Variation of subclinical psychosis across 16 sites in Europe and Brazil: findings from the multi-national EU-GEI study.

BACKGROUND: Incidence of first-episode psychosis (FEP) varies substantially across geographic regions. Phenotypes of subclinical psychosis (SP), such as psychotic-like experiences (PLEs) and schizotypy, present several similarities with psychosis. We aimed to examine whether SP measures varied across different sites and whether this variation was comparable with FEP incidence within the same areas. We further examined contribution of environmental and genetic factors to SP. METHODS: We used data from 1497 controls recruited in 16 different sites across 6 countries. Factor scores for several psychopathological dimensions of schizotypy and PLEs were obtained using multidimensional item response theory models. Variation of these scores was assessed using multi-level regression analysis to estimate individual and between-sites variance adjusting for age, sex, education, migrant, employment and relational status, childhood adversity, and cannabis use. In the final model we added local FEP incidence as a second-level variable. Association with genetic liability was examined separately. RESULTS: Schizotypy showed a large between-sites variation with up to 15% of variance attributable to site-level characteristics. Adding local FEP incidence to the model considerably reduced the between-sites unexplained schizotypy variance. PLEs did not show as much variation. Overall, SP was associated with younger age, migrant, unmarried, unemployed and less educated individuals, cannabis use, and childhood adversity. Both phenotypes were associated with genetic liability to schizophrenia. CONCLUSIONS: Schizotypy showed substantial between-sites variation, being more represented in areas where FEP incidence is higher. This supports the hypothesis that shared contextual factors shape the between-sites variation of psychosis across the spectrum.

The risk of hospitalization for psychotic disorders following hospitalization for COVID-19: a French nationwide longitudinal study.

COVID-19, like other infectious diseases, may be a risk factor for psychotic disorders. We aimed to compare the proportions of hospitalizations for psychotic disorders in the 12 months following discharge from hospital for either COVID-19 or for another reason in the adult general population in France during the first wave of the pandemic. We conducted a retrospective longitudinal nationwide study using the national French administrative healthcare database. Psychotic disorders were first studied as a whole, and then chronic and acute disorders separately. The role of several adjustment factors, including sociodemographics, a history of psychotic disorder, the duration of the initial hospitalization, and the level of care received during that hospitalization, were also analyzed. Between 1 January 2020 and 30 June 2020, a total of 14,622 patients were hospitalized for psychotic disorders in the 12 months following discharge from hospital for either COVID-19 or another reason. Initial hospitalization for COVID-19 (vs. another reason) was associated with a lower rate of subsequent hospitalization for psychotic disorders (0.31% vs. 0.51%, odds ratio (OR) = 0.60, 95% confidence interval (CI) [0.53-0.67]). This was true for both chronic and acute disorders, even after adjusting for the various study variables. Importantly, a history of psychotic disorder was a major determinant of hospitalization for psychotic disorders (adjusted OR = 126.56, 95% CI [121.85-131.46]). Our results suggest that, in comparison to individuals initially hospitalized for another reason, individuals initially hospitalized for COVID-19 present a lower risk of hospitalization for first episodes of psychotic symptoms/disorders or for psychotic relapse in the 12 months following discharge. This finding contradicts the hypothesis that there is a higher risk of psychotic disorders after a severe COVID-19.

Current (but not ex) cigarette smoking is associated with worse cognitive performances in schizophrenia: results from the FACE-SZ cohort.

BACKGROUND: Tobacco use is common in subjects with schizophrenia (SZ) and has sometimes been associated with better functioning in short-term studies. Only few studies embrace an extensive examination of tobacco influence on clinical, cognitive and therapeutic characteristics in stabilized SZ outpatients. The objective of the present study was to assess the association between cognitive performances and smoking status in SZ subjects. METHODS: In total, 1233 SZ participants (73.9% men, mean age 31.5) were included and tested with a comprehensive battery. Tobacco status was self-declared (never-, ex-, or current smokers). Multivariable analyses including principal component analyses (PCA) were used. RESULTS: In total, 53.7% were smokers with 33.7% of them nicotine-dependent. Multiple factor analysis revealed that current tobacco smoking was associated with impaired general intellectual ability and abstract reasoning (aOR 0.60, 95% IC 0.41-0.88, p = 0.01) and with a lifetime alcohol use disorder (p = 0.026) and a lifetime cannabis use disorder (p < 0.001). Ex- and never-smokers differed for age, mean outcome, cannabis history and medication [ex-smokers being older (p = 0.047), likely to have higher income (p = 0.026), a lifetime cannabis use disorder (p < 0.001) and higher CPZeq doses (p = 0.005)]. Premorbid IQ in the three groups significantly differed with, from higher to lower: ex-smokers, never-smoker, current smokers (all p < 0.001). CONCLUSIONS: This study is the largest to date providing strong evidence that chronic smoking is associated with cognitive impairment in SZ, arguing against the self-medication hypothesis as a contributor to the high prevalence of smoking in SZ. Ex-smokers may also represent a specific subgroup. Longitudinal studies are warranted to determine the developmental impact of tobacco on neurocognition.

