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Objective: To compare the clinical symptomatology in patients with Early-Onset Schizophrenia (EOS, N = 176), especially the subgroup Very Early Onset Schizophrenia (VEOS) and Adult Onset Schizophrenia (AOS, N = 551)., Method: In a large French multicentric sample, 727 stable schizophrenia patients, classified by age at onset of the disorder, were assessed using standardized and extensive clinical and neuropsychological batteries: AOS with onset ≥ 18 years and EOS with onset < 18 years (including 22 VEOS < 13 years)., Results: The importance of better diagnosing EOS group, and in particularly VEOS, appeared in a longer DUP Duration of Untreated Psychosis (respectively, 2.6 years ± 4.1 and 8.1 years ± 5.7 vs. 1.0 years ± 2.5), more severe symptomatology (PANSS Positive And Negative Syndrome Scale scores), and lower educational level than the AOS group. In addition, the VEOS subgroup had a more frequent childhood history of learning disabilities and lower prevalence of right-handedness quotient than the AOS., Conclusion: The study demonstrates the existence of an increased gradient of clinical severity from AOS to VEOS. In order to improve the prognosis of the early forms of schizophrenia and to reduce the DUP, clinicians need to pay attention to the prodromal manifestations of the disease., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

A high rate of patients with schizophrenia (SZ) does not sufficiently respond to antipsychotic medication, which is associated with relapses and poor outcomes. Chronic peripheral inflammation has been repeatedly associated with schizophrenia risk and particularly to poor responders to treatment as usual with cognitive impairment in SZ subjects. The objective of present study was to confirm if ultra resistance to treatment in schizophrenia (UTRS) was associated to chronic peripheral inflammation in a non-selected sample of community-dwelling outpatients with schizophrenia. Participants were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia and received a thorough clinical assessment, including recording of current treatment. Current psychotic symptomatology was evaluated by the Positive and Negative Syndrome scale for Schizophrenia (PANSS). UTRS was defined by current clozapine treatment + PANSS total score ≥ 70. Functioning was evaluated by the Global Assessment of Functioning scale. High sensitivity CRP (hs-CRP) was measured for each participant as a proxy to define peripheral low-grade inflammation. 609 stabilized community-dwelling SZ subjects (mean age = 32.5 years, 73.6% male gender) have been included. 60 (9.9%) patients were classified in the UTRS group. In multivariate analyses, UTRS has been associated independently with chronic peripheral inflammation (OR = 2.6 [1.2-5.7], p = 0.01), illness duration (0R = 1.1 [1.0-1.2], p = 0.02) and impaired functioning (OR = 0.9 [0.9-0.9], p = 0.0002) after adjustment for age, sex, current daily tobacco smoking, metabolic syndrome and antidepressant consumption. Peripheral low-grade inflammation is associated with UTRS. Future studies should explore if anti-inflammatory strategies are effective in UTRS with chronic low-grade peripheral inflammation.

Psychosocial Interventions (PIs) have shown positive effects on clinical and functional outcomes of schizophrenia (SZ) in randomized controlled trials. However their effectiveness and accessibility remain unclear to date in "real world" schizophrenia. The objectives of the present study were (i) to assess the proportion of SZ outpatients who benefited from PIs between 2010 and 2015 in France after an Expert Center Intervention in a national multicentric non-selected community-dwelling sample; (ii) to assess PIs' effectiveness at 1-year follow-up. 183 SZ outpatients were recruited from FondaMental Advanced Centers of Expertise for Schizophrenia cohort. Baseline and 1-year evaluations included sociodemographic data, current treatments, illness characteristics and standardized scales for clinical severity, adherence to treatment, quality of life, a large cognitive battery, and daily functioning assessment. Only 7 (3.8%) received a PI before the evaluation, and 64 (35%) have received at least one PI during the 1-year follow-up. Having had at least one PI during the follow-up has been associated in multivariate analyses with significantly higher improvement in positive and negative symptoms (respectively p =0.031; p = 0.011), mental flexibility (TMT B, p = 0.029; C-VF, p = 0.02) and global functioning (p =0.042). CBT and SST were associated with higher cognitive improvements, while CRT was associated with clinical improvement. These results have not been demonstrated before and suggest that the effect of each PI is larger than its initial target. The present study has confirmed the PIs' effectiveness in a large sample of community-dwelling SZ outpatients at 1 year follow-up. Efforts to improve access to PI should be reinforced in public health policies.

