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Background Frequently associated with early psychosis, depressive and manic dimensions may play an important role in its course and outcome. While manic and depressive symptoms can alternate and co-occur, most of the studies in early intervention investigated these symptoms independently. The aim of this study was therefore to explore the co-occurrence of manic and depressive dimensions, their evolution and impact on outcomes. Methods We prospectively studied first-episode psychosis patients (N = 313) within an early intervention program over 3 years. Based on latent transition analysis, we identified sub-groups of patients with different mood profiles considering both manic and depressive dimensions, and studied their outcomes. Results Our results revealed six different mood profiles at program entry and after 1.5 years follow-up (absence of mood disturbance, co-occurrence, mild depressive, severe depressive, manic and hypomanic), and four after 3 years (absence of mood disturbance, co-occurrence, mild depressive and hypomanic). Patients with absence of mood disturbance at discharge had better outcomes. All patients with co-occurring symptoms at program entry remained symptomatic at discharge. Patients with mild depressive symptoms were less likely to return to premorbid functional level at discharge than the other subgroups. Patients displaying a depressive component had poorer quality of physical and psychological health at discharge. Conclusions Our results confirm the major role played by mood dimensions in early psychosis, and show that profiles with co-occurring manic and depressive dimensions are at risk of poorer outcome. An accurate assessment and treatment of these dimensions in people with early psychosis is crucial.

BACKGROUND: The Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT; www.coh-fit.com) is an anonymous and global online survey measuring health and functioning during the COVID-19 pandemic. The aim of this study was to test concurrently the validity of COH-FIT items and the internal validity of the co-primary outcome, a composite psychopathology "P-score". METHODS: The COH-FIT survey has been translated into 30 languages (two blind forward-translations, consensus, one independent English back-translation, final harmonization). To measure mental health, 1-4 items ("COH-FIT items") were extracted from validated questionnaires (e.g. Patient Health Questionnaire 9). COH-FIT items measured anxiety, depressive, post-traumatic, obsessive-compulsive, bipolar and psychotic symptoms, as well as stress, sleep and concentration. COH-FIT Items which correlated r ≥ 0.5 with validated companion questionnaires, were initially retained. A P-score factor structure was then identified from these items using exploratory factor analysis (EFA) and confirmatory factor analyses (CFA) on data split into training and validation sets. Consistency of results across languages, gender and age was assessed. RESULTS: From >150,000 adult responses by May 6th, 2022, a subset of 22,456 completed both COH-FIT items and validated questionnaires. Concurrent validity was consistently demonstrated across different languages for COH-FIT items. CFA confirmed EFA results of five first-order factors (anxiety, depression, post-traumatic, psychotic, psychophysiologic symptoms) and revealed a single second-order factor P-score, with high internal reliability (ω = 0.95). Factor structure was consistent across age and sex. CONCLUSIONS: COH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health. ispartof: JOURNAL OF AFFECTIVE DISORDERS vol:326 pages:249-261 ispartof: location:Netherlands status: published

Resume Le trouble bipolaire est l’une des pathologies chroniques les plus invalidantes pour laquelle le delai d’acces au diagnostic et aux soins adequats est de pres de dix ans, ce qui a pour consequences des comorbidites plus nombreuses, une plus grande severite de la maladie et une resistance aux traitements. S’inspirant des progres de l’intervention precoce dans la psychose, il est essentiel d’optimiser la detection et l’intervention de patients presentant un trouble bipolaire afin d’ameliorer leur pronostic. Cette revue narrative de la litterature des 30 dernieres annees synthetise les facteurs de risque et le syndrome a risque de transition vers un trouble bipolaire, concepts utiles en clinique pour le medecin traitant (generaliste ou psychiatre). Le modele du staging dans le trouble bipolaire permet d’organiser les interventions specifiques. Un cas clinique avec/sans detection et intervention precoces met en lumiere les enjeux lies a la detection et l’intervention precoces dans le trouble bipolaire, ses avantages et defis et les donnees scientifiques actuellement disponibles pouvant guider les priorites d’interventions cliniques.

Background and Hypothesis Although the thalamus has a central role in schizophrenia pathophysiology, contributing to sensory, cognitive, and sleep alterations, the nature and dynamics of the alterations occurring within this structure remain largely elusive. Using a multimodal magnetic resonance imaging (MRI) approach, we examined whether anomalies: (1) differ across thalamic subregions/nuclei, (2) are already present in the early phase of psychosis (EP), and (3) worsen in chronic schizophrenia (SCHZ). Study Design T1-weighted and diffusion-weighted images were analyzed to estimate gray matter concentration (GMC) and microstructural parameters obtained from the spherical mean technique (intra-neurite volume fraction [VFINTRA)], intra-neurite diffusivity [DIFFINTRA], extra-neurite mean diffusivity [MDEXTRA], extra-neurite transversal diffusivity [TDEXTRA]) within 7 thalamic subregions. Results Compared to age-matched controls, the thalamus of EP patients displays previously unreported widespread microstructural alterations (VFINTRA decrease, TDEXTRA increase) that are associated with similar alterations in the whole brain white matter, suggesting altered integrity of white matter fiber tracts in the thalamus. In both patient groups, we also observed more localized and heterogenous changes (either GMC decrease, MDEXTRA increase, or DIFFINTRA decrease) in mediodorsal, posterior, and ventral anterior parts of the thalamus in both patient groups, suggesting that the nature of the alterations varies across subregions. GMC and DIFFINTRA in the whole thalamus correlate with global functioning, while DIFFINTRA in the subregion encompassing the medial pulvinar is significantly associated with negative symptoms in SCHZ. Conclusion Our data reveals both widespread and more localized thalamic anomalies that are already present in the early phase of psychosis.

