Incidence and predictors of metabolic syndrome onset in individuals with bipolar disorders: A longitudinal study from the FACE-BD cohort.

INTRODUCTION: Metabolic syndrome (MetS) is a cluster of components including abdominal obesity, hyperglycemia, hypertension, and dyslipidemia. MetS is highly prevalent in individuals with bipolar disorders (BD) with an estimated global rate of 32.6%. Longitudinal data on incident MetS in BD are scarce and based on small sample size. The objectives of this study were to estimate the incidence of MetS in a large longitudinal cohort of 1521 individuals with BD and to identify clinical and biological predictors of incident MetS. METHODS: Participants were recruited from the FondaMental Advanced Center of Expertise for Bipolar Disorder (FACE-BD) cohort and followed-up for 3 years. MetS was defined according to the International Diabetes Federation criteria. Individuals without MetS at baseline but with MetS during follow-up were considered as having incident MetS. A logistic regression model was performed to estimate the adjusted odds ratio and its corresponding 95% confidence interval (CI) for an association between each factor and incident MetS during follow-up. We applied inverse probability-of-censoring weighting method to minimize selection bias due to loss during follow-up. RESULTS: Among individuals without MetS at baseline (n = 1521), 19.3% developed MetS during follow-up. Multivariable analyses showed that incident MetS during follow-up was significantly associated with male sex (OR = 2.2, 95% CI = 1.7-3.0, p < 0.0001), older age (OR = 2.14, 95% CI = 1.40-3.25, p = 0.0004), presence of a mood recurrence during follow-up (OR = 1.91, 95% CI = 1.22-3.00, p = 0.0049), prolonged exposure to second-generation antipsychotics (OR = 1.56, 95% CI = 0.99, 2.45, p = 0.0534), smoking status at baseline (OR = 1.30, 95% CI = 1.00-1.68), lifetime alcohol use disorders (OR = 1.33, 95% CI = 0.98-1.79), and baseline sleep disturbances (OR = 1.04, 95% CI = 1.00-1.08), independently of the associations observed for baseline MetS components. CONCLUSION: We observed a high incidence of MetS during a 3 years follow-up (19.3%) in individuals with BD. Identification of predictive factors should help the development of early interventions to prevent or treat early MetS.

Multimorbidity and the Etiology of Schizophrenia.

PURPOSE OF REVIEW: A global study of multimorbidity in schizophrenia, especially of the association with physical conditions, might offer much needed etiological insights. RECENT FINDINGS: Our review suggests that life-style factors and medication related to schizophrenia are only part of the explanation of the increase in risk for cardiovascular, metabolic, pulmonary disorders, and some cancers. Positive associations with autoimmune disorders (with the exception of rheumatoid arthritis) and epilepsy are promising avenues of research but to date have not been fully exploited. The same holds for the negative comorbidity seen for rheumatoid arthritis and some cancers (e.g., prostate). As a whole, our review suggests that most of the explored conditions have a different prevalence in schizophrenia than in the general population. Several hypotheses emerged from this review such as the role of immune and genetic factors, of sex hormones, and of more general variability factors.

The impact of parent history of severe mental illness on schizophrenia outcomes: results from the real-world FACE-SZ cohort.

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

Early-life factors associated with increased risk of disability pension in the national real-world schizophrenia FACE-SZ cohort study.

Among severe psychiatric disorders, schizophrenia has one of the highest impacts on professional and personal functioning with important indirect costs including disability pension allowance for the patients with the more severe forms of schizophrenia. To explore early-life factors associated with disability pension in schizophrenia. 916 patients were consecutively recruited at a national level in 10 expert centers and received a comprehensive standardized evaluation. Their disability pension status and early-life variables were reported from medical records and validated scales. Eight factors were explored: age, male sex, parental history of severe mental illness, childhood trauma exposure, education level, childhood ADHD, early age at schizophrenia onset and duration of untreated psychosis. 739 (80.7%) participants received a disability pension. In the multivariate model, early age at schizophrenia onset and low education level were associated with disability pension independently of age and sex while no significant association was found for parent history of severe mental illness, childhood trauma, childhood ADHD or duration of untreated psychosis. Low education level and early age at schizophrenia onset seem the best predictors of increased risk of disability pension in schizophrenia.

Chronic low-grade peripheral inflammation is associated with ultra resistant schizophrenia. Results from the FACE-SZ cohort.

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.

Towards an improved access to psychiatric rehabilitation: availability and effectiveness at 1-year follow-up of psychoeducation, cognitive remediation therapy, cognitive behaviour therapy and social skills training in the FondaMental Advanced Centers of Expertise-Schizophrenia (FACE-SZ) national cohort.

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.

[The 10-year findings from the FondaMental Academic Center of Expertise for Schizophrenia (FACE-SZ): Review and recommendations for clinical practice]. / Centres Experts Schizophrénie, un outil pour le soin et la recherche : retour sur 10 ans d'expérience.

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.

Metabolic syndrome and actigraphy measures of sleep and circadian rhythms in bipolar disorders during remission.

