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Previous studies set out profound cognitive impairments in subjects with treatment-resistant depression (TRD). However, little is known about the course of such alterations depending on levels of improvement in those patients followed longitudinally. The main objective of this study was to describe the course of cognitive impairments in responder versus non-responder TRD patients at one-year follow-up. The second aim was to evaluate the predictive aspect of cognitive impairments to treatment resistance in patients suffering from TRD. We included 131 patients from a longitudinal cohort (FACE-DR) of the French Network of Expert TRD Centers. They undertook comprehensive sociodemographic, clinical, global functioning, and neuropsychological testing (TMT, Baddeley task, verbal fluencies, WAIS-4 subtests, D2 and RLRI-16) at baseline (V0) and one-year follow-up (V1). Most patients ( n = 83; 63.36%) did not respond (47 women, 49.47 ± 12.64 years old), while one-third of patients responded ( n = 48, 30 women, 54.06 ± 12.03 years old). We compared the cognitive performances of participants to average theoretical performances in the general population. In addition, we compared the cognitive performances of patients between V1 and V0 and responder versus non-responder patients at V1. We observed cognitive impairments during the episode and after a therapeutic response. Overall, each of them tended to show an increase in their cognitive scores. Improvement was more prominent in responders at V1 compared to their non-responder counterparts. They experienced a more marked improvement in code, digit span, arithmetic, similarities, and D2 tasks. Patients suffering from TRD have significant cognitive impairments that persist but alleviate after therapeutic response. Cognitive remediation should be proposed after therapeutic response to improve efficiency and increase the daily functioning.

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., (© 2023. The Author(s).)

Background and Hypothesis: Treatment response to specific antipsychotic medications is difficult to predict on clinical grounds alone. The current study hypothesizes that the baseline complement pathway activity predicts the treatment response and investigates the relationship between baseline plasma biomarkers with treatment response to antipsychotic medications., Study Design: Baseline plasma samples were collected from first episode of psychosis patients (n = 243) from a multi-center clinical trial. The participants were treated with amisulpride for 4 weeks. Levels of complement and coagulation proteins at baseline were measured using both data-dependent and data-independent mass spectrometry approaches. The primary outcome was remission status at 4 weeks and the secondary outcomes included change in psychotic and functional symptoms over the period of treatment. In addition, immunoassays were performed at baseline for complement C1R, as well as for activation markers C4a and sC5b-9., Study Results: The plasma level of complement variant C4A was significantly associated with remission at 4 weeks. Moreover, higher levels of several complement and coagulation pathway proteins were associated with a reduction in psychotic symptoms and an improvement in functioning. Immunoassays showed an association of baseline levels of C1R and C4a as well as complement activation marker sC5b-9 levels with treatment response., Conclusion: The results demonstrated that the response to antipsychotic treatment might be related to pre-treatment levels of plasma complement and coagulation pathway proteins. This is consistent with independent evidence associating immune dysfunction with the pathophysiology of psychosis. Moreover, these results inform the development of novel therapeutic approaches that target the complement system for psychosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Objectives: An accelerated cellular ageing has been observed in bipolar disorder (BD) using biomarkers such as telomere length (TL) and mitochondrial DNA copy number (mtDNAcn). Several risk factors might drive premature ageing in individuals with BD, including a familial predisposition. This study compared TL and mtDNAcn between individuals with BD and their (un)-affected siblings, and explored factors that may explain proband-sibling differences., Methods: Sixty individuals with BD and seventy-four siblings (34 affected with BD or mood disorders and 40 unaffected) were included. Quantitative polymerase chain reaction (qPCR) was used to measure TL and mtDNAcn from peripheral blood genomic DNA., Results: TL and mtDNAcn did not significantly differ between probands and their siblings, whatever these latter were affected or not with mood disorders. However, the correlation plots of TL or mtDNAcn in proband-sibling pairs suggested that some pairs were discordant. The within proband-sibling pairs differences for TL and mtDNAcn were not explained by differences in all tested factors., Conclusions: This study shows that probands with BD and their siblings are concordant for TL and mtDNAcn suggesting that they may share some environmental or genetic determinants of these two biomarkers of cellular ageing.

Parent history of severe mental illness (PHSMI) may have long-term consequences in adult offspring due to genetic and early environmental factors in preliminary studies. To compare the outcomes associated in subjects with PHSMI to those in patients without PHSMI. The participants with schizophrenia and schizoaffective disorders were recruited in the ongoing FACE-SZ cohort at a national level (10 expert centers) and evaluated with a 1-day-long standardized battery of clinician-rated scales and patient-reported outcomes. PHSMI was defined as history of schizophrenia or bipolar disorders in at least one parent and was included as explanatory variable in multivariate models. Of the 724 included patients, 78 (10.7%) subjects were classified in the PHSMI group. In multivariate analyses, PHSMI patients had a better insight into schizophrenia and the need for treatment and reported more often childhood trauma history compared to patients without PHSMI. More specifically, those with paternal history of SMI reported more severe outcomes (increased childhood physical and emotional abuses, comorbid major depression and psychiatric hospitalizations). PHSMI is associated with increased risk of childhood trauma, major depressive disorder and psychiatric hospitalization and better insight in individuals with schizophrenia. Specific public health prevention programs for parents with SMI should be developed to help protect children from pejorative psychiatric outcomes. PHSMI may also explain in part the association between better insight and increased depression in schizophrenia., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Patients suffering from treatment-resistant depression (TRD) are at risk of suicide. Sleep and circadian rhythm alterations are widely recognized as core symptoms of major depressive disorder and are associated with suicidal ideation. Thus, sleep and circadian rhythm alterations may be targeted to prevent suicide., Methods: Patients were recruited from a prospective cohort of the French network of TRD expert centers. Mood, sleep and circadian rhythms were assessed at baseline; suicidal risk was assessed both at baseline and during a one-year follow-up with standardized subjective questionnaires., Results: Excessive daytime sleepiness (adjusted odds ratio aOR = 1.7(1-3.3), p = 0.04) and daytime dysfunction (aOR = 1.81(1.16-2.81), p = 0.0085) increased the risk of suicidal thoughts over the one-year follow-up period in patients with TRD after adjustment on age, gender, depression, trauma, anxiety, impulsivity, current daily tobacco smoking and body mass index. Hypnotics intake is associated with a reduced risk of suicidal ideation at one-year follow-up after the same adjustments (OR = 0.73(0.56-0.95), p = 0.019). Other associations between sleep quality or circadian rhythms and suicidal ideations at either baseline or one year did not remain significant in multivariate analyses after the same adjustments., Limitations: Sleep assessments were based on self-reported questionnaires rather than objective measures., Conclusions: Daytime sleepiness and dysfunction are predictors of suicidal ideations, whereas hypnotics intake is associated with a reduced risk of suicidal ideations. Diurnal symptoms of sleep disturbances are therefore red flags to target for preventing suicide in depressed patients, and hypnotics seem efficient in preventing suicide for patients with TRD., (Copyright © 2023. Published by Elsevier B.V.)