BackgroundAntipsychotic-induced metabolic adverse effects are risk factors for cardiometabolic comorbidities. Whether dose lowering could mitigate such effects remains unclear. The present study aims to investigate the associations between clozapine doses and modifications of weight, blood pressure, blood glucose, and lipid levels.Study DesignLinear mixed-effects models of weight changes over 1 year and of variations of other metabolic parameters over 4 months were applied to a prospective cohort of 115 patients. Age- and sex-stratified analyses of weight changes were also performed.Study ResultsEach 100 mg dose increment of clozapine was associated on average with a +0.48% weight increase (P = .004) over 1 year of treatment. Weight increase was greater for treatment duration ≤3 vs >3 months (+0.84% and +0.47% per month, respectively, P < .001), with a significant association with the dose for durations >3 months (+0.54%, P = .004) and a trend for durations ≤3 months (+0.33%, P = .075). Dose increments of 100 mg were also associated with weight increases of +0.71% among adults (P = .001), +1.91% among the elderly (P < .001) and +1.32% among men (P < .001) with no associations among women (P = .62). Among young adults, weight change was positively associated with doses ≤300 mg/day (+2.19% per 100 mg, P = .001), whereas no association was found with doses >300 mg/day (P = .60). No significant effect of clozapine dose on other metabolic parameters was found.ConclusionsThis study reports a modest effect of clozapine dose increases on weight gain over 1 year with differences among age categories and sexes and no dose effect on other metabolic parameters over 4 months.

Reduction of duration of untreated psychosis (DUP) remains a key goal of early intervention programs. While a significant body of literature suggests that a short DUP has a positive impact on outcome, little is known regarding the threshold above which various dimensions of outcome are impaired. In this study, we explore the DUP threshold that best discriminates subgroups with poorer outcome regarding global functioning and quality of life after 3 years of treatment. A total of 432 patients were followed-up prospectively over 3 years. Several hypothetical cut-off points for DUP were tested in order to maximize differences in effect size for quality of life and general functioning. While a DUP cut-off of 86 weeks defined two subpopulations with a difference of greatest effect size in quality of life after 3 years, it is already at a cut-off of 3 weeks of DUP that two subpopulations with a difference in global functioning of the greatest effect size was reached. DUP seems to have a differential impact on the various components of outcome, and in particular on quality of life and global functioning. Our data suggest that aiming at very short DUP is justified, but that DUP over 3 weeks are still compatible with good quality of life after 3 years of treatment.

Patients suffering from mental disorders are at high risk of developing cardiovascular diseases, leading to a reduction in life expectancy. Genetic variants can display greater influence on cardiometabolic features in psychiatric cohorts compared to the general population. The difference is possibly due to an intricate interaction between the mental disorder or the medications used to treat it and metabolic regulations. Previous genome wide association studies (GWAS) on antipsychotic-induced weight gain included a low number of participants and/or were restricted to patients taking one specific antipsychotic. We conducted a GWAS of the evolution of body mass index (BMI) during early (i.e., ≤ 6) months of treatment with psychotropic medications inducing metabolic disturbances (i.e., antipsychotics, mood stabilizers and some antidepressants) in 1135 patients from the PsyMetab cohort. Six highly correlated BMI phenotypes (i.e., BMI change and BMI slope after distinct durations of psychotropic treatment) were considered in the analyses. Our results showed that four novel loci were associated with altered BMI upon treatment at genome-wide significance (p −8): rs7736552 (near MAN2A1), rs11074029 (in SLCO3A1), rs117496040 (near DEFB1) and rs7647863 (in IQSEC1). Associations between the four loci and alternative BMI-change phenotypes showed consistent effects. Replication analyses in 1622 UK Biobank participants under psychotropic treatment showed a consistent association between rs7736552 and BMI slope (p = 0.017). These findings provide new insights into metabolic side effects induced by psychotropic drugs and underline the need for future studies to replicate these associations in larger cohorts.

Given the unpredictable rapid onset and ubiquitous consequences of weight gain induced by antipsychotics (AP), there is a pressing need to get insights into the underlying processes at the brain system level that will allow stratification of “at risk” patients. The pathophysiological hypothesis at hand is focused on brain networks governing impulsivity that are modulated by neuro-inflammatory processes. To this aim, we investigated brain anatomy and functional connectivity in patients with early psychosis (median age: 23 years, IQR = 21–27) using anthropometric data and magnetic resonance imaging acquired one month to one year after initiation of AP medication. Our analyses included 19 patients with high and rapid weight gain (i.e., ≥ 5% from baseline weight after one month) and 23 patients with low weight gain (i.e., P = 0.03). Here, the observed brain differences comprised nodes of impulsivity networks - reduced frontal lobe grey matter volume (Pcorrected=0.007) and higher striatal volume (Pcorrected=0.048) paralleled by disruption of fronto-striatal functional connectivity (R=-0.32; P = 0.04). Weight gain was associated with the inflammatory biomarker plasminogen activator inhibitor-1 (β = 4.9, P = 0.002). There was no significant association between increased BMI or weight gain and brain anatomy characteristics in both cohorts of young and middle-aged healthy individuals. Our findings support the notion of weight gain in treated psychotic patients associated with poor impulse control, impulsivity-related brain networks and chronic inflammation.