Cannabis use as a potential mediator between childhood adversity and first-episode psychosis: results from the EU-GEI case-control study.

BACKGROUND: Childhood adversity and cannabis use are considered independent risk factors for psychosis, but whether different patterns of cannabis use may be acting as mediator between adversity and psychotic disorders has not yet been explored. The aim of this study is to examine whether cannabis use mediates the relationship between childhood adversity and psychosis. METHODS: Data were utilised on 881 first-episode psychosis patients and 1231 controls from the European network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Detailed history of cannabis use was collected with the Cannabis Experience Questionnaire. The Childhood Experience of Care and Abuse Questionnaire was used to assess exposure to household discord, sexual, physical or emotional abuse and bullying in two periods: early (0-11 years), and late (12-17 years). A path decomposition method was used to analyse whether the association between childhood adversity and psychosis was mediated by (1) lifetime cannabis use, (2) cannabis potency and (3) frequency of use. RESULTS: The association between household discord and psychosis was partially mediated by lifetime use of cannabis (indirect effect coef. 0.078, s.e. 0.022, 17%), its potency (indirect effect coef. 0.059, s.e. 0.018, 14%) and by frequency (indirect effect coef. 0.117, s.e. 0.038, 29%). Similar findings were obtained when analyses were restricted to early exposure to household discord. CONCLUSIONS: Harmful patterns of cannabis use mediated the association between specific childhood adversities, like household discord, with later psychosis. Children exposed to particularly challenging environments in their household could benefit from psychosocial interventions aimed at preventing cannabis misuse.

History of learning disorders is associated with worse cognitive and functional outcomes in schizophrenia: results from the multicentric FACE-SZ cross-sectional dataset.

Schizophrenia is associated with early neurodevelopmental disorders, including most frequently learning disorders (LD), among them dyslexia and dyspraxia. Despite the demonstrated links between schizophrenia and LD, specific clinical patterns of the schizophrenia with a history of LD subgroup remain unknown. The aim of the present study was to investigate cognitive impairment, symptoms and functional outcome associated with a history of LD in a large cross-sectional, multicentric, sample of schizophrenia subjects. 492 community-dwelling subjects with schizophrenia (75.6% male, mean age 30.8 years) were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia in France and received a thorough clinical assessment. The 51 (10.4%) subjects identified with a history of LD had significantly impaired general cognitive ability (Wechsler Adult Intelligence Scale Full Scale Total IQ: Cohen's d = 0.50, p = 0.001), processing speed (d = 0.19), verbal comprehension (d = 0.29), working memory (d = 0.31), cognitive inhibition and flexibility (d = 0.26), central executive functioning (d = 0.26), phonemic verbal fluency (d = 0.22) and premorbid intellectual ability (d = 0.48), as well as with a worse functional outcome (Global Assessment of Functioning, d = 0.21), independently of age, sex, education level, symptoms, treatments, and addiction comorbidities. These results indicate that a history of LD is associated with later cognitive impairment and functional outcome in schizophrenia. This suggests that history of LD is a relevant clinical marker to discriminate subgroups of patients with schizophrenia with different profiles in a precision psychiatry framework.

The puzzle of quality of life in schizophrenia: putting the pieces together with the FACE-SZ cohort.