Background: The cerebellum contains more than 50% of all neurons in the brain and is involved in a broad range of cognitive functions, including social communication and social cognition. Inconsistent atypicalities in the cerebellum have been reported in individuals with autism compared to controls suggesting the limits of categorical case control comparisons. Alternatively, investigating how clinical dimensions are related to neuroanatomical features, in line with the Research Domain Criteria approach, might be more relevant. We hypothesized that the volume of the "cognitive" lobules of the cerebellum would be associated with social difficulties., Methods: We analyzed structural MRI data from a large pediatric and transdiagnostic sample (Healthy Brain Network). We performed cerebellar parcellation with a well-validated automated segmentation pipeline (CERES). We studied how social communication abilities-assessed with the social component of the Social Responsiveness Scale (SRS)-were associated with the cerebellar structure, using linear mixed models and canonical correlation analysis., Results: In 850 children and teenagers (mean age 10.8 ± 3 years; range 5-18 years), we found a significant association between the cerebellum, IQ and social communication performance in our canonical correlation model., Limitations: Cerebellar parcellation relies on anatomical boundaries, which does not overlap with functional anatomy. The SRS was originally designed to identify social impairments associated with autism spectrum disorders., Conclusion: Our results unravel a complex relationship between cerebellar structure, social performance and IQ and provide support for the involvement of the cerebellum in social and cognitive processes., (© 2023. The Author(s).)

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., Competing Interests: Declaration of competing interest The authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Response to lithium (Li) is highly variable in bipolar disorders (BD). Despite decades of research, no clinical predictor(s) of response to Li prophylaxis have been consistently identified. Recently, we developed epigenetic Methylation Specific High-Resolution Melting (MS-HRM) assays able to discriminate good responders (GR) from non-responders (NR) to Li in individuals with BD type 1 (BD-I). This study examined whether a combination of clinical and epigenetic markers can distinguish NR from other types of Li responders., Methods: We recorded clinical variables that are potentially associated with Li response in 64 individuals with BD-I. MS-HRM assays were performed on DNA isolated from peripheral blood. We used backward stepwise logistic regression analyses, followed by receiver operating characteristic (ROC) curve analysis to estimate the performance of the clinical variables, alone then in combination with the epigenetic biomarkers, to identify GR and partial responders (PaR) vs NR., Results: Polarity at onset, psychotic symptoms at onset and family history of BD classified correctly 70% of individuals according to their Li response (PaR + GR = 86%; NR = 35%). When combined with the epigenetic biomarkers, these three clinical variables plus alcohol misuse (and one DMR: Differentially Methylated Region) correctly classified 86% of individuals, improving the prediction of PaR + GR (93%) and of NR (70%). The ROC analysis demonstrated an improvement in the area under the curve from 0.75 (clinical variables alone) to 0.87 (combination of clinical and epigenetic markers)., Conclusions: Combining clinical predictors and DNA methylation markers of Li response may have greater utility in clinical practice than relying on clinical characteristics alone., (© 2023. The Author(s).)

Mental disorders often begin early in life and constitute five of the top ten causes of disability. Their total cost across Europe is estimated at more than 4% of GDP (more than € 600 billion). The last study investigating the cost of mental disorders in France by our group was based on data from 2007 and yielded an estimated indirect and direct cost of € 109 billions. The objective of this study was thus to provide an overall updated cost of mental health in France ten years later and before the COVID-19 pandemic. We estimated the costs related to the direct healthcare and medico-social system, loss of productivity and loss of quality of life. We conducted a literature search to identify direct healthcare, medico-social, indirect (loss of productivity and income compensation) and loss of quality of life during 2018. We included costs related to major psychiatric disorders, including autism and intellectual disability, but excluded the costs related to dementia. Our estimate of the total cost of mental disorders in France, including medical (14%), social (8%), indirect (27%) and loss of quality of life (51%), was € 163 billions in 2018. This total cost includes money spend, forgone earnings and DALYs lost. We found a 50% increase in costs relative to our previous 2007 study. Large-scale cost-effective interventions such as specialized consultations or the development of ambulatory care could help decrease direct healthcare costs related to hospitalization and productivity loss while greatly improving the quality of life of patients., Competing Interests: Conflict of interest All authors (C.L., O.G., L.BS., I.D.Z., M.L., Ad.D.) declare no conflicts of interests., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)

Objectives: Up to 70% individuals with bipolar disorder (BD) are lifetime tobacco smokers, a major modifiable risk factor for morbidity. However, quitting smoking is rarely proposed to individuals with BD, mainly because of fear of unfavorable metabolic or psychiatric changes. Evaluating the physical and mental impact of tobacco cessation is primordial. The aim of this study was to characterize the psychiatric and nonpsychiatric correlates of tobacco smoking status (never- vs. current vs. former smokers) in individuals with BD., Methods: 3860 individuals with ascertained BD recruited in the network of Fondamental expert centers for BD between 2009 and 2020 were categorized into current, former, and never tobacco smokers. We compared the sociodemographic and clinical characteristics assessed by standard instruments (e.g., BD type, current symptoms load, and non-psychiatric morbidity-including anthropometric and biological data) of the three groups using multinomial regression logistic models. Corrections for multiple testing were applied., Results: Current smokers had higher depression, anxiety, and impulsivity levels than former and never-smokers, and also higher risk of comorbid substance use disorders with a gradient from never to former to current smokers-suggesting shared liability. Current smokers were at higher risk to have a metabolic syndrome than never-smokers, although this was only evidenced in cases, who were not using antipsychotics., Conclusions: Tobacco smoking was associated with high morbidity level. Strikingly, as in the general population, quitting smoking seemed associated with their return to the never-smokers' levels. Our findings strongly highlight the need to spread strategies to treat tobacco addiction in the BD population., (© 2023 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Suicidal ideation (SI) is a major suicide risk factor; therefore, it is crucial to identify individuals with SI. Discrepancies between the clinicians and patients' estimation of SI may lead to under-evaluating the suicide risk. Yet, studies on discrepancies between self- and clinician-rated SI are lacking, although identifying the patients' sociodemographic and clinical characteristics associated with such discrepancies might help to reduce the under-evaluation risk. Therefore, the aim of this study was to identify features associated with SI rating discrepancies in patients with bipolar disorder (BD) because of the high prevalence of suicide in this population. Among the patients recruited by the French network of FondaMental expert centers for BD, patients with SI (i.e. ≥2 for item 12 of the Quick Inventory of Depressive Symptomatology-Self Report and/or ≥3 for item 10 of the clinician-rated Montgomery and Åsberg Depression Rating Scale) were selected and divided in concordant (i.e. SI in both self- and clinician-rated questionnaires; n = 130; 25.6%), and discordant (i.e. SI in only one questionnaire; n = 377; 74.4%). Depression severity was the feature most associated with SI evaluation discrepancy, especially in patients with SI identified only with the self-rated questionnaire. Clinician may under-evaluate SI presence in patients with low depression level., Competing Interests: Declaration of Competing Interest None of the authors declare conflict of interests related to this manuscript., (Copyright © 2023. Published by Elsevier B.V.)