Objective: Existing staging models have not been fully validated. Thus, after classifying patients with schizophrenia according to the staging model proposed by McGorry et al. (2010), we explored the validity of this staging model and its stability after one-year of follow-up., Method: Using unsupervised machine-learning algorithm, we classified 770 outpatients into 5 clinical stages, the highest being the most severe. Analyses of (co)variance were performed to compare each stage in regard to socio-demographics factors, clinical characteristics, co-morbidities, ongoing treatment and neuropsychological profiles., Results: The precision of clinical staging can be improved by sub-dividing intermediate stages (II and III). Clinical validators of class IV include the presence of concomitant major depressive episode (42.6% in stage IV versus 3.4% in stage IIa), more severe cognitive profile, lower adherence to medication and prescription of >3 psychotropic medications. Follow-up at one-year showed good stability of each stage., Conclusion: Clinical staging in schizophrenia could be improved by adding clinical elements such as mood symptoms and cognition to severity, relapses and global functioning. In terms of therapeutic strategies, attention needs to be paid on the factors associated with the more stages of schizophrenia such as treatment of comorbid depression, reduction of the number of concomitant psychotropic medications, improvement of treatment adherence, and prescription of cognitive remediation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Predicting psychotic relapse is one of the major challenges in the daily care of schizophrenia., Objectives: To determine the predictors of psychotic relapse and follow-up withdrawal in a non-selected national sample of stabilized community-dwelling SZ subjects with a machine learning approach., Methods: Participants were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia and received a thorough clinical and cognitive assessment, including recording of current treatment. Relapse was defined by at least one acute psychotic episode of at least 7 days, reported by the patient, her/his relatives or by the treating psychiatrist, within the 2-year follow-up. A classification and regression tree (CART) was used to construct a predictive decision tree of relapse and follow-up withdrawal., Results: Overall, 549 patients were evaluated in the expert centers at baseline and 315 (57.4%) (mean age = 32.6 years, 24% female gender) were followed-up at 2 years. On the 315 patients who received a visit at 2 years, 125(39.7%) patients had experienced psychotic relapse at least once within the 2 years of follow-up. High anger (Buss&Perry subscore), high physical aggressiveness (Buss&Perry scale subscore), high lifetime number of hospitalization in psychiatry, low education level, and high positive symptomatology at baseline (PANSS positive subscore) were found to be the best predictors of relapse at 2 years, with a percentage of correct prediction of 63.8%, sensitivity 71.0% and specificity 44.8%. High PANSS excited score, illness duration <2 years, low Buss&Perry hostility score, high CTQ score, low premorbid IQ and low medication adherence (BARS) score were found to be the best predictors of follow-up withdrawal with a percentage of correct prediction of 52.4%, sensitivity 62%, specificity 38.7%., Conclusion: Machine learning can help constructing predictive score. In the present sample, aggressiveness appears to be a good early warning sign of psychotic relapse and follow-up withdrawal and should be systematically assessed in SZ subjects. The other above-mentioned clinical variables may help clinicians to improve the prediction of psychotic relapse at 2 years., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: The present article is a synthesis of the first 10 years of follow-up of the FondaMental Academic Center of Expertise for Schizophrenia (FACE-SZ) cohort., Methods: More than 700 community-dwelling stabilized subjects have been recruited and evaluated to date. The mean age was 32 years with 75 % males, the mean illness duration was 11 years, the mean age at illness onset was 21 years, the mean duration of untreated psychosis was 1.5 years and 55 % were current daily tobacco smokers., Results: The major findings of the FACE-SZ cohort may be summarized as follows: the metabolic syndrome is twice more frequent in schizophrenia as compared to the general population and is not correctly assessed and treated; cognitive disturbances have been found in benzodiazepine consumers and in patients with chronic low-grade peripheral inflammation; major depressive disorder (MDD) is a common current comorbid condition in about 20% of the subjects at the evaluation. MDD is associated with impaired quality of life and with increased nicotine dependency in SZ daily tobacco smokers. Improving depression and negative symptoms may be the most effective strategies to improve quality of life in schizophrenia; the duration of untreated psychosis is much longer in cannabis smokers and in subjects with an age at illness onset<19 years. Adherence to treatment is diminished in subjects who report a subjective negative feeling after treatment intake independent of objective side effects (extrapyramidal syndrome and weight gain). Akathisia has been found in 18% of the subjects and has been associated with antipsychotic polytherapy., Conclusions: In the light of these results, some recommendations for clinical care may be suggested. The early detection of schizophrenia should be specifically increased in adolescents and/or cannabis smokers. All patients should be administered a comprehensive neuropsychological evaluation at the beginning of the illness and after stabilization under treatment. Improving metabolic parameters and lifestyle (diet and physical activity) should be reinforced. The benefit/risk ratio of benzodiazepine and antipsychotic polytherapy should be regularly reevaluated and withdrawn as soon as possible. If MDD remains underdiagnosed and undertreated, improving depression may strongly improve the quality of life of SZ subjects. In the end, Cognitive Remediation Therapy and anti-inflammatory strategies should be more frequently included in therapeutic strategies., (Copyright © 2018. Published by Elsevier Masson SAS.)

Background: Extrapyramidal side effects (EPS) have been identified as a complication of antipsychotic treatment. Previous meta-analyses have investigated EPS prevalence and risk factors in randomized clinical trials with highly selected patients, but studies in real-world schizophrenia are missing., Objective: To examine the prevalence and clinical correlates associated with EPS in a nonselected national multicenter sample of stabilized patients with schizophrenia., Methods: Between 2010 and 2016, patients suffering from schizophrenia (DSM-IV-TR criteria) were recruited through the FondaMental Academic Centers of Expertise for Schizophrenia (FACE-SZ) network and data were collected during a comprehensive 1-day-long standardized evaluation. The Simpson-Angus Scale and the Abnormal Involuntary Movement Scale were used to assess drug-induced parkinsonism (DIP) and tardive dyskinesia, respectively., Results: The overall prevalence of DIP and tardive dyskinesia was 13.2% and 8.3%, respectively, in this community-dwelling sample of 674 patients. DIP was associated with negative symptoms (Positive and Negative Syndrome Scale [PANSS] subscore) (adjusted odds ratio [aOR] = 1.102, P < .001), first-generation antipsychotic prescription (aOR = 2.038, P = .047), and anticholinergic drug administration (aOR = 2.103, P = .017) independently of sex, age, disorganization (PANSS disorganized factor), and antipsychotic polytherapy. Tardive dyskinesia was associated with PANSS disorganized factor (aOR = 1.103, P = .049) independently of sex, age, negative symptoms, excitation, first-generation antipsychotic prescription, and benzodiazepine and anticholinergic drug administration., Conclusions: Our results indicate the high prevalence of EPS in a nonselected community-dwelling clinically stable sample of outpatients with schizophrenia. In the monitoring of antipsychotic treatment, EPS should be systematically evaluated, especially when negative symptoms and disorganization or cognitive alteration are present. Monotherapy with a second-generation antipsychotic should be preferentially initiated for patients with these side effects., (© Copyright 2019 Physicians Postgraduate Press, Inc.)