In view of its heterogeneity, schizophrenia needs new diagnostic tools based on mechanistic biomarkers that would allow early detection. Complex interaction between genetic and environmental risk factors may lead to NMDAR hypofunction, inflammation and redox dysregulation, all converging on oxidative stress. Using computational analysis, the expression of 76 genes linked to these systems, known to be abnormally regulated in schizophrenia, was studied in skin-fibroblasts from early psychosis patients and age-matched controls (N = 30), under additional pro-oxidant challenge to mimic environmental stress. To evaluate the contribution of a genetic risk related to redox dysregulation, we investigated the GAG trinucleotide polymorphism in the key glutathione (GSH) synthesizing enzyme, glutamate-cysteine-ligase-catalytic-subunit (gclc) gene, known to be associated with the disease. Patients and controls showed different gene expression profiles that were modulated by GAG-gclc genotypes in combination with oxidative challenge. In GAG-gclc low-risk genotype patients, a global gene expression dysregulation was observed, especially in the antioxidant system, potentially induced by other risks. Both controls and patients with GAG-gclc high-risk genotype (gclcGAG-HR) showed similar gene expression profiles. However, under oxidative challenge, a boosting of other antioxidant defense, including the master regulator Nrf2 and TRX systems was observed only in gclcGAG-HR controls, suggesting a protective compensation against the genetic GSH dysregulation. Moreover, RAGE (redox/inflammation interaction) and AGMAT (arginine pathway) were increased in the gclcGAG-HR patients, suggesting some additional risk factors interacting with this genotype. Finally, the use of a machine-learning approach allowed discriminating patients and controls with an accuracy up to 100%, paving the way towards early detection of schizophrenia.

Resume Objectifs Explorer les facteurs personnels et contextuels, ainsi que leurs interactions qui sont lies aux comportements violents (CV) en cours d’hospitalisation psychiatrique. Methode Au total, 4518 patients, âges de 18 a 65 ans, admis en soins psychiatriques aigus, ont ete inclus dans l’etude. Le CV, defini comme une agression physique a l’encontre d’autrui, a ete evalue a l’aide du Staff Observation Aggression Scale-Revised (SOAS-R). Des modeles de regression logistique et des arbres de classification et de regression ont ete realises. Resultats Au total, 414 CV ont ete recenses durant l’etude. Concernant les facteurs individuels, l’âge, le fait de vivre dans un foyer avant l’hospitalisation, de presenter des troubles cognitifs, une schizophrenie ou une schizophrenie avec comorbidite d’abus de substances sont significativement lies aux CV alors que, pour les facteurs contextuels, ce sont les hospitalisations sous contrainte, les longues durees de sejours, et la repetition des hospitalisations. L’analyse conjointe des facteurs individuels et contextuels montre une association significative entre l’âge, le fait de vivre dans un foyer, les troubles cognitifs, le placement involontaire, la duree anterieure du sejour et les CV. Les analyses d’interaction revelent que les hospitalisations repetees et pour de longues durees sont liees aux CV. Conclusion Ces resultats identifient un sous-groupe de patients a risque de CV, hauts utilisateurs de soins en milieu hospitalier. L’exploration plus poussee des parcours institutionnels de ces patients pourrait permettre de promouvoir des modes d’accompagnement psychiatriques plus adaptes a leur situation et de prevenir l’apparition de CV.

Resume Objectifs Le developpement d’une politique d’intervention precoce des les stades debutants du trouble bipolaire (TB), c’est-a-dire les symptomes d’etat a risque de TB et le premier episode maniaque/hypomaniaque, represente un enjeu crucial pour optimiser le pronostic des personnes concernees. Methode Revue narrative de litterature sur le sujet de l’intervention precoce chez les sujets presentant un stade debutant de TB, incluant une premiere partie sur les facteurs de risque et les caracteristiques cliniques, une seconde sur les outils utilises pour le depistage precoce, et une troisieme sur les approches therapeutiques de ces stades debutants. Resultats Le clinicien doit s’appuyer sur la connaissance des facteurs de risque de TB et sur une semeiologie specifique des stades debutants. Il existe des outils et des criteres permettent un depistage precoce chez certaines populations a risque qui doivent faire l’objet d’une attention particuliere, comme les enfants de personnes vivant avec un TB. Les traitements pharmacologiques restent essentiellement symptomatiques pour les symptomes d’etat a risque, tandis que les stabilisateurs de l’humeur non antipsychotique en monotherapie doivent etre preferes pour le premier episode maniaque/hypomaniaque. Certaines approches non-pharmacologiques comme la psychoeducation, la psychotherapie et la rehabilitation ont prouve leur efficacite dans les stades debutants de TB. Conclusions Les dispositifs d’intervention precoce deja en place pour les stades debutant de psychose auraient toute legitimite a inclure des personnes concernees par un stade debutant de TB. Le developpement futur de recommandations specifiques sera indispensable pour structurer cette offre de soin.