Background: Converging evidence suggests that a subgroup of bipolar disorder (BD) with an early age at onset (AAO) may develop from aberrant neurodevelopment. However, the definition of early AAO remains unprecise. We thus tested which age cut-off for early AAO best corresponds to distinguishable neurodevelopmental pathways., Methods: We analyzed data from the FondaMental Advanced Center of Expertise-Bipolar Disorder cohort, a naturalistic sample of 4421 patients. First, a supervised learning framework was applied in binary classification experiments using neurodevelopmental history to predict early AAO, defined either with Gaussian mixture models (GMM) clustering or with each of the different cut-offs in the range 14 to 25 years. Second, an unsupervised learning approach was used to find clusters based on neurodevelopmental factors and to examine the overlap between such data-driven groups and definitions of early AAO used for supervised learning., Results: A young cut-off, i.e. 14 up to 16 years, induced higher separability [mean nested cross-validation test AUROC = 0.7327 (± 0.0169) for ⩽16 years]. Predictive performance deteriorated increasing the cut-off or setting early AAO with GMM. Similarly, defining early AAO below 17 years was associated with a higher degree of overlap with data-driven clusters (Normalized Mutual Information = 0.41 for ⩽17 years) relatively to other definitions., Conclusions: Early AAO best captures distinctive neurodevelopmental patterns when defined as ⩽17 years. GMM-based definition of early AAO falls short of mapping to highly distinguishable neurodevelopmental pathways. These results should be used to improve patients' stratification in future studies of BD pathophysiology and biomarkers.

As an integral part of autism spectrum symptoms, sensory processing issues including both hypo and hyper sensory sensitivities. These sensory specificities may result from an excitation/inhibition imbalance with a poorly understood of their level of convergence with genetic alterations in GABA-ergic and glutamatergic pathways. In our study, we aimed to characterize the hypo/hyper-sensory profile among autistic individuals. We then explored its link with the burden of deleterious mutations in a subset of individuals with available whole-genome sequencing data. To characterize the hypo/hyper-sensory profile, the differential Short Sensory Profile (dSSP) was defined as a normalized and centralized hypo/hypersensitivity ratio from the Short Sensory Profile (SSP). Including 1136 participants (533 autistic individuals, 210 first-degree relatives, and 267 controls) from two independent study samples (PARIS and LEAP), we observed a statistically significant dSSP mean difference between autistic individuals and controls, driven mostly by a high dSSP variability, with an intermediated profile represented by relatives. Our genetic analysis tended to associate the dSSP and the hyposensitivity with mutations of the GABAergic pathway. The major limitation was the dSSP difficulty to discriminate subjects with a similar quantum of hypo- and hyper-sensory symptoms to those with no such symptoms, resulting both in a similar ratio score of 0. However, the dSSP could be a relevant clinical score, and combined with additional sensory descriptions, genetics and endophenotypic substrates, will improve the exploration of the underlying neurobiological mechanisms of sensory processing differences in autism spectrum., (© 2022 International Society for Autism Research and Wiley Periodicals LLC.)

Cerebellar abnormalities have been reported in autism spectrum disorder (ASD). Beyond its role in hallmark features of ASD, the cerebellum and its connectivity with forebrain structures also play a role in navigation. However, the current understanding of navigation abilities in ASD is equivocal, as is the impact of the disorder on the functional anatomy of the cerebellum. In the present study, we investigated the navigation behavior of a population of ASD and typically developing (TD) adults related to their brain anatomy as assessed by structural and functional MRI at rest. We used the Starmaze task, which permits assessing and distinguishing two complex navigation behaviors, one based on allocentric learning and the other on egocentric learning of a route with multiple decision points. Compared to TD controls, individuals with ASD showed similar exploration, learning, and strategy performance and preference. In addition, there was no difference in the structural or functional anatomy of the cerebellar circuits involved in navigation between the two groups. The findings of our work suggest that navigation abilities, spatio-temporal memory, and their underlying circuits are preserved in individuals with ASD., (© 2022 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Evidences suggest that inflammation is increased in a subgroup of patients with depression. Moreover, increased peripheral inflammatory markers (cells and proteins) are associated with some, but not all depressive symptoms. On the other hand, similar studies on bipolar disorders mainly focused on blood cytokines. Here, we analysed data from a large (N = 3440), well-characterized cohort of individuals with bipolar disorder using Kendall partial rank correlation, multivariate linear regression, and network analyses to determine whether peripheral blood cell counts are associated with depression severity, its symptoms, and dimensions. Based on the self-reported 16-Item Quick Inventory of Depressive Symptomatology questionnaire scores, we preselected symptom dimensions based on literature and data-driven principal component analysis. We found that the counts of all blood cell types were only marginally associated with depression severity. Conversely, white blood cell count was significantly associated with the sickness dimension and its four components (anhedonia, slowing down, fatigue, and appetite loss). Platelet count was associated with the insomnia/restlessness dimension and its components (initial, middle, late insomnia and restlessness). Principal component analyses corroborated these results. Platelet count was also associated with suicidal ideation. In analyses stratified by sex, the white blood cell count-sickness dimension association remained significant only in men, and the platelet count-insomnia/restlessness dimension association only in women. Without implying causation, these results suggest that peripheral blood cell counts might be associated with different depressive symptoms in individuals with bipolar disorder, and that white blood cells might be implicated in sickness symptoms and platelets in insomnia/agitation and suicidal ideation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Metabolic Syndrome (MetS) is a major health epidemic of Western countries and patients with schizophrenia is a particularly vulnerable population due to lifestyle, mental illness and treatment factors. However, we lack prospective data to guide prevention. The aim of our study is then to determine MetS incidence and predictors in schizophrenia., Method: Participants were recruited in 10 expert centers at a national level and followed-up for 3 years. MetS was defined according to the International Diabetes Federation criteria. Inverse probability weighting methods were used to correct for attrition bias., Results: Among the 512 participants followed-up for 3 years, 77.9% had at least one metabolic disturbance. 27.5% were identified with MetS at baseline and excluded from the analyses. Among the rest of participants (N = 371, mean aged 31.2 (SD = 9.1) years, with mean illness duration of 10.0 (SD = 7.6) years and 273 (73.6%) men), MetS incidence was 20.8% at 3 years and raised to 23.6% in tobacco smokers, 29.4% in participants receiving antidepressant prescription at baseline and 42.0% for those with 2 disturbed metabolic disturbances at baseline. Our multivariate analyses confirmed tobacco smoking and antidepressant consumption as independent predictors of MetS onset (adjusted odds ratios (aOR) = 3.82 [1.27-11.45], p = 0.016, and aOR = 3.50 [1.26-9.70], p = 0.0158). Antidepressant prescription predicted more specifically increased lipid disturbances and paroxetine was associated with the highest risk of MetS onset., Conclusion: These results are an alarm call to prioritize MetS prevention and research in schizophrenia. We have listed interventions that should be actively promoted in clinical practice., Competing Interests: Declaration of Competing Interest All authors reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Patients with psychiatric disorders are exposed to high risk of COVID-19 and increased mortality. In this study, we set out to assess the clinical features and outcomes of patients with current psychiatric disorders exposed to COVID-19., Methods: This multi-center prospective study was conducted in 22 psychiatric wards dedicated to COVID-19 inpatients between 28 February and 30 May 2020. The main outcomes were the number of patients transferred to somatic care units, the number of deaths, and the number of patients developing a confusional state. The risk factors of confusional state and transfer to somatic care units were assessed by a multivariate logistic model. The risk of death was analyzed by a univariate analysis., Results: In total, 350 patients were included in the study. Overall, 24 (7%) were transferred to medicine units, 7 (2%) died, and 51 (15%) patients presented a confusional state. Severe respiratory symptoms predicted the transfer to a medicine unit [odds ratio (OR) 17.1; confidence interval (CI) 4.9-59.3]. Older age, an organic mental disorder, a confusional state, and severe respiratory symptoms predicted mortality in univariate analysis. Age >55 (OR 4.9; CI 2.1-11.4), an affective disorder (OR 4.1; CI 1.6-10.9), and severe respiratory symptoms (OR 4.6; CI 2.2-9.7) predicted a higher risk, whereas smoking (OR 0.3; CI 0.1-0.9) predicted a lower risk of a confusional state., Conclusion: COVID-19 patients with severe psychiatric disorders have multiple somatic comorbidities and have a risk of developing a confusional state. These data underline the need for extreme caution given the risks of COVID-19 in patients hospitalized for psychiatric disorders.

Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment. Infections, inflammation, and autoimmune diseases are over-represented in schizophrenia leading to immune system-centered hypotheses. Complement component C4 is genetically and neurobiologically associated with schizophrenia, and its dual activity peripherally and in the brain makes it an exceptional target for biomarker development. Studies to evaluate the biomarker potential of plasma or serum C4 in schizophrenia do so to understand how peripheral C4 might reflect central nervous system-derived neuroinflammation, synapse pruning, and other mechanisms. This effort, however, has produced mostly conflicting results, with peripheral C4 sometimes elevated, reduced, or unchanged between comparison groups. We undertook a pilot biomarker development study to systematically identify sociodemographic, genetic, and immune-related variables (autoimmune, infection-related, gastrointestinal, inflammatory), which may be associated with plasma C4 levels in schizophrenia (SCH; n = 335) and/or in nonpsychiatric comparison subjects (NCs; n = 233). As with previously inconclusive studies, we detected no differences in plasma C4 levels between SCH and NCs. In contrast, levels of general inflammation, C-reactive protein (CRP), were significantly elevated in SCH compared to NCs (ANOVA, F = 20.74, p &lt; 0.0001), suggestive that plasma C4 and CRP may reflect different sources or causes of inflammation. In multivariate regressions of C4 gene copy number variants, plasma C4 levels were correlated only for C4A (not C4B, C4L, C4S) and only in NCs (R Coeff = 0.39, CI = 0.01-0.77, R2 = 0.18, p &lt; 0.01; not SCH). Other variables associated with plasma C4 levels only in NCs included sex, double-stranded DNA IgG, tissue-transglutaminase (TTG) IgG, and cytomegalovirus IgG. Toxoplasma gondii IgG was the only variable significantly correlated with plasma C4 in SCH but not in NCs. Many variables were associated with plasma C4 in both groups (body mass index, race, CRP, N-methyl-D-aspartate receptor (NMDAR) NR2 subunit IgG, TTG IgA, lipopolysaccharide-binding protein (LBP), and soluble CD14 (sCD14). While the direction of most C4 associations was positive, autoimmune markers tended to be inverse, and associated with reduced plasma C4 levels. When NMDAR-NR2 autoantibody-positive individuals were removed, plasma C4 was elevated in SCH versus NCs (ANOVA, F = 5.16, p &lt; 0.02). Our study was exploratory and confirmation of the many variables associated with peripheral C4 requires replication. Our preliminary results point toward autoimmune factors and exposure to the pathogen, T. gondii, as possibly significant contributors to variability of total C4 protein levels in plasma of individuals with schizophrenia., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Prior research suggests that psychiatric disorders could be linked to increased mortality among patients with COVID-19. However, whether all or specific psychiatric disorders are intrinsic risk factors of death in COVID-19 or whether these associations reflect the greater prevalence of medical risk factors in people with psychiatric disorders has yet to be evaluated., Methods: We performed an observational, multicenter, retrospective cohort study to examine the association between psychiatric disorders and mortality among patients hospitalized for laboratory-confirmed COVID-19 at 36 Greater Paris University hospitals., Results: Of 15,168 adult patients, 857 (5.7%) had an ICD-10 diagnosis of psychiatric disorder. Over a mean follow-up period of 14.6 days (SD = 17.9), 326 of 857 (38.0%) patients with a diagnosis of psychiatric disorder died compared with 1276 of 14,311 (8.9%) patients without such a diagnosis (odds ratio 6.27, 95% CI 5.40-7.28, p < .01). When adjusting for age, sex, hospital, current smoking status, and medications according to compassionate use or as part of a clinical trial, this association remained significant (adjusted odds ratio 3.27, 95% CI 2.78-3.85, p < .01). However, additional adjustments for obesity and number of medical conditions resulted in a nonsignificant association (adjusted odds ratio 1.02, 95% CI 0.84-1.23, p  = .86). Exploratory analyses after the same adjustments suggested that a diagnosis of mood disorders was significantly associated with reduced mortality, which might be explained by the use of antidepressants., Conclusions: These findings suggest that the increased risk of COVID-19-related mortality in individuals with psychiatric disorders hospitalized for COVID-19 might be explained by the greater number of medical conditions and the higher prevalence of obesity in this population and not by the underlying psychiatric disease., (© 2022 The Authors.)

Marked heterogeneity in suicide attempters has been observed, with earlier onset being linked to stronger heritability, more childhood maltreatment. Nitric oxide signalling system might be implicated in this relationship through its role in the stress response/adaptation. This study examined how NOS genetic variants and childhood maltreatment were associated with age at first suicide attempt (SA). Adult patients with SA history (N = 414) filled in the Childhood Trauma Questionnaire, and six functionally relevant NOS2 and NOS3 polymorphisms were genotyped. Analyses included χ 2 , Mann-Whitney U tests, Kendall's regression, multivariate linear and Cox survival regressions, and a moderation analysis. The NOS3 promotor 27-bp variable number tandem repeat (VNTR) bb homozygous state and childhood emotional abuse were independently associated with earlier age at first SA, which was robust after controlling for confounders [regression coefficient - 3.975, 95% CI -6.980 - (-0.970), p = 0.010, and - 1.088, 95% CI -2.172 - (-0.004), p = 0.049]. No interaction was observed. In the Cox proportional hazards model for age at first SA, the hazard ratio for patients with childhood emotional abuse and NOS3 27-bp VNTR bb was 0.533 (95% CI 0.394-0.720, p < 0.001) compared to patients without. Intermediate scores were observed with either only the risk genotype or only childhood emotional abuse. A graded relationship was also observed for repeated SA, family history of SA, and severe SA history. These results are preliminary due to a low statistical power and call for replication and further characterization of the role of nitric oxide system in the susceptibility to early-onset SB., (Copyright © 2022. Published by Elsevier Inc.)