OBJECTIVE: This study explored the correlations between sleep and circadian rhythm measures and the metabolic syndrome (MetS) components in remitted patients with bipolar disorder (BD). METHOD: Euthymic patients with BD (n = 67) were recorded by 3 weeks with actigraphy. We used nonparametric correlations to study the links between the MetS parameters, atherogenic index of plasma (AIP), sleep efficacy, sleep latency, fragmentation index, and phase and amplitude of rhythms. We performed multivariable analyses to take into account potential confounding factors such as sleep apnea risk, antipsychotics use, and smoker status. RESULTS: We found correlations between lower sleep efficiency and higher triglyceride levels (P = 0.002), lower M10 onset (beginning of the 10 most active hours during the 24-h cycle) and higher systolic blood pressure (P = 0.03), higher fragmentation index and higher systolic blood pressure (P = 0.009), lower sleep efficiency, higher fragmentation index, and higher AIP (respectively P = 0.02 and P = 0.04). These correlations mostly remained significant when adjusting for confounders, with the exception of M10 onset and systolic blood pressure. CONCLUSION: Sleep efficiency and fragmentation index might contribute to the cardiovascular risk of patients with BD independently of major confounding factors. Although these associations did not imply causality, proposing interventions on sleep quality and circadian rhythm regularity might contribute to reduce cardiovascular risk in patients with BD.

Benzodiazepine long-term administration is associated with impaired attention/working memory in schizophrenia: results from the national multicentre FACE-SZ data set.

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.

Relationships between low-grade peripheral inflammation and psychotropic drugs in schizophrenia: results from the national FACE-SZ cohort.

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.

Chronic low-grade peripheral inflammation is associated with severe nicotine dependence in schizophrenia: results from the national multicentric FACE-SZ cohort.

Chronic peripheral inflammation (CPI) has been associated with cognitive impairment in schizophrenia (SZ). However, its sources remain unclear, more specifically it is not known whether tobacco smoking is a source of inflammation or not in SZ subjects. Moreover, nicotine (NIC), the major psychoactive compound of tobacco, shows strong anti-inflammatory properties in vitro, as well as inducing a severe biological dependence when administered repeatedly. The objective of the present study was to determine if CPI was associated with tobacco smoking and/or NIC dependence in schizophrenia. Three hundred and forty five stabilized community-dwelling SZ subjects aged 16 years or older (mean age = 32 years, 73% male) were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia and assessed with validated scales. CPI was defined by a highly sensitive C-reactive protein (hsCRP) ≥3 mg/L. Current tobacco status was self-declared. Severe NIC dependence was defined by a Fagerstrom Test for Nicotine Dependence score ≥7. Overall, 159 (46.1%) were non-smokers, 117 (33.9%) and 69 (20%) were current tobacco smokers with, respectively, low and severe nicotine dependence. In a multivariate model, CPI remained associated with severe NIC dependence (29 vs 15%, OR = 2.8, p = 0.003) and body mass index (OR = 1.1, p < 0.0001), independently of socio-demographic characteristics and antidepressant intake. No association of CPI with low to moderate tobacco smoking dependence, number of daily smoked cigarettes, cannabis use, alcohol use or illness characteristics was found (all p > 0.05). CPI was associated with severe NIC dependence but not with tobacco smoking with low to moderate NIC dependence in SZ, independently of socio-demographic variables, body mass index, alcohol consumption and antidepressant intake. This result highlights the potential CPI consequences of the high prevalence of heavy tobacco smoking in SZ, indicating the importance of new therapeutic strategies for tobacco cessation in SZ.

Birth by cesarean section and schizophrenia: results from the multicenter FACE-SZ data-set.

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.

[Metabolic syndrome and bipolar disorder: Is sleep the missing link?] / Syndrome métabolique et troubles bipolaires : le sommeil est-il le chaînon manquant ?