Resume Introduction La duree de psychose non traitee est un facteur important de mauvais pronostic, toutefois il manque des outils pour faciliter le reperage des situations a risque d’evolution vers la psychose. Nous presentons ici la validation d’une version francaise de l’auto-questionnaire 16-items Prodromal Questionnaire (fPQ16). Methodes Entre novembre 2016 et mai 2018, le fPQ16 a ete propose a tous les patients d’une consultation pour adolescents et jeunes adultes. La « comprehensive assesment of at-risk mental state » (CAARMS) permettait de determiner si la personne atteint les criteres d’etat a ultra haut risque (UHR) ou de psychose. L’analyse de la validite concurrentielle du fPQ16 avec la CAARMS a ete realisee au moyen de courbes ROC. Resultats Cent sujets ont ete inclus. La moyenne d’âge etait de 19,85 ans (± 3,3 ans). Cinquante-huit pour cent des patients inclus presentaient un etat UHR (40 %) ou de psychose (18 %) a la CAARMS. Le score cut-off retenu en faveur d’un etat UHR ou de psychose etait a 4 items cotes positivement, avec une sensibilite a 91 % et une specificite a 60 %. La valeur predictive positive du fPQ16 etait de 76 %. L’aire sous la courbe etait de 0,85 (p Discussion Le fPQ16 montre de bonnes performances de screening dans notre population, avec un cut-off de 4, plus bas que lors de precedentes etudes. Sa bonne acceptabilite et sa brievete en font un outil pertinent de screening a evaluer maintenant dans des services de soin de premiere ligne. L’adjonction d’items testant la desorganisation pourrait ameliorer sa specificite.

Background Several psychotropic drugs can induce weight gain and metabolic alterations. The authors compared metabolic evolutions of patients switching versus continuing psychotropic treatments with different risk profiles. Methods Patients either switched from a high- to a medium- (N = 36) or low-risk drug (N = 27), from a medium- to a low-risk drug (N = 71), or to a same-risk drug (N = 61). Controls were kept using either a high- (N = 35), medium- (N = 155), or low-risk drug (N = 47). The evolution over 2 years of weight and metabolic parameters was analyzed using linear mixed-effect models, also examining the influence of polygenic risk scores for body mass index (BMI) or BMI and psychiatric disorders. Study Results High-, medium-, or low-risk controls gained on average 1.32%, 0.42%, and 0.36% more weight per month than patients switching from or within these risk categories (P Conclusion Psychotropic switches to a lower- or same-risk drug can attenuate weight gain, with only switching high to low resulting in weight loss.

Polygenic risk prediction remains an important aim of genetic association studies. Currently, the predictive power of schizophrenia polygenic risk scores (PRSs) is not large enough to allow highly accurate discrimination between cases and controls and thus is not adequate for clinical integration. Since PRSs are rarely used to reveal biological functions or to validate candidate pathways, to fill this gap, we investigated whether their predictive ability could be improved by building genome-wide (GW-PRSs) and pathway-specific PRSs, using distance- or expression quantitative trait loci (eQTLs)- based mapping between genetic variants and genes. We focused on five pathways (glutamate, oxidative stress, GABA/interneurons, neuroimmune/neuroinflammation and myelin) which belong to a critical hub of schizophrenia pathophysiology, centred on redox dysregulation/oxidative stress. Analyses were first performed in the Lausanne Treatment and Early Intervention in Psychosis Program (TIPP) study (n = 340, cases/controls: 208/132), a sample of first-episode of psychosis patients and matched controls, and then validated in an independent study, the epidemiological and longitudinal intervention program of First-Episode Psychosis in Cantabria (PAFIP) (n = 352, 224/128). Our results highlighted two main findings. First, GW-PRSs for schizophrenia were significantly associated with early psychosis status. Second, oxidative stress was the only significantly associated pathway that showed an enrichment in both the TIPP (p = 0.03) and PAFIP samples (p = 0.002), and exclusively when gene-variant linking was done using eQTLs. The results suggest that the predictive accuracy of polygenic risk scores could be improved with the inclusion of information from functional annotations, and through a focus on specific pathways, emphasizing the need to build and study functionally informed risk scores., National Center of Competence in Research (NCCR) “SYNAPSY-The Synaptic Bases of Mental Diseases” from the Swiss National Science Foundation (n°51AU40_125759 to KQD & PC), and Alamaya Foundation. SP was supported by European Union’s Horizon 2020 Research and Innovation Program (Psych-STRATA). The PAFIP cohort was funded by the following grants (to BC-F): Instituto de Salud Carlos III (FIS00/3095, PI020499, PI050427, PI060507), Plan Nacional de Drogas Research (2005-Orden sco/3246/2004), SENY Fundatio Research (2005-0308007), Fundacion Marques de Valdecilla (A/02/07, API07/011) and MINECO/FEDER (SAF2016-76046-R, SAF2013-46292-R). JV-B was supported by Instituto de Investigación Sanitaria Valdecilla (INT/A21/10, INT/A20/04). Open access funding provided by University of Lausanne.