Particulate matters with a diameter of less than 10 µm (PM 10 ) or less than 2.5 µm (PM 2.5 ) are major air pollutants. Their relationship to psychiatric disorders has not yet been extensively studied. We aimed to explore the relationship between PM 10 and PM 2.5 air pollution peaks and the daily number of emergency visits for psychotic and mood disorders. Clinical data were collected from the Emergency Department of a Paris suburb (Créteil, France) from 2008 to 2018. Air pollution data were measured by the Paris region air quality network (Airparif) and collected from public databases. Pollution peak periods were defined as days for which the daily mean level of PM was above nationally predefined warning thresholds (20 µg/m 3 for PM 2.5 , and 50 µg/m 3 for PM 10 ), and the 6 following days. Multivariable analyses compared the number of daily visits for psychotic and mood (unipolar and bipolar) disorders according to pollution peak, using negative binomial regression. After adjustment on meteorological variables (temperature, humidity, amount of sunshine in minutes), the daily number of emergency visits for psychotic disorders was significantly higher during PM 2.5 and PM 10 air pollution peak periods; while the number of visits for unipolar depressive disorders was higher only during PM 10 peak periods (β = 0.059, p-value = 0.034). There were no significant differences between peak and non-peak periods for bipolar disorders. Differences in the effects of PM air pollution on psychotic and mood disorders should be analyzed in further studies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD., Methods: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors., Results: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning., Conclusions: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness., (© 2022 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Background: Mental disorders are at-risk of severe COVID-19 outcomes. There is limited and heterogeneous national data in hospital settings evaluating the risks associated with any pre-existing mental disorder, and susceptible subgroups. Our study aimed to investigate the association between pre-existing psychiatric disorders and outcomes of adults hospitalised for COVID-19., Method: We used data obtained from the French national hospital database linked to the state-level psychiatric registry. The primary outcome was 30-days in-hospital mortality. Secondary outcomes were to compare the length of hospital stay, Intensive Care Unit (ICU) admission and ICU length. Propensity score matching analysis was used to control for COVID-19 confounding factors between patients with or without mental disorder and stratified by psychiatric subgroups., Results: Among 97 302 adults hospitalised for COVID-19 from March to September 2020, 10 083 (10.3%) had a pre-existing mental disorder, mainly dementia (3581 [35.5%]), mood disorders (1298 [12.9%]), anxiety disorders (995 [9.9%]), psychoactive substance use disorders (960 [9.5%]), and psychotic disorders (866 [8.6%]). In propensity-matched analysis, 30-days in-hospital mortality was increased among those with at least one pre-existing mental disorder (hazard ratio (HR) 1.15, 95% CI 1.08-1.23), psychotic disorder (1.90, 1.24-2.90), and psychoactive substance disorders (1.53, 1.10-2.14). The odds of ICU admission were consistently decreased for patients with any pre-existing mental disorder (OR 0.83, 95% CI 0.76-0.92) and for those with dementia (0.64, 0.53-0.76)., Conclusion: Pre-existing mental disorders were independently associated with in-hospital mortality. These findings underscore the important need for adequate care and targeted interventions for at-risk individuals with severe mental illness., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: In people with schizophrenia, major areas of everyday life are impaired, including independent living, productive activities, social relationships and overall quality of life. Enhanced understanding of factors that hinder real-life functioning is vital for treatments to translate into more positive outcomes., Aim: The goal of the present study was to identify factors associated with motivation deficits in real-life schizophrenia, and to assess its contribution to impaired functioning and quality of life., Methods: Based on previous literature and clinical experience, several factors were selected and grouped into factors potentially explaining motivation deficits. Some of these variables were never investigated before in relationship with motivation deficits., Results: In 561 patients with schizophrenia of the national FACE-SZ cohort living in the community, 235 (41.9%) reported severe motivation deficits. These deficits were found to be significantly associated with impaired socially useful activities, psychological and physical quality of life (in almost all domains), alcohol use disorder (aOR = 2.141, p  = 0.021), severe nicotine dependence (aOR = 2.906, p  < 0.001) independently of age and sex. No significant association was found for body mass index, metabolic syndrome or physical activity level. In the second model, we identified the following modifiable factors associated with motivation deficits: history of suicide attempt (aOR = 2.297, p  = 0.001), positive symptoms (aOR = 1.052, p  = 0.006), current major depressive episode (aOR = 2.627, p  < 0.001), sleep disorders (aOR = 1.474, p  = 0.024) and lower medication adherence (aOR = 0.836, p  = 0.001) independently of gender, current alcohol use disorder, second-generation antipsychotics and akathisia. No significant association was found for negative symptoms, childhood trauma and inflammation. These results were maintained after removing patients with schizoaffective disorders or those with major depressive disorder., Interpretation: Motivation deficits are frequent and remain persistent unmet need in real-world schizophrenia that should be addressed in future guidelines. Based on our results, literature and clinical experience, we recommend to address in priority major depression, sleep, suicide, positive symptoms (when present and as early as possible) and medication adherence to improve motivation deficits of schizophrenia.

This study of a cohort of 1-year treatment-compliant survivors of a suicide attempt examined for the first time whether a high CYP2D6-CYP2C19 metabolic capacity (pharmacogenes related to psychopathology, suicide, and attempt severity) and/or polypharmacy treatments predicted repeat suicide attempts, adjusting for sociodemographic and clinical factors as confounders. Of the 461 (63% women) consecutively hospitalized patients who attempted suicide and were evaluated and treated after an index attempt, 191 (67.5% women) attended their 6- and 12-month follow-up sessions. Clinicians were blinded to the activity scores (AS) of their genotypes, which were calculated as the sum of the values assigned to each allele (CYP2C19 *2, *17; CYP2D6 *3, *4, *4xN, *5, *6, *10, wtxN). No differences were found in polypharmacy prescription patterns and the variability of CYP2D6 and CYP2C19 genotypes between adherents and dropouts, but the formers were older, with a higher frequency of anxiety and bipolar disorders and fewer alcohol and substance use disorders. The risk of reattempts was higher for CYP2D6 ultrarapid (AS > 2) metabolizers (β = 0.561, p = 0.005) and violent suicide survivors (β = -0.219, p = 0.042) if the attempt occurred during the first 6-month period, individuals with an increased number of MINI DSM-IV Axis I mental disorders (β = 0.092, p = 0.032) during the second 6-month period and individuals with a combined high CYP2D6-CYP2C19 metabolic capacity (AS > 4) (β = 0.345, p = 0.024) and an increased use of drugs other than antidepressants, anxiolytics-depressants and antipsychotics-lithium (β = 0.088, p = 0.005) in multiple repeaters during both periods. CYP2D6 and CYP2C19 rapid metabolism and polypharmacy treatment for somatic comorbidities must be considered to prevent the severe side effects of short-term multiple suicide reattempts after a previous attempt., (© 2022. The Author(s).)