BACKGROUND: The determinants of quality of life (QoL) in schizophrenia are largely debated, mainly due to methodological discrepancies and divergence about the concepts concerned. As most studies have investigated bi- or tri-variate models, a multivariate model accounting for simultaneous potential mediations is necessary to have a comprehensive view of the determinants of QOL. We sought to estimate the associations between cognitive reserve, cognition, functioning, insight, depression, schizophrenic symptoms, and QoL in schizophrenia and their potential mediation relationships. METHODS: We used structural equation modeling with mediation analyses to test a model based on existing literature in a sample of 776 patients with schizophrenia from the FondaMental Foundation FACE-SZ cohort. RESULTS: Our model showed a good fit to the data. We found better functioning to be positively associated with a better QoL, whereas better cognition, better insight, higher levels of depression, and schizophrenic symptoms were associated with a lower QoL in our sample. Cognitive reserve is not directly linked to QoL, but indirectly in a negative manner via cognition. We confirm the negative relationship between cognition and subjective QoL which was previously evidenced by other studies; moreover, this relationship seems to be robust as it survived in our multivariate model. It was not explained by insight as some suggested, thus the mechanism at stake remains to be explained. CONCLUSION: The pathways to subjective QoL in schizophrenia are complex and the determinants largely influence each other. Longitudinal studies are warranted to confirm these cross-sectional findings.

Recommendations of the Schizophrenia Expert Center network for adequate physical activity in real-world schizophrenia (FACE-SZ).

The World Health Organization (WHO) recommends adults complete 150-300 min per week of moderate physical activity or 75-150 min of vigorous physical activity or an equivalent combination of both, to optimize health. To explore the factors associated with adequate MVPA in stabilized outpatients with schizophrenia. 425 stabilized outpatients were recruited in the national FACE-SZ cohort between 2015 and 2018 were evaluated with the International Physical Activity Questionnaire and a 1-day long standardized battery. We explored in multivariate analyses the clinical and pharmacological factors associated with MVPA (model 1) and the biological factors and patient-reported outcomes (model 2). Overall, only 86 (20.2%) of the 425 participants achieved the recommended MVPA threshold. In model 1, the adequate MVPA group was associated with younger age, mood stabilizers prescription and adherence to treatment, independent of sex, positive and depressive symptoms, first-generation antipsychotics prescription, anxiolytic medication, and akathisia. In model 2, adequate MVPA was associated with better glycemic and lipidic profile and better physical and psychological well-being, self-esteem, sentimental life, and resilience independently of age, sex, and current psychotic severity. The expert centers recommend the importance of promoting promote effective MVPA programs for stabilized patients with schizophrenia. Interventions studies suggest that MVPA may be a useful strategy to maximize physical and psychological well-being and self-esteem and potentially to prevent or manage metabolic disturbances.

Schizophrenia: Developmental Variability Interacts with Risk Factors to Cause the Disorder: Nonspecific Variability-Enhancing Factors Combine with Specific Risk Factors to Cause Schizophrenia.

A new etiological model is proposed for schizophrenia that combines variability-enhancing nonspecific factors acting during development with more specific risk factors. This model is better suited than the current etiological models of schizophrenia, based on the risk factors paradigm, for predicting and/or explaining several important findings about schizophrenia: high co-morbidity rates, low specificity of many risk factors, and persistence in the population of the associated genetic polymorphisms. Compared with similar models, e.g., de-canalization, common psychopathology factor, sexual-selection, or differential sensitivity to the environment, this proposal is more general and integrative. Recently developed research methods have proven the existence of genetic and environmental factors that enhance developmental variability. Applying such methods to newly collected or already available data can allow for testing the hypotheses upon which this model is built. If validated, this model may change the understanding of the etiology of schizophrenia, the research models, and preventionbrk paradigms.

Relationship between neurocognition and theory of mind as a function of symptomatic profile in schizophrenia: results from the national FACE-SZ cohort.

INTRODUCTION: Deficits in theory of mind (ToM) can vary depending on the predominant schizophrenia symptoms, and though most neurocognitive functions are involved in ToM, all may not be associated with the same symptoms. With consideration to the relationships between symptoms, neurocognition and ToM, the aim of the present study is to identify the neurocognitive functions influencing ToM capacities according to symptomatic profile. METHODS: The study is based on a sample of 124 adults with schizophrenia from a French national cohort. Patients were divided into two groups according to their scores on the five Wallwork factors of the Positive and Negative Syndrome Scale using hierarchical clustering before carrying out multivariable analyses. RESULTS: The "disorganised group" (n = 89) showed high scores on the disorganised factor, and had a ToM associated with reasoning, visual recognition and speed of processing. The "positive group" (n = 35) showed high scores on the positive and depressive factors, and had a ToM associated with working memory. CONCLUSIONS: These results suggest that neurocognitive predictors of ToM in schizophrenia are different according to the predominant clinical dimension, thus refining our knowledge of the relationship between symptoms, neurocognition and ToM, and acknowledging their status as important predictors of patients' functional status.