Objective: Hypovitaminosis D has been associated with respectively major depressive disorder, schizophrenia (SZ) and cognitive disorders in the general population, and with positive and negative symptoms and metabolic syndrome in schizophrenia. The objectives were (i) to determine the prevalence of hypovitaminosis D and associated factors (with a focus on depression and cognition) in a national non-selected multicentric sample of community-dwelling SZ subjects (ii) to determine the rate of SZ patients being administered vitamin D supplementation and associated factors., Methods: A comprehensive 2 daylong clinical and neuropsychological battery was administered in 140 SZ subjects included between 2015 and 2017 in the national FondaMental Expert Center (FACE-SZ) Cohort. Hypovitaminosis D was defined by blood vitamin D level <25 nM. Depressive symptoms were assessed by the Positive and Negative Syndrome Scale depressive subscore and current anxiety disorder by the Structured Clinical Interview for Mental Disorders., Results: Hypovitaminosis D has been found in 21.4% of the subjects and none of them had received vitamin D supplementation in the previous 12 months. In multivariate analysis, hypovitaminosis D has been significantly associated with respectively higher depressive symptoms (aOR = 1.18 [1.03-1.35], p = 0.02) and current anxiety disorder (aOR = 6.18 [2.15-17.75], p = 0.001), independently of age and gender. No association of hypovitaminosis D with respectively positive and negative symptoms, cognitive scores or other biological variables has been found (all p > 0.05), however, a trend toward significance has been found for metabolic syndrome (p = 0.06). Vitamin D supplementation has been administered during the previous 12 months in only 8.5% of the subjects but was associated with lower depressive symptoms (aOR = 0.67 [0.46-0.98], p = 0.04) and lower rate of current anxiety disorder (aOR = 0.06 [0.01-0.66], p = 0.02) compared to patients with hypovitaminosis D., Conclusion: Hypovitaminosis D is frequent and associated with depressive symptoms and anxiety disorders in schizophrenia. Vitamin D supplementation is associated with lower depressive and anxiety symptoms, however patients with hypovitaminosis D remain insufficiently treated., (Copyright © 2018. Published by Elsevier B.V.)

Objective: Latent Toxoplasma infection has been associated with widespread brain immune activation, increased blood brain barrier permeability, neural disruption, increased dopamine release in dopaminergic neurons, with NMDA activation and with schizophrenia (SZ) onset risk. Toxoplasma has been suggested to be a source of chronic low-grade inflammation and this inflammation has been associated with cognitive impairment in SZ. The objective of the present study were (i) to determine if latent Toxoplasma infection was associated with specific clinical features in stabilized SZ subjects, with cognitive impairment and with increased low-grade peripheral inflammation and (ii) to determine if Treatments with Anti-Toxoplasmic Activity (TATA) were associated with improved outcomes in subjects with latent Toxoplasma infection., Methods: A comprehensive 2 daylong clinical and neuropsychological battery was administered in 250 SZ subjects included between 2015 and 2017 in the national FondaMental Expert Center (FACE-SZ) Cohort. Solid phase-enzyme microplate immunoassay methods were used to measure IgG class of antibodies to T. gondii in blood sample. Latent Toxoplasma infection was defined by T. gondii IgG ratio ≥0.8, equivalent to ≥10 international units. Chronic peripheral inflammation was defined by highly sensitive C reactive protein blood level ≥ 3 mg/L., Results: Latent Toxoplasma infection has been found in 184 (73.6%) of this national multicentric sample. In the multivariate analyses, latent Toxoplasma infection has been significantly associated with higher PANSS negative (aOR = 1.1 [1.1-1.1], p = 0.04) and excitement subscores (aOR = 1.3 [1.1-1.6], p = 0.01), with two specific symptoms (i.e., reference delusion (aOR = 3.6 [1.2-10.6] p = 0.01) and alogia (aOR = 16.7 [2.0-134.7], p = 0.008)) and with chronic low-grade peripheral inflammation (27.2% vs. 7.6%, aOR = 3.8 [1.4-10.3], p = 0.004). Extrapyramidal symptoms remained significantly associated with latent Toxoplasma infection. On the opposite, no significant association of latent Toxoplasma infection with age, gender, age at SZ onset, suicide behavior or cognitive deficits has been found in these models (all p > 0.05). TATA were associated with lower depressive symptoms (aOR = 0.8[0.7-0.9], p = 0.01), and with lower rates of chronic peripheral inflammation (20.9% vs. 48.6%, aOR = 3.5 [1.5-7.9], p = 0.003) but not with higher cognitive scores (p > 0.05)., Conclusion: The present findings suggest that Toxoplasma is almost 3 times more frequent in SZ population compared to general population in France. The potential cerebral underpinnings of the association of latent Toxoplasma infection and the above-mentioned outcomes have been discussed. Future studies should confirm that TATA may be effective to reduce Toxoplasma-associated depressive symptoms and low-grade peripheral inflammation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Low-grade inflammation has repeatedly been associated with schizophrenia (SZ) and in particular with cognitive impairment. Female gender, overweight and tobacco smoking have been suggested as risk factors to increase inflammation while preclinical inconsistent findings have been found regarding the association with psychotropic drugs. The aim of this study was to explore if psychotropic drugs were associated with inflammation in SZ and to determine which psychotropic drug was associated with inflammation in stable SZ subjects while considering clinical confounding factors. Participants were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia and received a thorough clinical assessment, including recording of current treatment. High-sensitivity CRP (hs-CRP) was measured for each participant as a proxy to define peripheral low-grade inflammation. The zero-inflated Poisson regression model estimated the relationship between low-grade inflammation and psychotropic drug. Four hundred and five stabilized, community-dwelling SZ subjects (mean age = 32.6 years, 74% male gender) have been included. In total, 148 participants (36.5%) were