Background: The cerebellum contains more than 50% of the brain's neurons and is involved in social cognition. Cerebellar anatomical atypicalities have repeatedly been reported in individuals with autism. However, studies have yielded inconsistent findings, likely because of a lack of statistical power, and did not capture the clinical and neuroanatomical diversity of autism. Our aim was to better understand cerebellar anatomy and its diversity in autism., Methods: We studied cerebellar gray matter morphology in 274 individuals with autism and 219 control subjects of a multicenter European cohort, EU-AIMS LEAP (European Autism Interventions-A Multicentre Study for Developing New Medications; Longitudinal European Autism Project). To ensure the robustness of our results, we conducted lobular parcellation of the cerebellum with 2 different pipelines in addition to voxel-based morphometry. We performed statistical analyses with linear, multivariate (including normative modeling), and meta-analytic approaches to capture the diversity of cerebellar anatomy in individuals with autism and control subjects. Finally, we performed a dimensional analysis of cerebellar anatomy in an independent cohort of 352 individuals with autism-related symptoms., Results: We did not find any significant difference in the cerebellum when comparing individuals with autism and control subjects using linear models. In addition, there were no significant deviations in our normative models in the cerebellum in individuals with autism. Finally, we found no evidence of cerebellar atypicalities related to age, IQ, sex, or social functioning in individuals with autism., Conclusions: Despite positive results published in the last decade from relatively small samples, our results suggest that there is no striking difference in cerebellar anatomy of individuals with autism., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: After the Food and Drug Administration alert about antiepileptic medication and suicide, incident epilepsy has been associated with first or recurrent suicide attempts independently of psychiatric comorbidities and antiepileptic treatment. Following this thread, the aim of this study was to analyze if epilepsy was associated with a higher severity of lifetime suicide attempts (SAs)., Methods: Analyses were carried out on 1677 adults hospitalized between 1999 and 2012 after a SA in a specialized ward for affective episodes. Five severity features were studied: frequent SAs (&gt;2), early onset of first SA (≤26 years), history of violent SA, high suicide intent and high lethality of the SA. Adjusted logistic regression models were used to estimate the association between the lifetime diagnosis of epilepsy and the severity features., Results: Among suicide attempters, ninety-three patients reported a lifetime diagnosis of epilepsy (5.5%). Epileptic patients diagnosed after the first SA were more likely to be frequent suicide attempters than non-epileptic ones. They showed also higher SA planification scores., Limitations: Diagnosis accuracy is limited by the use of self-reports for epilepsy. The lack of precise information about the disease course and treatment have not allowed for further statistical analysis. With regard to psychiatric comorbidities, personality disorders could not be taken into account., Conclusions: Suicide attempters with epilepsy present an increased severity in some aspects of their suicidal behavior regardless of demographic and clinical variables. Our results give support to the existence of a bidirectional association between epilepsy and suicidal behavior., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aims: Gene x environment (G×E) interactions, i.e. genetic modulation of the sensitivity to environmental factors and/or environmental control of the gene expression, have not been reliably established regarding aetiology of psychotic disorders. Moreover, recent studies have shown associations between the polygenic risk scores for schizophrenia (PRS-SZ) and some risk factors of psychotic disorders, challenging the traditional gene v. environment dichotomy. In the present article, we studied the role of GxE interaction between psychosocial stressors (childhood trauma, stressful life-events, self-reported discrimination experiences and low social capital) and the PRS-SZ on subclinical psychosis in a population-based sample., Methods: Data were drawn from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, in which subjects without psychotic disorders were included in six countries. The sample was restricted to European descendant subjects ( n = 706). Subclinical dimensions of psychosis (positive, negative, and depressive) were measured by the Community Assessment of Psychic Experiences (CAPE) scale. Associations between the PRS-SZ and the psychosocial stressors were tested. For each dimension, the interactions between genes and environment were assessed using linear models and comparing explained variances of 'Genetic' models (solely fitted with PRS-SZ), 'Environmental' models (solely fitted with each environmental stressor), 'Independent' models (with PRS-SZ and each environmental factor), and 'Interaction' models (Independent models plus an interaction term between the PRS-SZ and each environmental factor). Likelihood ration tests (LRT) compared the fit of the different models., Results: There were no genes-environment associations. PRS-SZ was associated with positive dimensions ( β = 0.092, R 2 = 7.50%), and most psychosocial stressors were associated with all three subclinical psychotic dimensions (except social capital and positive dimension). Concerning the positive dimension, Independent models fitted better than Environmental and Genetic models. No significant GxE interaction was observed for any dimension., Conclusions: This study in subjects without psychotic disorders suggests that (i) the aetiological continuum hypothesis could concern particularly the positive dimension of subclinical psychosis, (ii) genetic and environmental factors have independent effects on the level of this positive dimension, (iii) and that interactions between genetic and individual environmental factors could not be identified in this sample.

As COVID-19 becomes endemic, identifying vulnerable population groups for severe infection outcomes and defining rapid and effective preventive and therapeutic strategies remains a public health priority. We performed an umbrella review, including comprehensive studies (meta-analyses and systematic reviews) investigating COVID-19 risk for infection, hospitalization, intensive care unit (ICU) admission, and mortality in people with psychiatric disorders, and outlined evidence- and consensus-based recommendations for overcoming potential barriers that psychiatric patients may experience in preventing and managing COVID-19, and defining optimal therapeutic options and current research priorities in psychiatry. We searched Web of Science, PubMed, and Ovid/PsycINFO databases up to 17 January 2022 for the umbrella review. We synthesized evidence, extracting when available pooled odd ratio estimates for the categories "any mental disorder" and "severe mental disorders." The quality of each study was assessed using the AMSTAR-2 approach and ranking evidence quality. We identified four systematic review/meta-analysis combinations, one meta-analysis, and three systematic reviews, each including up to 28 original studies. Although we rated the quality of studies from moderate to low and the evidence ranged from highly suggestive to non-significant, we found consistent evidence that people with mental illness are at increased risk of COVID-19 infection, hospitalization, and most importantly mortality, but not of ICU admission. The risk and the burden of COVID-19 in people with mental disorders, in particular those with severe mental illness, can no longer be ignored but demands urgent targeted and persistent action. Twenty-two recommendations are proposed to facilitate this process.

