BD, independently associated with acute symptomatology and a longer duration of illness. Quinaldic acid has seldomly been investigated by previous studies and appears an important state marker in SCZ and BD. As serum samples are used in this study, it is not possible to extrapolate these findings to the brain.

A human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disorders.

Autism spectrum disorders (ASD) are neurodevelopmental conditions that are for subsets of individuals, underpinned by dysregulated immune processes, including inflammation, autoimmunity, and dysbiosis. Consequently, the major histocompatibility complex (MHC)-hosted human leukocyte antigen (HLA) has been implicated in ASD risk, although seldom investigated. By utilizing a GWAS performed by the EU-AIMS consortium (LEAP cohort), we compared HLA and MHC genetic variants, single nucleotide polymorphisms (SNP), and haplotypes in ASD individuals, versus typically developing controls. We uncovered six SNPs, namely rs9268528, rs9268542, rs9268556, rs14004, rs9268557, and rs8084 that crossed the Bonferroni threshold, which form the underpinnings of 3 independent genetic pathways/blocks that differentially associate with ASD. Block 1 (rs9268528-G, rs9268542-G, rs9268556-C, and rs14004-A) afforded protection against ASD development, whilst the two remaining blocks, namely rs9268557-T, and rs8084-A, associated with heightened risk. rs8084 and rs14004 mapped to the HLA-DRA gene, whilst the four other SNPs located in the BTNL2 locus. Different combinations amongst BTNL2 SNPs and HLA amino acid variants or classical alleles were found either to afford protection from or contribute to ASD risk, indicating a genetic interplay between BTNL2 and HLA. Interestingly, the detected variants had transcriptional and/or quantitative traits loci implications. As BTNL2 modulates gastrointestinal homeostasis and the identified HLA alleles regulate the gastrointestinal tract in celiac disease, it is proposed that the data on ASD risk may be linked to genetically regulated gut inflammatory processes. These findings might have implications for the prevention and treatment of ASD, via the targeting of gut-related processes.

Clinical and pharmacological correlates of caffeine consumption in subjects with schizophrenia - Data from the FACE-SZ cohort.

Caffeine is the most consumed psychoactive substance worldwide. Previous studies suggested higher caffeine consumption in subjects with schizophrenia spectrum disorders (SSD) as well as associations with symptoms, medication and medication side-effects. In a large and well-characterized sample of SSD subjects we explored the association between caffeine consumption and clinical (psychosis related, severity, general health) as well as pharmacological (antipsychotic treatment, sedation potential) variables. Eight hundred four subjects with data on their caffeine (coffee and tea) consumption successively recruited were included in this study. After controlling for potential confounders (demographic variables, smoking) only the negative dimension of psychosis was associated with the amount of caffeine ingested. Less severe negative symptoms were associated with higher caffeine consumption. The effect size of this association was small (partial correlation coefficient = -0.12) but significant.

Cognitive performance at first episode of psychosis and the relationship with future treatment resistance: Evidence from an international prospective cohort study.

BACKGROUND: Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia, with recent research finding systematic biological differences between antipsychotic resistant and responsive patients. Our aim was to determine whether cognitive impairment at first episode significantly differs between future antipsychotic responders and resistant cases. METHODS: Analysis of data from seven international cohorts of first-episode psychosis (FEP) with cognitive data at baseline (N = 683) and follow-up data on antipsychotic treatment response: 605 treatment responsive and 78 treatment resistant cases. Cognitive measures were grouped into seven cognitive domains based on the pre-existing literature. We ran multiple imputation for missing data and used logistic regression to test for associations between cognitive performance at FEP and treatment resistant status at follow-up. RESULTS: On average patients who were future classified as treatment resistant reported poorer performance across most cognitive domains at baseline. Univariate logistic regressions showed that antipsychotic treatment resistance cases had significantly poorer IQ/general cognitive functioning at FEP (OR = 0.70, p = .003). These findings remained significant after adjusting for additional variables in multivariable analyses (OR = 0.76, p = .049). CONCLUSIONS: Although replication in larger studies is required, it appears that deficits in IQ/general cognitive functioning at first episode are associated with future treatment resistance. Cognitive variables may be able to provide further insight into neurodevelopmental factors associated with treatment resistance or act as early predictors of treatment resistance, which could allow prompt identification of refractory illness and timely interventions.