found with undetectable blood hs-CRP level. The probability of having an undetectable CRP was associated with a lower body mass index (p < 0.0001) and no cyamemazine add-on antipsychotic therapy (p = 0.001). The other 257 participants (63.5%) were found to have low-grade inflammation (hs-CRP > 0 mg/L). Low-grade inflammation was significantly associated with female gender (p = 0.004), higher body mass index (p < 0.0001), current tobacco smoking (p < 0.0001), clomipramine (p = 0.04), quetiapine (p < 0.0001) and hypnotic (p = 0.0006) consumption while decreased hs-CRP blood levels was associated with aripiprazole (p = 0.004) and valproate/valpromide (p = 0.03) consumption. The present study suggests that some psychotropic drugs (quetiapine, cyamemazine, clomipramine) may be associated with increased peripheral low-grade inflammation in SZ patients while others (aripiprazole, valproate) may be associated with decreased peripheral low-grade inflammation. These results should be replicated in SZ and non-SZ populations and the biological underpinnings should be further explored.

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.

Introduction: Little is known about perception of physical pain in schizophrenia (SZ). Some studies have suggested that patients with SZ may have an increased pain threshold, while others have suggested that patients with SZ may suffer from undetected and untreated high physical pain levels. The objectives of this study were (i) to investigate the prevalence of self-reported physical pain in stabilized SZ subjects, and (ii) to determine whether physical pain was associated with psychiatric characteristics and somatic comorbidities (iii) to determine whether antidepressants and benzodiazepine administration were associated with lower self-reported pain., Method: 468 community-dwelling stable SZ subjects (73% men, mean aged 32 years) were recruited in the Schizophrenia Expert Center national network. Patients with moderate to extreme pain, assessed with the EQ5D-5L questionnaire, were classified as belonging to the "pain group"., Results: 104 (22.2%) reported moderate to extreme pain levels. In multivariate analysis, pain has been associated with headache (OR = 2.63 [1.04-6.63], p = 0.04), higher anxiety (OR = 1.61 [1.18-2.21], p = 0.003), higher current depressive symptoms (OR = 1.09 [1.01-1.17], p = 0.03), history of childhood trauma (1.03 [1.01-1.06], p = 0.01) and older age (OR = 1.04 [1.01-1.07], p = 0.03), independently of current psychotic severity, sociodemographic variables, antipsychotic, antidepressant and benzodiazepine treatments. No association with addictive behaviors or illness characteristics has been found., Conclusion: The present findings suggest that community-dwelling SZ outpatients report a high rate of self-reported physical pain, associated with headache, depression and anxiety and history of childhood trauma. Physical pain should be systematically assessed and specifically treated, when needed, in patients with SZ., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Reducing the duration of untreated psychosis (DUP) may improve the prognosis of schizophrenia. This study investigated the prevalence, and associated risk factors, of long DUP in a large, non-selected sample of community-dwelling schizophrenia patients (SZ)., Method: 478 community-dwelling stable SZ participants (122 women and 356 men; mean age 32.37±9.86years) were recruited between 2010 and 2016. The mean retrospective DUP was evaluated from both patient and family reports, as well as hospital/psychiatrists records. Long DUP was defined as >2years., Results: The mean DUP was 1.5years. 80 participants (16.7%) had a DUP>2years. In multivariate analyses, after adjustment for sex, education level, history of childhood trauma and history of maternal schizophrenia or bipolar disorder, long DUP was associated with a younger age of illness onset (19.3±6.67years vs. 22.0±6.51years, adjusted odd ratio aOR=0.91, 95%CI [0.86; 0.97], p=0.003) and cannabis use disorder (20.0% vs. 10.3%, aOR=2.41, 95%CI [1.14-5.09], p=0.02)., Conclusion: A high proportion of SZ patients still have a long DUP. The present results suggest that illness onset before age 19years and cannabis use are associated with long DUP in schizophrenia patients. Early psychosis detection programs should prioritize the targeting of these populations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: Sex differences can yield important clues regarding illness pathophysiology and its treatment. Schizophrenia (SZ) has a lower incidence rate, and a better prognosis, in women versus men. The present study investigated the cognitive profiles of both sexes in a large multi-centre sample of community-dwelling SZ patients., Method: 544 community-dwelling stable SZ subjects (141 women and 403 men; mean age 34.5±12.1 and 31.6±8.7years, respectively) were tested with a comprehensive battery of neuropsychological tests., Results: Although community-dwelling SZ men had more risk factors for impaired cognition (including first-generation antipsychotics administration and comorbid addictive disorders), women had lower scores on a wide range of cognitive functions, including current and premorbid intellectual functioning, working memory, semantic memory, non-verbal abstract thinking and aspects of visual exploration. However, women scored higher in tests of processing speed and verbal learning, as well as having a lower verbal learning bias. No sex difference were evident for visuospatial learning abilities, cued verbal recall, sustained attention and tests of executive functions, including cognitive flexibility, verbal abstract thinking, verbal fluency and planning abilities., Conclusion: Sex differences are evident in the cognitive profiles of SZ patients. The impact on daily functioning and prognosis, as well as longitudinal trajectory, should be further investigated in the FACE-SZ follow-up study. Sex differences in cognition have implications for precision-medicine determined therapeutic strategies., Limits: Given the restricted age range of the sample, future research will have to determine cognitive profiles across gender in late onset SZ., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: The effect of benzodiazepine long-term administration (BLTA) in cognitive functioning of subjects with schizophrenia (SZ) has been partially