Background: As mHealth may contribute to suicide prevention, we developed emma , an application using Ecological Momentary Assessment and Intervention (EMA/EMI)., Objective: This study evaluated emma usage rate and acceptability during the first month and satisfaction after 1 and 6 months of use., Methods: Ninety-nine patients at high risk of suicide used emma for 6 months. The acceptability and usage rate of the EMA and EMI modules were monitored during the first month. Satisfaction was assessed by questions in the monthly EMA (Likert scale from 0 to 10) and the Mobile App Rating Scale (MARS; score: 0-5) completed at month 6. After inclusion, three follow-up visits (months 1, 3, and 6) took place., Results: Seventy-five patients completed at least one of the proposed EMAs. Completion rates were lower for the daily than weekly EMAs (60 and 82%, respectively). The daily completion rates varied according to the question position in the questionnaire (lower for the last questions, LRT = 604.26, df = 1, p -value < 0.0001). Completion rates for the daily EMA were higher in patients with suicidal ideation and/or depression than in those without. The most used EMI was the emergency call module ( n = 12). Many users said that they would recommend this application (mean satisfaction score of 6.92 ± 2.78) and the MARS score at month 6 was relatively high (overall rating: 3.3 ± 0.87)., Conclusion: Emma can target and involve patients at high risk of suicide. Given the promising users' satisfaction level, emma could rapidly evolve into a complementary tool for suicide prevention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Morgiève, Yasri, Genty, Dubois, Leboyer, Vaiva, Berrouiguet, Azé and Courtet.)

The microbiota-gut-brain axis is important in anxiety-depressive disorders. These conditions are associated with dysbiosis of the intestinal microbiota, intestinal hyperpermeability and an increase in circulating markers of inflammation and oxidative stress. They are also associated with a deregulation of the glutamine-glutamate-γ-aminobutyric acid cycle, with impairment of the excitatory/inhibitory balance in the brain. Our aim was to examine the impact of chronic treatment with the probiotic organism Lacticaseibacillus rhamnosus GG , alone or in combination with glutamine and curcumin, in a validated model of anxiety-depressive disorder in mice. Six-month-old mice (n=144) were exposed to chronic unpredictable mild stress (CUMS) stimulation for 3 weeks and emotional disturbances were assessed using two tests assessing anxiety (elevated plus maze test) and depressive-like behaviour (tail suspension test). After discontinuation of CUMS, mice were force-fed once-daily with curcumin, glutamine and probiotic alone or in combination for 21 consecutive days. Emotional reactivity was assessed in two separate behavioural tests: open field test and forced swim test. The outcomes of the interventions were compared with those induced by acute intraperitoneal administration of clomipramine, one of the major tricyclic antidepressants used in humans. Two independent sets of experiment were performed in this study, in order to evaluate the effects of two different formulations based on the utilisation of the probiotic L. rhamnosus GG in its live or inactivated form. CUMS led to an impairment of the emotional state of 6-month-old mice. However, chronic treatment with a combination of glutamine, curcumin and L. rhamnosus GG rescued the anxiety and depressive-like phenotype with an efficiency similar to clomipramine. A synergistic effect of the three compounds was observed, suggesting that simultaneous action on different targets is a relevant approach for the management of anxiety-depressive disorders.

Objectives: High rates of non-right-handedness (NRH) and mixed-handedness exist in neurodevelopmental disorders. Dysfunctional neurodevelopmental pathways may be implicated in the underlying pathophysiology of bipolar disorders (BD), at least in some subgroups. Yet little is known about correlates of NRH and mixed-handedness in BD. The objectives of this national study are to determine (i) the prevalence of NRH and mixed-handedness in a well-stabilized sample of BD individuals; (ii) if NRH/mixed-handedness in BD is associated with a different clinical, biological and neurocognitive profile., Methods: We included 2174 stabilized individuals. Participants were tested with a comprehensive battery of neuropsychological tests. Handedness was assessed using a single oral question. Learning and/or language disorders and obstetrical complications were recorded using childhood records. Common environmental, clinical and biological parameters were assessed., Results: The prevalence of NRH and mixed-handedness were, respectively, 11.6 and 2.4%. Learning/language disorders were found in 9.7% out of the total sample and were associated with atypical handedness (only dyslexia for mixed-handedness (p < 0.01), and dyslexia and dysphasia for NRH (p = 0.01 and p = 0.04, respectively). In multivariate analyses, NRH was associated with a younger age of BD onset (aOR 0.98 (95% CI 0.96-0.99) and lifetime substance use disorder (aOR 1.40 (95% CI 1.03-1.82) but not with any of the cognitive subtasks. Mixed-handedness was associated in univariate analyses with lifetime substance use disorder, lifetime cannabis use disorder (all p < 0.01) and less mood stabilizer prescription (p = 0.028). No association was found between NRH or mixed-handedness and the following parameters: trauma history, obstetrical complications, prior psychotic symptoms, bipolar subtype, attention deficit/hyperactivity disorder, peripheral inflammation or body mass index., Conclusions: Handedness may be associated with specific features in BD, possibly reflecting a specific subgroup with a neurodevelopmental load., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Bipolar disorder (BD) is a complex and dynamic condition with a typical onset in late adolescence or early adulthood followed by an episodic course with intervening periods of subthreshold symptoms or euthymia. It is complicated by the accumulation of comorbid medical and psychiatric disorders. The etiology of BD remains unknown and no reliable biological markers have yet been identified. This is likely due to lack of comprehensive ontological framework and, most importantly, the fact that most studies have been based on small nonrepresentative clinical samples with cross-sectional designs. We propose to establish large, global longitudinal cohorts of BD studied consistently in a multidimensional and multidisciplinary manner to determine etiology and help improve treatment. Herein we propose collection of a broad range of data that reflect the heterogenic phenotypic manifestations of BD that include dimensional and categorical measures of mood, neurocognitive, personality, behavior, sleep and circadian, life-story, and outcomes domains. In combination with genetic and biological information such an approach promotes the integrating and harmonizing of data within and across current ontology systems while supporting a paradigm shift that will facilitate discovery and become the basis for novel hypotheses., (© 2022 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Objective: To study the ageing-related pharmacological modifications about major depressive episodes in the elderly and their impact on the efficiency and tolerability of antidepressants., Methods: Research through Pubmed and the Cochrane Database of Systematic Reviews, using the following keywords "antidepressant" ; "treatment"; "late life depression"; "elderly"; up until July 2021., Results: Antidepressants were found to be more efficient than a placebo in the elderly's response to and remission from major depressive episodes. Some depressive episode subtypes seem to be less responsive to antidepressants, such as depressive episodes of vascular origin, for which treating cardiovascular risk factors by statins, angiotensin receptor blockers or calcium channel blockers seems relevant. Two other depressive episode subtypes were highlighted : post-stroke depressive episodes and those induced by major neurocognitive disorders. Antidepressants showed an efficient response in the first case but not in the second. Even though antidepressants are known to stimulate cognitive performances in animals, as yet there is not sufficient evidence to prove they indeed improve cognitive functions, or reduce the risk of developing a neurocognitive disorder, or decelerate the cognitive decline in major neurocognitive disorders in humans. Ageing creates pharmacodynamical changes that increase older people's vulnerability to the side effects of antidepressants. Moreover, age-related pharmacokinetic modifications can also change every step in a drug's transformation process in the body, which leads to a high probability of having adverse effects. Since most antidepressants are eliminated using the P450 cytochrome system, their dosage must be adapted to changes of the P450 system. Somatic comorbidities can, in themselves, influence the pharmacokinetics of antidepressants. Many antidepressants interact with the P450 cytochrome and the P-GP protein, which puts them at a high risk of drug interactions. There is no proven efficiency difference between antidepressant classes. Some antidepressant adverse effects can be of particular importance in the elderly, like the risk of bleeding, cardiovascular episodes, hyponatremia, falling and fractures, anticholinergic effects, extrapyramidal syndrome, epilepsy, liver disease and death. Selective serotonin reuptake inhibitors have an indication as the first line of treatment, avoiding paroxetine and fluoxetine. Serotonin and norepinephrine re-uptake inhibitors are relevant if the patient presents psychomotor retardation or pain, while keeping in mind to check blood pressure. Tricyclics and monoamine oxidase inhibitors should be avoided because of their anticholinergic effects. Bupropion can be prescribed if the patient has extreme fatigue. Mirtazapine is useful when the patient presents sleep or appetite disturbance. Several molecules can be used in the case of drug-resistant depression, such as associating aripiprazole with small-dosage antidepressants, or electroconvulsive therapy, or repetitive Transcranial Magnetic Stimulation (rTMS). Ketamine and psychostimulants seem to have antidepressant effects, but complementary studies are needed to conclude., Conclusions: Unipolar major depressive episodes in the elderly are frequent and their medicinal treatment has specific features. Knowing the specificities of antidepressant use in the elderly allows to optimize its efficiency and to limit the risk of inappropriate prescription leading to harmful adverse effects., (Copyright © 2022 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