Adolescents are at high risk of incident psychopathology. Fleeting psychotic experiences (PEs) that emerge in young people in response to stress may be warning signs that are missed by research that fails to study stressed populations, such as late high school and college/university students. Our aim in this systematic review was to conduct a meta-analysis that estimates prevalence rates of PEs in students, and to assess whether these rates differ by gender, age, culture, and COVID-19 exposure.We searched nine electronic databases, from their inception until January 31, 2022 for relevant studies. We pooled the estimates using the DerSimonian-Laird technique and random-effects meta-analysis. Our main outcome was the prevalence of self-reported PEs in high school and college/university students. We subsequently analyzed our data by age, gender, population, country, culture, evaluation tool, and COVID-19 exposure.Out of 486 studies retrieved, a total of 59 independent studies met inclusion criteria reporting 210' 024 students from 21 different countries. Nearly one in four students (23.31%; 95% CI 18.41%-29.05%), reported having experienced PEs (heterogeneity [Q = 22,698.23 (62), p = 0.001] τThis meta-analysis revealed high prevalence rates of self-reported PEs among teen and young adult students, which may have significance for mental health screening in school settings. An important realization is that PEs may have very different mental health meaning in different cultures.

The factorial structure of schizophrenia symptoms has been much debated but little is known on its degree of unicity, specificity as well as its dynamic over time. Symptom differentiation is a phenomenon according to which patients' symptoms could differentiate from one another during illness to form more independent, distinct dimensions. On the contrary, symptom dedifferentiation is an increase in the correlations between those symptoms over time. The goal of this study was to investigate symptom differentiation or dedifferentiation over time in recent onset psychosis using the Positive and Negative Syndrome Scale. A confirmatory factor analysis model based on the consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia was estimated on seven different time points over a three-year period. A general factor capturing common variance between every symptom was also included. Explained common variance was computed for the general factor and each specific factor. Three hundred and sixty-two recent onset psychosis patients were assessed. Results showed no evidence for either symptom differentiation or dedifferentiation over time. Specific symptoms accounted for >70 % of the variance suggesting a high degree of specificity of the symptomatology. Overall, this study adds support for a highly multidimensional approach to clinical symptom assessment with an explicit focus on depression. The premise behind the staging approach being inherently one-dimensional, implications for further research is discussed.

Objective To describe the implementation of early intervention for psychosis in 3 French-speaking countries, the challenges encountered and potential facilitators for successful implementation. Methods Narrative synthesis of the scientific and grey literature on early intervention for psychosis programs implementation in the French-speaking world. Results Compared to other countries (Australia, United Kingdom, etc.), early intervention program implementation in the French-speaking world has been delayed and faces various challenges, making its widespread implementation still very heterogeneous. Although a large proportion of the population has access to early intervention services (EIS) in Quebec (Canada), adherence with certain essential components of the model still poses challenges. However, various facilitators, including government involvement through the publication of a provincial framework standardizing practices, dedicated funding, and clinical support for program implementation and continuous improvement through the National Centre of Excellence in Mental Health (a provincial organization) and a provincial community of practice, the Association québécoise des programmes pour premiers épisodes psychotiques (AQPPEP), which offers mentoring and continuing education, have been identified. In France, although the implementation has been more heterogenous, several centers already offer EIS, and there is growing interest in this model, as expressed by several teams, giving hope for the implementation of a network of EIS throughout the country. Since 2007, the "Réseau transition" has been organizing scientific meetings, specialized training, validation of tools and is working on publishing a reference tool adapted to the French system to standardize EIS. In French-speaking Switzerland, although programs were implemented relatively early (in 2000 in Geneva, and in 2004 in Lausanne), they remained associated to individual initiatives and local choices. This is largely due to the complete autonomy of each of the 26 cantons in the organization of the healthcare system and the absence of a national mental health policy. However, a French-speaking Swiss group has been set up in 2020, to support the implementation of 5 programs in 5 cantons. Several specificities of the organization of mental health care in each country may have an impact on implementation. These include the relative autonomy of different catchment areas, and the separation of child and adolescent psychiatry from adult services. Furthermore, it seems that poor involvement in quality assurance activities and the lack of monitoring of adherence to expert recommendations on essential components of the EIS model may impact program implementation. Conclusion In addition to continuing national efforts, a francophone branch of the International Early Psychosis Association (IEPA) founded by Swiss, French and Quebec leaders to join forces on a larger scale seeks to promote networking as well as tool and expertise sharing through an annual international francophone conference focused on early intervention in first-episode psychosis.