explored to date. The objective was to assess BLTA-associated cognitive impairment with a comprehensive cognitive battery in a non-selected multicentric/national community-dwelling sample of stabilized SZ subjects., Method: 407 community-dwelling stabilized SZ subjects were consecutively included in the FondaMental Academic Centers of Expertise for Schizophrenia Cohort (FACE-SZ). Patients taking daily benzodiazepine were defined as BLTA+ as all patients examined by the Expert Center were clinically stabilized and under stable dose of treatment for at least 3 months. Each patient has been administered a 1-day long comprehensive cognitive battery (including The National Adult Reading Test, the Wechsler Adult Intelligence Scale, the Trail Making Test, the California Verbal Learning Test, the Doors test, and The Continuous Performance Test-Identical Pairs)., Results: In the multivariate analyses, results showed that BLTA was associated with impaired attention/working memory (OR 0.60, 95% confidence interval 0.42-0.86; p = 0.005) independently of socio-demographic variables and illness characteristics. Verbal and performance current IQ-[respectively, OR 0.98, 95% CI (0.96;0.99), p = 0.016 and 0.98, 95% CI(0.97;0.99), p = 0.034] but not premorbid IQ-(p > 0.05) have been associated with BLTA in a multivariate model including the same confounding variables., Conclusion: BLTA is associated with impaired attention/working memory in schizophrenia. The BLTA benefit/risk ratio should be regularly reevaluated. Alternative pharmacological and non-pharmacological strategies for comorbid anxiety disorders and sleep disorders should be preferred when possible. It seems reasonable to withdraw BLTA before the start of cognitive remediation therapy, as soon as possible, to improve the effectiveness of this therapy. Limits: the delay between the last benzodiazepine intake and testing, as well as the specific class of benzodiazepines (long half-life vs. short half-life), and the number of benzodiazepine daily intakes have not been recorded in the present study. The precise motive for BLTA prescription and sleep disturbances have not been reported, which is a limit for the interpretation of the present results.

Objectives: Mindfulness based interventions (MBI) have recently gained much interest in western medicine. MBSR paradigm is based on teaching participants to pay complete attention to the present experience and act nonjudgmentally towards stressful events. During this mental practice the meditator focuses his or her attention on the sensations of the body. While the distractions (mental images, thoughts, emotional or somatic states) arise the participant is taught to acknowledge discursive thoughts and cultivate the state of awareness without immediate reaction. The effectiveness of these programs is well documented in the field of emotional response regulation in depression (relapse prevention), anxiety disorders, obsessive-compulsive disorder or eating disorders. Furthermore, converging lines of evidence support the hypothesis that mindfulness practice improves cognition, especially the ability to sustain attention and think in a more flexible manner. Nevertheless, formal rehabilitation programs targeting cognitive disturbances resulting from psychiatric (depression, disorder bipolar, schizophrenia) or neurologic conditions (brain injury, dementia) seldom rely on MBI principles. This review of literature aims at discussing possible links between MBI and clinical neuropsychology., Methods: We conducted a review of literature using electronic databases up to December 2016, screening studies with variants of the keywords ("Mindfulness", "MBI", "MBSR", "Meditation") OR/AND ("Cognition", "Attention", "Executive function", "Memory", "Learning") RESULTS: In the first part, we describe key concepts of the neuropsychology of attention in the light of Posner's model of attention control. We also underline the potential scope of different therapeutic contexts where disturbances of attention may be clinically relevant. Second, we review the efficacy of MBI in the field of cognition (thinking disturbances, attention biases, memory and executive processes impairment or low metacognitive abilities), mood (emotional dysregulation, anxiety, depression, mood shifts) and somatic preoccupations (stress induced immune dysregulation, chronic pain, body representation, eating disorders, sleep quality, fatigue). In psychiatry, these three components closely coexist and interact which explains the complexity of patient assessment and care. Numerous studies show that meditation inspired interventions offer a promising solution in the prevention and rehabilitation of cognitive impairment. In the last part, we discuss the benefits and risks of integrating meditation practice into broader programs of cognitive remediation and therapeutic education in patients suffering from cognitive disorders. We propose a number of possible guidelines for developing mindfulness inspired cognitive remediation tools. Along with Jon Kabatt Zinn (Kabatt-Zinn & Maskens, 2012), we suggest that the construction of neuropsychological tools relies on seven attitudinal foundations of mindfulness practice., Conclusions: This paper highlights the importance of referring to holistic approaches such as MBI when dealing with patients with neuropsychological impairment, especially in the field of psychiatry. We advocate introducing mindfulness principles in order to help patients stabilize their attention and improve cognitive flexibility. We believe this transition in neuropsychological care may offer an interesting paradigm shift promoting a more efficient approach towards cognition and its links to emotion, body, and environment., (Copyright © 2017 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Metabolic syndrome (MetS) is highly prevalent in schizophrenia. However very little is known about the time course of MetS and its components. The few longitudinal studies that have been carried out had small sample sizes and a short follow-up. The aim of our study was to evaluate the prevalence of MetS and its components, at baseline and one year later, and to investigate predictors of weight gain (WG) in a cohort of individuals with schizophrenia. We followed 167 schizophrenia patients from the FACE-SZ cohort for one year. The Structured Clinical Interview for DSM-IV (SCID) was used to confirm the diagnosis of schizophrenia. Data on socio-demographic and clinical characteristics, antipsychotic treatment, and comorbidities were collected, and a blood sample was drawn. We found that the prevalence of MetS increased from 21.0% to 26.6% after one year. Patients with baseline depressive symptoms had a 4.5-fold higher risk of WG at the one-year follow-up (p = 0.02) than those without depressive symptoms, after adjusting for confounding variables. WG also correlated with high levels of metabolic parameters and peripheral inflammation. These findings highlight the need to systematically diagnose depression in Schizophrenia. Future studies should determine whether specific pharmacological and non-pharmacological interventions for depression in SZ subjects are effective in preventing rapid high weight gain., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Children born by cesarean section ("c-birth") are known to have different microbiota and a natural history of different disorders including allergy, asthma and overweight compared to vaginally born ("v-birth") children. C-birth is not known to increase the risk of schizophrenia (SZ), but to be associated with an earlier age at onset. To further explore possible links between c-birth and SZ, we compared clinical and biological characteristics of c-born SZ patients compared to v-born ones. Four hundred and fifty-four stable community-dwelling SZ patients (mean age = 32.4 years, 75.8 % male gender) were systematically included in the multicentre network of FondaMental Expert Center for schizophrenia. Overall, 49 patients (10.8 %) were c-born. These subjects had a mean age at schizophrenia onset of 21.9 ± 6.7 years, a mean duration of illness of 10.5 ± 8.7 years and a mean PANSS total score of 70.9 ± 18.7. None of these variables was significantly associated with c-birth. Multivariate analysis showed that c-birth remained associated with lower CRP levels (aOR = 0.07; 95 % CI 0.009-0.555, p = 0.012) and lower premorbid ability (aOR = 0.945; 95 % CI 0.898-0.994, p = 0.03). No significant association between birth by C-section and, respectively, age, age at illness onset, sex, education level, psychotic and mood symptomatology, antipsychotic treatment, tobacco consumption, birth weight and mothers suffering from schizophrenia or bipolar disorder has been found. Altogether, the present results suggest that c-birth is associated with lower premorbid intellectual functioning and lower blood CRP levels in schizophrenia. Further studies should determine the mechanisms underlying this association.

The association between advanced paternal age (APA) and increased risk of schizophrenia (SZ) is well established. The objectives of the present study were to further determine if SZ participants with APA (APA+), versus those without (APA-), had: (i) different illness characteristics; (ii) different responses to antipsychotic medication; and (iii) different cognitive characteristics. Participants were a non-selected representative multicentric sample of stabilized community-dwelling people diagnosed with SZ included in the FACE-SZ cohort. 389 participants (73% males, mean aged 32.7 years, mean illness duration 10.8 years) formed the study sample, with each comprehensively evaluated, clinically and neuropsychologically, over 2 days. 118 participants (30.3%) were defined as APA+ according to their father's age at birth (≥35 years). APA+ was associated with a wide range of cognitive dysfunctions in univariate analyses. In multivariate analyses, the only significant difference was the age at onset, with a mean 1.6 year earlier in APA+, compared to APA- (20.7 vs. 22.3 years; p=0.02). This difference is independent of sociodemographic characteristics and I.Q. No association with clinical symptomatology and treatment response was found. The present study supports the neomutation hypothesis and confirms APA as a relevant clinical variable to discriminate potential schizophrenia subtypes. Potential underlying pathophysiological mechanisms are discussed., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Depression and negative symptoms have been associated with impaired Quality of life (QoL) in schizophrenia (SZ). However, childhood trauma may influence both QoL and depression in SZ patients, with consequences for the management of impaired QoL in SZ patients. The aim of the present study was to determine if childhood trauma was associated with impaired QoL in schizophrenia., Method: A sample of 544 community-dwelling stabilized SZ patients enrolled in FACE-SZ cohort were utilized in this study (74.1% males, mean aged 32.3years, mean illness duration 10.6years). QoL was self-reported with the S-QoL18 questionnaire. Childhood trauma was self-reported with the Childhood Trauma Questionnaire. Depression was measured by the Calgary Depression Rating Scale for Schizophrenia. Psychotic severity was measured by the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). Other clinical factors, treatments, comorbidities, functioning and sociodemographical variables were also recorded, with validated scales., Results: Overall, 151 participants (27.8%) had a current major depressive episode and 406 (82.5%) reported at least one episode of historical childhood trauma. In multivariate analyses, lower QoL total score was associated with a history of childhood trauma (β=-0.21, p<0.0001), psychotic negative symptoms (β=-0.11, p=0.04), current depression (β=-0.0.38, p<0.0001) and male gender (β=-0.16, p<0.0001)., Conclusion: Impaired QoL is independently associated with negative symptoms, depression and childhood trauma in schizophrenia., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: This study assesses the psychometric properties of Ward's seven-subtest short form (SF) for WAIS-IV in a sample of adults with schizophrenia (SZ) and schizoaffective disorder., Method: Seventy patients diagnosed with schizophrenia or schizoaffective disorder were administered the full version of the WAIS-IV. Four different versions of the Ward's SF were then calculated. The subtests used were: Similarities, Digit Span, Arithmetic, Information, Coding, Picture Completion, and Block Design (BD version) or Matrix Reasoning (MR version). Prorated and regression-based formulae were assessed for each version., Results: The actual and estimated factorial indexes reflected