Religiosity and prevalence of suicide, psychiatric disorders and psychotic symptoms in the French general population.

We aimed to examine the association between religious beliefs and observance and the prevalence of psychiatric disorders, psychotic symptoms and history of suicide attempts in the French general population. The cross-sectional survey interviewed 38,694 subjects between 1999 and 2003, using the MINI. Current religious beliefs and observance were identified by means of two questions: "are you a believer?" and "are you religiously observant?". We studied the association between religiosity and psychiatric outcomes using a multivariable logistic regression model adjusted for sociodemographic characteristics, including migrant status. Religious beliefs were positively associated with psychotic symptoms and disorders [OR = 1.37, 95% CI (1.30-1.45) and OR = 1.38, 95% CI (1.20-1.58)], unipolar depressive disorder [OR = 1.15, 95% CI (1.06-1.23)] and generalized anxiety disorder [OR = 1.13, 95% CI (1.06-1.21)], but negatively associated with bipolar disorder [OR = 0.83, 95% CI (0.69-0.98)], alcohol use disorders [OR = 0.69, 95% CI (0.62-0.77)], substance use disorders [OR = 0.60, 95% CI (0.52-0.69)] and suicide attempts [OR = 0.90, 95% CI (0.82-0.99)]. Religious observance was positively associated with psychotic symptoms and disorders [OR = 1.38, 95% CI (1.20-1.58) and OR = 1.25, 95% CI (1.07-1.45)], but negatively associated with social anxiety disorder [OR = 0.87, 95% CI (0.76-0.99)], alcohol use disorders [OR = 0.60, 95% CI (0.51-0.70)], substance use disorders [OR = 0.48, 95% CI (0.38-0.60)] and suicide attempts [OR = 0.80, 95% CI (0.70-0.90)]. Among believers, religious observance was not associated with psychotic outcomes. Religiosity appears to be a complex and bidirectional determinant of psychiatric symptoms and disorders. In this respect, religiosity should be more thoroughly assessed in epidemiological psychiatric studies, as well as in clinical practice.

A comprehensive model of predictors of quality of life in older adults with schizophrenia: results from the CSA study.

BACKGROUND: Numerous factors are known to influence quality of life of adults with schizophrenia. However, little is known regarding the potential predictors of quality of life in the increasing population of older adults with schizophrenia. The main objective of the present study was to propose a comprehensive model of quality of life in this specific population. METHODS: Data were derived from the Cohort of individuals with Schizophrenia Aged 55 years or more (CSA) study, a large (N = 353) multicenter sample of older adults with schizophrenia or schizoaffective disorder recruited from French community mental-health teams. We used structural equation modeling to simultaneously examine the effects of six broad groups of clinical factors previously identified as potential predictors of quality of life in this population, including (1) severity of general psychopathology, (2) severity of depression, (3) severity of cognitive impairment, (4) psychotropic medications, (5) general medical conditions and (6) sociodemographic characteristics. RESULTS: General psychopathology symptoms, and in particular negative and depressive symptoms, cognitive impairment, reduced overall functioning and low education were significantly and independently associated with diminished quality of life (all p < 0.05). Greater number of medical conditions and greater number of antipsychotics were also independently and negatively associated with quality of life, although these associations did not reach statistical significance in sensitivity analyses, possibly due to limited statistical power. CONCLUSION: Several domains are implicated in quality of life among older adults with schizophrenia. Interventions targeting these factors may help improve importantly quality of life of this vulnerable population.

Psychotic, Mood, and Anxiety Disorders and Venous Thromboembolism: A Systematic Review and Meta-Analysis.