Objectives This article aims to synthesize the critical stages in the development of early detection and intervention services (EIS) for psychosis over the past 30 years, and to review key literature on the essential components and effectiveness of these programs. Method We conducted a narrative review of the literature on the international development of EIS leading to its endorsement as a service delivery model for young people with first-episode psychosis (FEP). We also reviewed various international and Canadian guidelines to identify consensus about the essential components of EIS for psychosis and their effectiveness. Challenges to the implementation of these different essential components are presented, along with practical solutions to addressing them. A particular emphasis is placed on implementing EIS in the Quebec context. Results Based on a model developed in the early 1990s, EIS for psychosis have now been disseminated worldwide and are deployed on a large scale in some regions, such as the United Kingdom and Quebec. The model's gradual expansion has been facilitated by efforts to identify its main objectives and the components essential to achieve them, and by several studies demonstrating its effectiveness. Along with an important philosophical shift to optimism and hope, EIS have typically focused on the twin aims of reducing treatment delay (or the duration of untreated psychosis) and enhancing engagement in specialized, phase-specific, developmentally appropriate treatment. A meta-analysis (published in 2018) demonstrated the superiority of EIS for psychosis compared to standard treatment on several outcomes including hospitalizations, relapse of symptoms, treatment discontinuation, and vocational and social functioning. Based on these studies and expert consensus, many jurisdictions around the world have developed guidelines to ensure compliance with essential components that are associated with the effectiveness of EIS, while accounting for their contextual realities. The components that have been prioritized include outreach to enable early identification and referral; rapid access to care and youth-friendly services; a range of biopsychosocial interventions (pharmacotherapy, cognitive behavioral therapy, psychoeducation, family interventions, integrated substance use interventions, employment and educational support); a shared-decision making approach; and the intensive case management approach adapted to FEP, which are all delivered by an interdisciplinary team. There is also increasing acknowledgement of the value of continuous evaluation that informs treatment decision-making and quality improvement. Conclusion EIS for psychosis have developed gradually and research has demonstrated its effectiveness. Disseminating the model in ways that ensure fidelity to its core values and the implementation of its essential components is needed to ensure effectiveness; and instill hope for recovery and improve the quality of lives of young people with psychosis and their families.

Objectives The emergence of early intervention for first episode psychosis (FEP) in the 1990s represents a major advance in mental health. It was demonstrated that by providing intensive interventions tailored to the specific needs of youth at the onset of FEP, it became possible to sustainably improve their subsequent course. This model of early intervention for psychosis (EIP) is accompanied by a major revision of conceptions of psychotic disorders and a major change in philosophy of care. The purpose of this article is to provide a historical perspective on the development of EIP, to discuss the challenges associated with its implementation, and to offer possible solutions. Methods Experts consensus identifying the most salient challenges in implementing Early intervention for psychosis, and proposing the most feasible solutions, based on their assessment of the literature to address them. Results To optimize the implementation and efficiency of EIP programs, 7 avenues were identified: 1) Better targeting of hard-to-reach populations and systematizing the admission of all FEP patients in EIP programs. 2) Reducing the duration of untreated psychosis should be a major goal of EIP programs, requiring early detection efforts through public awareness, training of front-line professionals, and improving treatment access processes and delays. 3) Measures to maintain patient engagement in a follow-up should be implemented systematically. 4) Family involvement should be more actively supported by teams throughout follow-up, including strategies to promote patient acceptance of their involvement. 5) Future research will provide a better understanding of how to modulate the duration and intensity of EIP follow-up according to patient profiles, in particular in order to maintain the results achieved during PPEP over the longer term. 6) The modalities for managing at-risk mental states remain to be clarified, both in terms of the approaches to be offered to them and the health care structure that would be most appropriate to accommodate them. 7) The implementation of EIP programs must be continued, particularly in the French-speaking world, which is at very different stages from one country to another and even within each country. Conclusion EIP improve the outcomes of youth with FEP in terms of recovery, mortality and suicide. Solutions to challenges encountered in their widespread implementation must be operationalized to ensure that this care is accessible to the greatest number of people in a timely manner to maximize its impact at the population level.

Background: Atypical antipsychotics can induce metabolic side effects, but whether they are dose-dependent remains unclear. Objective: To assess the effect of risperidone and/or paliperidone dosing on weight gain and blood lipids, glucose, and blood pressure alterations. Methods: Data for 438 patients taking risperidone and/or its metabolite (paliperidone) for up to 1 year were obtained between 2007 and 2018 from a longitudinal study monitoring metabolic parameters. Results: For each milligram increase in dose, we observed a weight increase of 0.16% at 1 month of treatment (P = .002) and increases of 0.29%, 0.21%, and 0.25% at 3, 6, and 12 months of treatment, respectively (P < .001 for each). Moreover, dose increases of 1 mg raised the risk of a ≥ 5% weight gain after 1 month (OR = 1.18; P = .012), a strong predictor of important weight gain in the long term. When we split the cohort into age categories, the dose had an effect on weight change after 3 months of treatment (up to 1.63%, P = .008) among adolescents (age ≤ 17 years), at 3 (0.13%, P = .013) and 12 (0.13%, P = .036) months among adults (age > 17 and < 65 years), and at each timepoint (up to 1.58%, P < .001) among older patients (age ≥ 65 years). In the whole cohort, for each additional milligram we observed a 0.05 mmol/L increase in total cholesterol (P = .018) and a 0.04 mmol/L increase in LDL cholesterol (P = .011) after 1 year. Conclusions: Although of small amplitude, these results show an effect of daily risperidone dose on weight gain and blood cholesterol levels. Particular attention should be given to the decision of increasing the drug dose, and minimum effective dosages should be preferred.