the typical pattern observed in schizophrenia. The four SFs correlated significantly with their full-version counterparts, but the Perceptual Reasoning Index (PRI) correlated below the acceptance threshold for all four versions. The regression-derived estimates showed larger differences compared to the full form. The four forms revealed comparable but generally low clinical category agreement rates for factor indexes. All SFs showed an acceptable reliability, but they were not correlated with clinical outcomes., Conclusions: The WAIS-IV SF offers a good estimate of WAIS-IV intelligence quotient, which is consistent with previous results. Although the overall scores are comparable between the four versions, the prorated forms provided a better estimation of almost all indexes. MR can be used as an alternative for BD without substantially changing the psychometric properties of the SF. However, we recommend a cautious use of these abbreviated forms when it is necessary to estimate the factor index scores, especially PRI, and Processing Speed Index., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Inflammation, measured by abnormal blood C-reactive protein (CRP) level, has been described in schizophrenia (SZ), being inconsistently related to impaired cognitive functions. The aim of the present study is to investigate cognitive impairment associated with abnormal CRP levels in a large multi-centric sample of community-dwelling SZ patients, using a comprehensive neuropsychological battery., Method: Three hundred sixty-nine community-dwelling stable SZ subjects (76.2% men, mean age 32.7 y) were included and tested with a comprehensive battery of neuropsychological tests. Abnormal CRP level was defined as >3mg/L., Results: Multiple factor analysis revealed that abnormal CRP levels, found in 104 patients (28.2%), were associated with impaired General Intellectual Ability and Abstract Reasoning (aOR = 0.56, 95% CI 0.35-0.90, P = .014), independently of age, sex, education level, psychotic symptomatology, treatments, and addiction comorbidities. Abnormal CRP levels were also associated with the decline of all components of working memory (respectively effect size [ES] = 0.25, P = .033; ES = 0.27, P = .04; ES = 0.33, P = .006; and ES = 0.38, P = .004) and a wide range of other impaired cognitive functions, including memory (ES = 0.26, P = .026), learning abilities (ES = 0.28, P = .035), semantic memory (ES = 0.26, P = .026), mental flexibility (ES = 0.26, P = .044), visual attention (ES = 0.23, P = .004) and speed of processing (ES = 0.23, P = .043)., Conclusion: Our results suggest that abnormal CRP level is associated with cognitive impairment in SZ. Evaluating the effectiveness of neuroprotective anti-inflammatory strategies is needed in order to prevent cognitive impairment in SZ., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Schizophrenia (SZ) is a chronic, severe disease, which results in misperception of reality, major social withdrawal, and cognitive disturbances. One type of cognitive disturbance, known as executive dysfunction, is widely considered as a primary determinant of functional outcome. However, classic neuropsychological measures of executive functioning (EF) poorly represent patients' functional outcome, and thus seem inappropriate for evaluating the real-world functional impact of diseases such as SZ. We hypothesized that the Multiple Errands Test (MET), an ecological assessment of executive function would show greater ability to measure everyday adaptive functioning SZ, compared to conventional EF assessment methods. 100 clinically stable SZ patients were administered the MET, Wisconsin Card Sorting Test - 64 and a paper version of MET. Correlation analyses were performed between each EF measure and functional outcome, as measured by the Social Autonomy Scale (SAS). After adjusting for age, education, IQ and illness duration, SAS was significantly predicted by MET global score. No other EF measure correlated with SAS. Results from this study suggest that MET offers a valuable prediction of daily life functional outcome in this large sample of SZ patients. Therefore, it could be used as a complementary measure to improve the identification of executive dysfunctions prior to psychosocial interventions., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The relation between C-Reactive Protein (CRP), depression and antidepressant consumption has been well explored in major depressive disorders but not in schizophrenia, which has a high rate of depression comorbidity. The objectives of this study were: (i) to determine the prevalence of abnormal CRP levels, depression and antidepressant consumption in a multicenter community-dwelling sample of subjects with schizophrenia (ii) to determine the association between abnormal CRP levels, depression and antidepressant consumption in schizophrenia., Method: 219 stable patients with schizophrenia (mean age=31.6 years, 75.3% male gender) were systematically included in the multicentre network of FondaMental Expert Center for schizophrenia (FACE-SZ) and assessed with a dedicated electronic medical record including the Structured Clinical Interview for DSM-IV Axis I Disorders and Calgary Depression Scale for depression. High sensitivity CRP (hs-CRP) was measured with an assay using nephelometry (Dade Behring). Abnormal CRP level was defined by levels >3mg/L. Current medication was recorded., Results: Overall, 63 subjects (28.8%) were found to have abnormal CRP levels, 43 (20.1%) received a diagnosis of comorbid current depression, and 51 (31.9%) had ongoing antidepressant treatment. In univariate analysis, abnormal CRP levels were found to be significantly associated with body mass index (BMI) (p<0.0001), hypertriglyceridemia (p=0.0015), high waist circumference (p<0.0001), metabolic syndrome (p=0.0011), abdominal obesity (p<0.0001) and with antidepressant consumption (p=0.01), while depression, psychotic symptomatology, age of onset, illness duration, sociodemographic characteristics, current tobacco or cannabis status, hypertension or high fasting glucose were not (all p>0.05). In a multivariate model, abnormal CRP was associated with antidepressant consumption independently of other confounding variables (adjusted Odds Ratio=2.8, 95% confidence interval 1.22-6.62). Metabolic syndrome was also independently associated with abnormal