OBJECTIVE: Several studies have shown that psychiatric disorders can be associated with venous thromboembolism (VTE) risk, that is, pulmonary embolism (PE) and/or deep vein thrombosis (DVT). In this study, we provide a systematic review and meta-analyses of the studies addressing this issue. METHODS: All studies addressing the risk of VTE phenomena (whole VTE, PE, DVT, fatal VTE) in individuals with psychotic, mood, and anxiety disorders published between 1998 and 2019 were reviewed and included in the meta-analyses. Main characteristics of the studies and data concerning VTE risk were extracted. The methodological qualities of the studies were also analyzed. A random-effects meta-analysis model was used. A meta-analysis was conducted separately for each disorder, as well as separately for unadjusted and adjusted studies. Meta-analyses were repeated considering only good-quality studies. Heterogeneity was assessed. RESULTS: Sixteen studies were reviewed and 15 included in the meta-analyses. Psychotic and bipolar disorders were significantly associated with VTE risk (VTE, DVT, PE, and fatal VTE for psychotic disorder: odds ratios [ORs] between 1.29 and 2.20; VTE, DVT, and PE for bipolar disorder: ORs between 1.22 and 2.14). Depression and anxiety disorders were associated with VTE risk only in adjusted analyses (DVT and PE for depression: ORs = 1.29; VTE and PE for anxiety disorders: ORs between 1.14 and 1.49). CONCLUSIONS: The risk of VTE among individuals with psychiatric disorders may be explained by hypercoagulability and stasis, with both being related to, and independent of, treatment adverse effects. VTE risk should be taken into consideration in the treatment for people with psychiatric disorders.

Assessing metacognitive and help-seeking strategies in schizophrenia: design and psychometric validation of the Versailles Metacognitive Strategies Evaluation Questionnaire.

OBJECTIVES: The aim of this study is to design a questionnaire, the Versailles Metacognitive Strategies Evaluation Questionnaire, for assessing the use of metacognitive and help-seeking strategies in three key-domains of impaired daily functioning in schizophrenia. To evaluate its psychometric properties (internal consistency, factor structure, convergent and divergent validity, and stability). DESIGN: Development of a questionnaire and psychometric validation procedure in patients with schizophrenia compared with healthy controls. Stability over one year was assessed in the patient group. SETTING: Schizophrenia Centers of Expertise (French FondaMental Network). SUBJECTS: A total of 141 patients with schizophrenia, among whom 77 participated in the second evaluation; 97 healthy subjects. MAIN MEASURES: The Versailles Metacognitive Strategies Evaluation Questionnaire, Positive and Negative Symptoms Scale, Personal and Social Performance Scale, Evaluation of Cognitive Processes involved in Disability in Schizophrenia Scale, Schizophrenia Quality of Life Questionnaire, and Stages of Recovery Instrument. RESULTS: From the 36-items version, stepwise exploratory factor analysis (oblimin) produced a 25-items scale which had a 3-factors structure (hygiene concern, social relationships, and hygiene help-seeking). Cronbach's were respectively equal to 0.91, 0.82, and 0.78. One-year stability was good (intra-class correlation coefficient = 0.7). The three factors showed good convergent validity with measures of quality of life (rho = 0.34, P ⩽ 0.001). The first two factors correlated with recovery (N = 34, rho = 0.53, P ⩽ 0.001). On the contrary, the factors exhibited divergent validity, with no significant correlation, with symptoms and cognitive and psychosocial functioning (P > 0.05). Factor structure in healthy controls did not match with that of patients, all items but one were found significantly different among groups. CONCLUSION: The Versailles Metacognitive Strategies Evaluation Questionnaire provides a simple and valid means to assess metacognitive strategies in individuals with schizophrenia.

Assessing cross-national invariance of the Community Assessment of Psychic Experiences (CAPE).

BACKGROUND: The Community Assessment of Psychic Experiences (CAPE) is a 42-item self-report questionnaire that has been developed and validated to measure the dimensions of psychosis in the general population. The CAPE has a three-factor structure with dimensions of positive, negative and depression. Assessing the cross-national equivalence of a questionnaire is an essential prerequisite before pooling data from different countries. In this study, our aim was to investigate the measurement invariance of the CAPE across different countries. METHODS: Data were drawn from the European Union Gene-Environment Interaction (EU-GEI) study. Participants (incident cases of psychotic disorder, controls and siblings of cases) were recruited in Brazil, France, Italy, the Netherlands, Spain and UK. To analyse the measurement invariance across these samples, we tested configural invariance (i.e. identical structures of the factors), metric invariance (i.e. equivalence of the factor loadings) and scalar invariance (i.e. equivalence of the thresholds) of the three CAPE dimensions using multigroup categorical confirmatory factor analysis methods. RESULTS: The configural invariance model fits well, providing evidence for identical factorial structure across countries. In comparison with the configural model invariance, the fit indices were very similar in the metric and scalar invariance models, indicating that factor loadings and thresholds did not differ across the six countries. CONCLUSION: We found that, across six countries, the CAPE showed equivalent factorial structure, factor loadings and thresholds. Thus, differences observed in scores between individuals from different countries should be considered as reflecting different levels of psychosis.