IntroductionRecent efforts have been made to apply machine learning and deep learning approaches to the automated classification of schizophrenia using structural magnetic resonance imaging (sMRI) at the individual level. However, these approaches are less accurate on early psychosis (EP) since there are mild structural brain changes at early stage. As cognitive impairments is one main feature in psychosis, in this study we apply a multi-task deep learning framework using sMRI with inclusion of cognitive assessment to facilitate the classification of patients with EP from healthy individuals. MethodUnlike previous studies, we used sMRI as the direct input to perform EP classifications and cognitive estimations. The proposed deep learning model does not require time-consuming volumetric or surface based analysis and can provide additionally cognition predictions. Experiments were conducted on an in-house data set with 77 subjects and a public ABCD HCP-EP data set with 164 subjects. ResultsWe achieved 74.9 +/- 4.3% five-fold cross-validated accuracy and an area under the curve of 71.1 +/- 4.1% on EP classification with the inclusion of cognitive estimations. DiscussionWe reveal the feasibility of automated cognitive estimation using sMRI by deep learning models, and also demonstrate the implicit adoption of cognitive measures as additional information to facilitate EP classifications from healthy controls.

The concept of affective psychosis regroups psychotic disorders with mood syndrome. Previous studies provided evidence to support a dichotomy between affective and non-affective psychoses although questions remain regarding the utility and validity of such a category to develop clinical guidelines. The aim of this study is to explore similarities and differences within affective psychoses to question whether strategies would apply to all the diagnoses falling under this umbrella term. Using Bayesian model comparison methods, we explored the homogeneity of the characteristics of first-episode affective patients (N = 77) treated in a specialized 3-year early intervention in psychosis programme. Our analysis revealed affective psychoses display many similarities regarding socio-demographic variables, the course of positive and manic symptoms over three years, and outcome at discharge. Our results did not support the heterogeneous model. However, despite no significant differences in the course of symptoms with the major depressive disorder group, the schizoaffective disorder group displayed a more severe clinical picture at the beginning of the programme and a poorer functional outcome than the two other groups. Absence of clear boundaries and the several similarities within affective psychoses suggest they can usefully be grouped to define treatment strategies that are easily legible by clinicians.

BackgroundPrevention of violent behaviors (VB) in the early phase of psychosis (EPP) is a real challenge. Impulsivity was shown to be strongly related to VB, and different evolutions of impulsivity were noticed along treatments. One possible variable involved in the relationship between VB and the evolution of impulsivity is cannabis use (CU). The high prevalence of CU in EPP and its relationship with VB led us to investigate: 1/the impact of CU and 2/the impact of early CU on the evolution of impulsivity levels during a 3-year program, in violent and non-violent EPP patients.Methods178 non-violent and 62 violent patients (VPs) were followed-up over a 3 year period. Age of onset of CU was assessed at program entry and impulsivity was assessed seven times during the program. The evolution of impulsivity level during the program, as a function of the violent and non-violent groups of patients and CU precocity were analyzed with linear mixed-effects models.ResultsOver the treatment period, impulsivity level did not evolve as a function of the interaction between group and CU (coef. = 0.02,p= 0.425). However, when including precocity of CU, impulsivity was shown to increase significantly only in VPs who start consuming before 15 years of age (coef. = 0.06,p= 0.008).ConclusionThe precocity of CU in VPs seems to be a key variable of the negative evolution of impulsivity during follow-up and should be closely monitored in EPP patients entering care since they have a higher risk of showing VB.

Early detection and intervention in schizophrenia requires mechanism-based biomarkers that capture neural circuitry dysfunction, allowing better patient stratification, monitoring of disease progression and treatment. In prefrontal cortex and blood of redox dysregulated mice (Gclm-KO ± GBR), oxidative stress induces miR-137 upregulation, leading to decreased COX6A2 and mitophagy markers (NIX, Fundc1, and LC3B) and to accumulation of damaged mitochondria, further exacerbating oxidative stress and parvalbumin interneurons (PVI) impairment. MitoQ, a mitochondria-targeted antioxidant, rescued all these processes. Translating to early psychosis patients (EPP), blood exosomal miR-137 increases and COX6A2 decreases, combined with mitophagy markers alterations, suggest that observations made centrally and peripherally in animal model were reflected in patients’ blood. Higher exosomal miR-137 and lower COX6A2 levels were associated with a reduction of ASSR gamma oscillations in EEG. As ASSR requires proper PVI-related networks, alterations in miR-137/COX6A2 plasma exosome levels may represent a proxy marker of PVI cortical microcircuit impairment. EPP can be stratified in two subgroups: (a) a patients’ group with mitochondrial dysfunction “Psy-D”, having high miR-137 and low COX6A2 levels in exosomes, and (b) a “Psy-ND” subgroup with no/low mitochondrial impairment, including patients having miR-137 and COX6A2 levels in the range of controls. Psy-D patients exhibited more impaired ASSR responses in association with worse psychopathological status, neurocognitive performance, and global and social functioning, suggesting that impairment of PVI mitochondria leads to more severe disease profiles. This stratification would allow, with high selectivity and specificity, the selection of patients for treatments targeting brain mitochondria dysregulation and capture the clinical and functional efficacy of future clinical trials.