An antiviral effect of lithium has been proposed, but never investigated for coronavirus disease 2019 (COVID-19). Using electronic health records of 26 554 patients with documented serum lithium levels during the pandemic, we show that the 6-month COVID-19 infection incidence was lower among matched patients with 'therapeutic' (0.50-1.00) versus 'subtherapeutic' (0.05-0.50) lithium levels (hazard ratio (HR) = 0.82, 95% CI 0.69-0.97, P = 0.017) and among patients with 'therapeutic' lithium levels versus matched patients using valproate (HR = 0.79, 95% CI 0.67-0.92, P = 0.0023). Lower rates of infection were observed for both new COVID-19 diagnoses and positive polymerase chain reaction tests, regardless of underlying psychiatric diagnosis and vaccination status.

Background: The FACE-BD cohort is an observational cohort of individuals with bipolar disorders (BD) who benefited from a systematic evaluation with evidence-based treatment recommendations and who were followed-up every year for 3 years in France. The objectives were to describe the lifetime course of BD, associated psychiatric and somatic comorbidities, and cognition profile. This cohort aims to identify clinical/biological signatures of outcomes, trajectories of functioning and transition between clinical stages. This article summarizes 10 years of findings of the FACE-BD cohort., Method & Results: We included 4422 individuals, all having a baseline assessment, among which 61.2% had at least one follow-up visit at either one, two or three years. A subsample of 1200 individuals had at least one biological sample (serum, plasma, DNA). Assessments include family history of psychiatric disorders, psychiatric diagnosis, current mood symptoms, functioning, hospitalizations, suicidal attempts, physical health, routine blood tests, treatment history, psychological dimensions, medico-economic data and a cognitive assessment. Studies from this cohort illustrate that individuals with BD display multiple coexistent psychiatric associated conditions including sleep disturbances, anxiety disorders, substance use disorders and suicide attempts as well as a high prevalence of metabolic syndrome. During follow-up, we observed a 55% reduction of the number of days of hospitalization and a significant improvement in functioning., Conclusions: The FACE-BD cohort provides a strong research infrastructure for clinical research in BD and has a unique position among international cohorts because of its comprehensive clinical assessment and sustainable funding from the French Ministry of Health., (Copyright © 2022. Published by Elsevier B.V.)

Background: Bipolar disorder (BD) is a severe chronic psychiatric disorder affecting 0.5 to 1% of the population worldwide. To date, most studies have estimated the cost of BD via information sourced from insurance claims with limited information on clinical characteristics and course of BD. The aims of this study are (i) to estimate the direct healthcare cost associated with BD and to identify contributing factors and (ii) to study the evolution of cost during a two-year follow-up period., Method: We analyzed a sample of 1116 individuals with BD included in the Advanced Centers of Expertise in Bipolar Disorder cohort. We estimated the direct healthcare cost per year and per patient, and we identified the clinical features of patients with BD associated with higher direct healthcare costs. In a subsample of patients followed up for two years centers of expertise for BD, we studied the evolution of direct healthcare cost., Results: The average cost of bipolar disorder was € 6910 per year and per patient. Clinical features of BD, sociodemographic characteristics, and associated addiction were associated with higher direct healthcare costs. In the subsample of patients followed-up for two years, direct healthcare cost dropped by more than 50%, strongly suggesting the beneficial effect of specialized care organization., Limitation: We did not estimate indirect healthcare and intangible costs., Conclusion: Our study investigates the cost of BD and its evolution in a deeply phenotyped longitudinal sample. Cost-utility and cost-effectiveness analyses are required to inform resource allocation decisions and to promote innovative healthcare organizations., (Copyright © 2022. Published by Elsevier B.V.)

Objective: The potential role of sub-optimal pharmacological treatment in the poorer outcomes observed in bipolar disorder (BD) with vs. without comorbid substance use disorders (SUDs) is not known. Thus, we investigated whether patients with BD and comorbid SUD had different medication regimens than those with BD alone, in samples from France and Norway, focusing on compliance to international guidelines., Methods: Seven hundred and seventy patients from France and Norway with reliably ascertained BD I or II (68% BD-I) were included. Medication information was obtained from patients and hospital records, and preventive treatment was categorized according to compliance to guidelines. We used Bayesian and regression analyses to investigate associations between SUD comorbidity and medication. In the Norwegian subsample, we also investigated association with lack of medication., Results: Comorbid SUDs were as follows: current tobacco smoking, 26%, alcohol use disorder (AUD), 16%; cannabis use disorder (CUD), 10%; other SUDs, 5%. Compliance to guidelines for preventive medication was lacking in 8%, partial in 44%, and complete in 48% of the sample. Compliance to guidelines was not different in BD with and without SUD comorbidity, as was supported by Bayesian analyses (highest Bayes Factor = 0.16). Cross national differences in treatment regimens led us to conduct country-specific adjusted regression analyses, showing that (1) CUD was associated with increased antipsychotics use in France (OR = 2.4, 95% CI = 1.4-3.9, p = 0.001), (2) current tobacco smoking was associated with increased anti-epileptics use in Norway (OR = 4.4, 95% CI = 1.9-11, p < 0.001), and (3) AUD was associated with decreased likelihood of being medicated in Norway (OR = 1.2, 95% CI = 1.04-1.3, p = 0.038)., Conclusion: SUD comorbidity in BD was overall not associated with different pharmacological treatment in our sample, and not related to the level of compliance to guidelines. We found country-specific associations between comorbid SUDs and specific medications that warrant further studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Icick, Melle, Etain, Høegh, Gard, Aminoff, Leboyer, Andreassen, Belzeaux, Henry, Bjella, Kahn, Steen, Bellivier and Lagerberg.)