Obsessive-Compulsive Symptoms in Schizophrenia: an Up-To-Date Review of Literature.

PURPOSE OF REVIEW: This review will aim to summarize the current body of epidemiological, clinical and therapeutic knowledge concerning specific co-occurrence of obsessive-compulsive symptoms (OCSs) and schizophrenia spectrum disorder. RECENT FINDINGS: Almost 30% of the patients with schizophrenia display OCS, and three main contexts of emergence are identified: prodromal symptoms of schizophrenia, co-occurrence of OCS and schizophrenia and antipsychotics-induced OCS. Recent clinical studies show that patients with SZ and OCS have more severe psychotic and depressive symptoms, higher suicidality and lower social functioning. A recent cognitive investigation found that OCS and delusions share specific metacognitive profiles, particularly through a heightened need to control thoughts. Finally, a recent cross-sectional study of clozapine-induced OCS found a dose-response relationship between clozapine and OCS. OCS appeared reliably as linked to poorer outcomes among patients with schizophrenia. However, the specific clinical value of OCS among other prodromal symptoms of schizophrenia remains unknown.

Screening for cognitive deficits with the Evaluation of Cognitive Processes involved in Disability in Schizophrenia scale.

OBJECTIVE:: This study aimed to evaluate the validity of the Evaluation of Cognitive Processes involved in Disability in Schizophrenia scale (ECPDS) to discriminate for cognitive impairment in schizophrenia. DESIGN:: This multicentre cross-sectional study used a validation design with receiver operating characteristic (ROC) curve analysis. SETTINGS:: The study was undertaken in a French network of seven outward referral centres. SUBJECTS:: We recruited individuals with clinically stable schizophrenia diagnosed based on the Structured Clinical Interview for assessing Diagnostic and Statistical Manual of Mental Disorders (4th ed., rev.; DSM-IV-R) criteria. MAIN MEASURES:: The index test for cognitive impairment was ECPDS (independent variable), a 13-item scale completed by a relative of the participant. The reference standard was a standardized test battery that evaluated seven cognitive domains. Cognitive impairment was the dependent variable and was defined as an average z-score more than 1 SD below the normative mean in two or more cognitive domains. RESULTS:: Overall, 97 patients were included (67 with schizophrenia, 28 with schizoaffective disorder, and 2 with schizophreniform disorder). The mean age was 30.2 (SD 7.7) years, and there were 75 men (77.3%). There were 59 (60.8%) patients with cognitive impairment on the neuropsychological battery, and the mean ECPDS score was 27.3 (SD 7.3). The ROC curve analysis showed that the optimal ECPDS cut-off was 29.5. The area under the curve was 0.77, with 76.3% specificity and 71.1% sensitivity to discriminate against cognitive impairment. CONCLUSION:: The ECPDS is a valid triage tool for detecting cognitive impairment in schizophrenia, before using an extensive neuropsychological battery, and holds promise for use in everyday clinical practice.

A Multilevel Functional Study of a SNAP25 At-Risk Variant for Bipolar Disorder and Schizophrenia.

The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in SNAP25, rs6039769, that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined in vitro and in vivo approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed in vitro that the rs6039769 C allele was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the SNAP25b/SNAP25a ratio was increased in schizophrenic patients carrying the rs6039769 at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia.SIGNIFICANCE STATEMENT Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.

Remission of depression in patients with schizophrenia and comorbid major depressive disorder: results from the FACE-SZ cohort.