Introduction Our aim was to, firstly, identify characteristics at first-episode of psychosis that are associated with later antipsychotic treatment resistance (TR) and, secondly, to develop a parsimonious prediction model for TR. Methods We combined data from ten prospective, first-episode psychosis cohorts from across Europe and categorised patients as TR or non-treatment resistant (NTR) after a mean follow up of 4.18 years (s.d. = 3.20) for secondary data analysis. We identified a list of potential predictors from clinical and demographic data recorded at first-episode. These potential predictors were entered in two models: a multivariable logistic regression to identify which were independently associated with TR and a penalised logistic regression, which performed variable selection, to produce a parsimonious prediction model. This model was internally validated using a 5-fold, 50-repeat cross-validation optimism-correction. Results Our sample consisted of N = 2216 participants of which 385 (17 %) developed TR. Younger age of psychosis onset and fewer years in education were independently associated with increased odds of developing TR. The prediction model selected 7 out of 17 variables that, when combined, could quantify the risk of being TR better than chance. These included age of onset, years in education, gender, BMI, relationship status, alcohol use, and positive symptoms. The optimism-corrected area under the curve was 0.59 (accuracy = 64 %, sensitivity = 48 %, and specificity = 76 %). Implications Our findings show that treatment resistance can be predicted, at first-episode of psychosis. Pending a model update and external validation, we demonstrate the potential value of prediction models for TR. Funding: This work was supported by a Stratified Medicine Programme grant to JHM from the Medical Research Council (grant number MR/L011794/1 which funded the research and supported S.E.S., D.A., A.F.P, L.K., R.M.M., D.S., J.T.R.W, & J.H.M.); funding from the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King's College London to D.A. and D.S; and funding from the Collaboration for Leadership in Applied Health Research and Care (CLAHRC) South London at King's College Hospital National Health Service Foundation Trust to S.E.S. The views expressed are those of the author(s) and not necessarily those of the Medical Research Council, National Health Service, the National Institute for Health Research, or the Department of Health. The AESOP (London, UK) cohort was funded by the UK Medical Research Council (Ref: G0500817). The Belfast (UK) cohort was funded by the Research and Development Office of Northern Ireland. The Bologna (Italy) cohort was funded by the European Community's Seventh Framework Program under grant agreement (agreement No.HEALTH-F2-2010–241909, Project EU-GEI). The GAP (London, UK) cohort was funded by the UK National Institute of Health Research(NIHR) Specialist Biomedical Research Centre for Mental Health, South London and Maudsley NHS Mental Health Foundation Trust (SLaM) and the Institute of Psychiatry, Psychology, and Neuroscience at King's College London; Psychiatry Research Trust; Maudsley Charity Research Fund; and the European Community's Seventh Framework Program grant (agreement No. HEALTH-F2-2009-241909, Project EU-GEI). The Lausanne (Switzerland) cohort was funded by the Swiss National Science Foundation (no. 320030_135736/1 to P.C. and K.Q.D., no 320030-120686, 324730-144064 and 320030-173211 to C.B.E and P.C., and no 171804 to LA); National Center of Competence in Research (NCCR) “SYNAPSY - The Synaptic Bases of Mental Diseases” from the Swiss National Science Foundation (no 51AU40_125759 to PC and KQD); and Fondation Alamaya (to KQD). The Oslo (Norway) cohort was funded by the Research Council of Norway (#223273/F50, under the Centers of Excellence funding scheme, #300309, #283798) and the South-Eastern Norway Regional Health Authority (#2006233, #2006258, #2011085, #2014102, #2015088 to IM, #2017-112). The Paris (France) cohort was funded by European Community's Seventh Framework Program grant (agreement No. HEALTH-F2-2010–241909, Project EU-GEI). The Prague (Czech Republic) cohort was funded by the Ministry of Health of the Czech Republic (Grant Number: NU20-04-00393). The Santander (Spain) cohort was funded by the following grants (to B.C.F): Instituto de Salud Carlos III, FIS 00/3095, PI020499, PI050427, PI060507, Plan Nacional de Drogas Research Grant 2005-Orden sco/3246/2004, and SENY Fundatio Research Grant CI 2005-0308007, Fundacion Marques de Valdecilla A/02/07 and API07/011. SAF2016-76046-R and SAF2013-46292-R (MINECO and FEDER). The West London (UK) cohort was funded The Wellcome Trust (Grant Number: 042025; 052247; 064607).

Introduction The atypical antipsychotic quetiapine is known to induce weight gain and other metabolic complications. The underlying mechanisms are multifactorial and poorly understood with almost no information on the effect of dosage. Concerns were thus raised with the rise in low-dose quetiapine off-label prescription (i. e., Methods In this study, we evaluated the influence of quetiapine dose for 474 patients included in PsyMetab and PsyClin studies on weight and metabolic parameter evolution. Weight, blood pressure, lipid, and glucose profiles were evaluated during a follow-up period of 3 months after treatment initiation. Results Significant dose-dependent metabolic alterations were observed. The daily dose was found to influence weight gain and increase the risk of undergoing clinically relevant weight gain (≥7% from baseline). It was also associated with a change in plasma levels of cholesterol (total cholesterol, LDL cholesterol, and HDL cholesterol) as well as with increased odds of developing hypertriglyceridemia, as well as total and LDL hypercholesterolemia. No impact of a dose increase on blood pressure and plasma glucose level was observed. Discussion The dose-dependent effect highlighted for weight gain and lipid alterations emphasizes the importance of prescribing the minimal effective dose. However, as the effect size of a dose increase on metabolic worsening is low, the potential harm of low-dose quetiapine should not be dismissed. Prescriptions must be carefully evaluated and regularly questioned in light of side effect onset.