CRP (adjusted Odds Ratio=2.6, 95% confidence interval 1.01-6.71)., Conclusion: Abnormal CRP levels in schizophrenia were found to be associated with antidepressant consumption, but not with depression. The potential mechanisms were discussed. Antidepressant consumption should be systematically recorded in future studies exploring inflammation in schizophrenia. Future clinical trials of interventions directed at lowering the level of CRP and other inflammatory markers are discussed., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Schizophrenia is probably the most severe psychiatric disorder with much suffering for the patients and huge costs for the society. Efforts to provide optimal care by general practitioners and psychiatrists are undermined by the complexity of the disorder and difficulties in applying clinical practice guidelines and new research findings to the spectrum of cases seen in day-to-day practice. An innovative model of assessment aimed at improving global care of people with schizophrenia provided by the French national network of schizophrenia expert centres is being described. Each centre has established strong links to local health services and provides support to clinicians in delivering personalized care plans. A common set of assessment tools has been adopted by the ten centres spread over the whole French territory. A web application, e-schizo(©) has been created to record data in a common computerized medical file. This network offers systematic, comprehensive, longitudinal, and multi-dimensional assessments of cases including a medical workup and an exhaustive neuropsychological evaluation. This strategy offers an effective way to transfer knowledge and share expertise. This network is a great opportunity to improve the global patient care and is conceived as being an infrastructure for research from observational cohort to translational research., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Impairments in selective attention have been proposed as an explanation for the source monitoring deficits in schizophrenia. We tested this hypothesis by examining correlations between source monitoring variables and a measure of selective attention (from the Stroop Test) in 54 individuals with schizophrenia subjects and 42 normal controls. We did not find significant correlations between source monitoring measures and selective attention. Selective attention impairments do not explain source monitoring deficits observed in schizophrenia. Source monitoring deficits deserve continued efforts to elucidate their causes and consequences.

SOURCE MONITORING FRAMEWORK: Source monitoring refers to the ability to remember the origin of information. Three source monitoring processes can be distinguished: external source monitoring, internal or self-monitoring and reality monitoring (i.e. discrimination between internal and external sources of information). Source monitoring decisions are based on memory characteristics recorded such as perceptions, contextual information or emotional reactions and heuristic or more controlled judgement processes., Brain Structures: Several studies suggested that specific structures in the prefrontal and the mediotemporal lobes are the main areas implicated in source monitoring., Assessment: A typical source monitoring paradigm includes an items generation stage and a second stage of recognition of items (old versus new) and identification of their sources: external (usually the examiner) or internal (the subject). Several indices can be calculated based on the raw data such as the number of false alarms, attribution biases or discrimination indexes. To date, there is no standardized source monitoring task and differences in the type of items used (words, pictures), in the cognitive or emotional effort involved or in the delay between the two test stages, contribute to the heterogeneity of results., Factors Influencing Source Monitoring: Factors such as age (either very young or very old) and emotions influence source monitoring performances. Influence of gender was not properly explored, whereas the role of IQ and selective attention is still debated., Source Monitoring Deficits in Neurological Disorders: Source monitoring deficits are observed mainly in disorders affecting frontotemporal areas, such as frontal trauma, Alzheimer's disease or frontotemporal dementia., Source Monitoring and Schizophrenia: Source monitoring errors (e.g. external misattribution of self-generated information) are observed in schizophrenia and seem to correlate with positive symptomatology, in particular auditory hallucinations, thought intrusion and alien control symptoms. These results are of particular interest in clinical research because source monitoring is one of the rare cognitive tests showing a correlation with the positive dimension. Source monitoring deficits have been proposed as a potential explanation for the positive symptoms and some, but not all studies lent support to this hypothesis. Heterogeneity of studied samples, in particular different criteria to define hallucinating subjects (e.g. currently versus anytime during their lives), could explain the discordant results., Source Monitoring in Psychiatric Disorders Within the Schizophrenic Spectrum: Source monitoring impairments were observed in pharmacological models of psychosis, in first degree relatives of schizophrenic patients, and also in the general population associated with schizotypal dimensions. These results support a relationship between source monitoring deficits and some of the symptomatic dimensions of the schizophrenic spectrum but still await replication., Source Monitoring and Other Psychiatric Disorders: Some studies found source monitoring deficits in other psychiatric conditions such as mania or obsessive-compulsive disorder. Thus, those studies suggest that source monitoring deficits may be not specific to schizophrenia., Conclusion: Source monitoring competencies are critical for good (i.e. adapted) everyday functioning. Source monitoring deficits have been suggested as a potential explanation for some (or all) positive psychotic symptoms. However, to date, methodological inconsistencies (especially with regard to test design and choice of subjects' samples) have precluded firm, definite conclusions., (Copyright © 2010 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)