BACKGROUND: Major depressive disorder (MDD) is underdiagnosed and undertreated in schizophrenia, and has been strongly associated with impaired quality of life.AimsTo determine the prevalence and associated factors of MDD and unremitted MDD in schizophrenia, to compare treated and non-treated MDD. METHOD: Participants were included in the FondaMental Expert Centers for Schizophrenia and received a thorough clinical assessment. MDD was defined by a Calgary score ≥6. Non-remitted MDD was defined by current antidepressant treatment (unchanged for >8 weeks) and current Calgary score ≥6. RESULTS: 613 patients were included and 175 (28.5%) were identified with current MDD. MDD has been significantly associated with respectively paranoid delusion (odds ratio 1.8; P = 0.01), avolition (odds ratio 1.8; P = 0.02), blunted affect (odds ratio 1.7; P = 0.04) and benzodiazepine consumption (odds ratio 1.8; P = 0.02). Antidepressants were associated with lower depressive symptoms score (5.4 v. 9.5; P < 0.0001); however, 44.1% of treated patients remained in non-remittance MDD. Nonremitters were found to have more paranoid delusion (odds ratio 2.3; P = 0.009) and more current alcohol misuse disorder (odds ratio 4.8; P = 0.04). No antidepressant class or specific antipsychotic were associated with higher or lower response to antidepressant treatment. MDD was associated with Metabolic syndrome (31.4 v. 20.2%; P = 0.006) but not with increased C-reactive protein. CONCLUSIONS: Antidepressant administration is associated with lower depressive symptom level in patients with schizophrenia and MDD. Paranoid delusions and alcohol misuse disorder should be specifically explored and treated in cases of non-remission under treatment. MetS may play a role in MDD onset and/or maintenance in patients with schizophrenia.Declaration of interestNone.

A latent class analysis of psychotic symptoms in the general population.

OBJECTIVE: Individuals with psychotic symptoms may actually correspond to various subgroups, characterized by different patterns of psychotic symptoms as well as specific sociodemographic and clinical correlates. We aimed to identify groups of individuals from the general population with specific patterns of psychotic symptoms. METHODS: In a 38,694-subject survey, a latent class analysis was performed to identify subgroups based on the distribution of seven psychotic symptoms taken from the Mini International Neuropsychiatric Interview. The different classes were subsequently compared according to sociodemographic and clinical correlates. RESULTS: The best fit was obtained with a four-class solution, including the following: (1) a class with a low prevalence of all psychotic symptoms ('LOW', 85.9%); (2) a class with a high prevalence of all psychotic symptoms ('HAL + DEL', 1.7%); and classes with a high prevalence of (3) hallucinations ('HAL', 4.5%) or (4) delusions ('DEL', 7.9%). The HAL + DEL class displayed higher rates of history of trauma, social deprivation and migrant status, while the HAL and DEL classes displayed intermediate rates between HAL + DEL and LOW. HAL + DEL displayed the highest rates of psychotic and non-psychotic disorders and the use of mental health treatment, while HAL and DEL displayed intermediate rates of these disorders between HAL + DEL and LOW. In comparison to the HAL class, psychotic and substance use disorders were more frequent in the DEL class, while anxiety and mood disorders were less frequent. CONCLUSION: These findings support the hypothesis of a continuum model relating the level of psychotic symptoms to the level of global psychopathology.

Nicotine dependence is associated with depression and childhood trauma in smokers with schizophrenia: results from the FACE-SZ dataset.

In a perspective of personalized care for smoking cessation, a better clinical characterization of smokers with schizophrenia (SZ) is needed. The objective of this study was to determine the clinical characteristics of SZ smokers with severe nicotine (NIC) dependence. 240 stabilized community-dwelling SZ smokers (mean age = 31.9 years, 80.4% male gender) were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia and assessed with validated scales. Severe NIC dependence was defined by a Fagerstrom questionnaire score ≥ 7. Depression was defined by a Calgary score ≥ 6. Childhood trauma was self-reported by the Childhood Trauma Questionnaire score (CTQ). Ongoing psychotropic treatment was recorded. Severe NIC dependence was identified in 83 subjects (34.6%), depression in 60 (26.3%). 44 (22.3%) subjects were treated by antidepressants. In a multivariate model, severe NIC dependence remained associated with depression (OR = 3.2, p = 0.006), male gender (OR = 4.5, p = 0.009) and more slightly with childhood trauma (OR = 1.03, p = 0.044), independently of socio-demographic characteristics, psychotic symptoms severity, psychotropic treatments and alcohol disorder. NIC dependence was independently and strongly associated with, respectively, depression and male gender in schizophrenia, and only slightly with history of childhood trauma. Based on these results, the care of both nicotine dependence and depression should be evaluated for an effective smoking cessation intervention in schizophrenia.