OBJECTIVE: To examine the pathophysiologic mechanisms that may link circadian disorder and metabolic syndrome in bipolar disorder (BP). METHOD: A systematic review of the literature was conducted from January 2013 to January 2015, using the Medline and Cochrane databases, using the keywords "metabolic syndrome", "obesity", "leptin" and "circadian disorders", "sleeping disorders" and cross-referencing them with "bipolar disorder". The following types of publications were candidates for review: (i) clinical trials; (ii) studies involving patients diagnosed with bipolar disorder; (iii) studies involving patients with sleeping disorder; or (iv) data about metabolic syndrome. RESULTS: Forty articles were selected. The prevalence of metabolic syndrome in BP was significantly higher compared to the general population (from 36 to 49% in the USA [Vancampfort, 2013]), and could be explained by several factors including reduced exercise and poor diet, genetic vulnerability, frequent depressive episodes, psychiatric comorbidity and psychotropic treatment. This high frequency of metabolic syndrome worsens the prognosis of these patients, increasing morbidity and mortality. Secondly, patients with BP experienced circadian and sleep disturbance, including modification in melatonin secretion. These perturbations are known to persist in periods of mood stabilization and are found in patients' relatives. Circadian disturbances are factors of relapse in bipolar patients, and they may also have a role in the metabolic comorbidities of these patients. Recent studies show that in populations of patients with bipolar disorder, a correlation between circadian disturbance and metabolic parameters are found. To identify the pathophysiological pathway connecting both could lead to a better comprehension of the disease and new therapeutics. In the overall population, mechanisms have been identified linking circadian and metabolic disorder involving hormones like leptin and ghrelin. These hormones are keys to regulation of energy balance in the organism, via their action on the hypothalamus, and are also regulated by sleep. We have hypothesized that these pathways could be implicated in the vulnerability of bipolar patients to metabolic syndrome. This hypothesis is supported by several studies showing dysregulation in leptin and ghrelin secretion in multiple psychiatric disorders, including bipolar disorder, as well as genetic variations of leptin and ghrelin genes in these diseases. We also assume that other mechanisms may be at stake to explain this link, such as melatonin dysregulation and inflammation. CONCLUSIONS: Circadian and sleeping disorder may have a role in the prevalence of metabolic syndrome in BP. Hormones like leptin and ghrelin could be the link between these perturbations. Prevention and treatment of circadian disorder in BP may greatly reduce the occurrence of MetS in these patients. Being aware of this statement and taking care of these troubles should be a big step forward for treatment of BP.

3-year incidence and predictors of metabolic syndrome in schizophrenia in the national FACE-SZ cohort.

AIMS: Metabolic Syndrome (MetS) is a major health epidemic of Western countries and patients with schizophrenia is a particularly vulnerable population due to lifestyle, mental illness and treatment factors. However, we lack prospective data to guide prevention. The aim of our study is then to determine MetS incidence and predictors in schizophrenia. METHOD: Participants were recruited in 10 expert centers at a national level and followed-up for 3 years. MetS was defined according to the International Diabetes Federation criteria. Inverse probability weighting methods were used to correct for attrition bias. RESULTS: Among the 512 participants followed-up for 3 years, 77.9% had at least one metabolic disturbance. 27.5% were identified with MetS at baseline and excluded from the analyses. Among the rest of participants (N = 371, mean aged 31.2 (SD = 9.1) years, with mean illness duration of 10.0 (SD = 7.6) years and 273 (73.6%) men), MetS incidence was 20.8% at 3 years and raised to 23.6% in tobacco smokers, 29.4% in participants receiving antidepressant prescription at baseline and 42.0% for those with 2 disturbed metabolic disturbances at baseline. Our multivariate analyses confirmed tobacco smoking and antidepressant consumption as independent predictors of MetS onset (adjusted odds ratios (aOR) = 3.82 [1.27-11.45], p = 0.016, and aOR = 3.50 [1.26-9.70], p = 0.0158). Antidepressant prescription predicted more specifically increased lipid disturbances and paroxetine was associated with the highest risk of MetS onset. CONCLUSION: These results are an alarm call to prioritize MetS prevention and research in schizophrenia. We have listed interventions that should be actively promoted in clinical practice.

Key findings on bipolar disorders from the longitudinal FondaMental Advanced Center of Expertise-Bipolar Disorder (FACE-BD) cohort.

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

Influence of childhood maltreatment on prevalence, onset, and persistence of psychiatric comorbidities and suicide attempts in bipolar disorders.

BACKGROUND: Psychiatric comorbidities and suicide attempts are highly prevalent in Bipolar Disorders (BD). We examined the associations between childhood maltreatment, psychiatric comorbidities, and suicide attempts, in terms of lifetime prevalence, sequence of onset, and current symptoms. METHODS: We assessed 3,047 individuals with BD for suicide attempts, anxiety disorders, substance use disorders, and eating disorders. Participants completed a self-report for the assessment of childhood maltreatment. Associations between childhood maltreatment and characteristics of comorbidities (lifetime prevalence, current symptoms, and age at onset) were examined using logistic regressions and network analyses. RESULTS: Psychiatric comorbidities were frequent with a mean number per individual of 1.23 (SD = 1.4). Most comorbidities occurred prior to the onset of BD. Participants who reported higher levels of childhood maltreatment had more frequent and multiple comorbidities, which were also more currently active at inclusion. Childhood maltreatment did not decrease the age of onset of comorbidities, but was associated with a faster accumulation of comorbidities prior to the onset of BD. Logistic regression and network analyses showed that emotional abuse and sexual abuse might play a prominent role in the lifetime prevalence of psychiatric comorbidities and suicide attempts. CONCLUSIONS: Childhood maltreatment was associated with suicide attempts, and with frequent, multiple, and persistent psychiatric comorbidities that accumulated more rapidly prior to the onset of BD. Hence, childhood maltreatment should be systematically assessed in individuals with BD, in particular when the course of the disorder is characterized by a high comorbid profile or by a high suicidality.

Clinical predictors of recurrences in bipolar disorders type 1 and 2: A FACE-BD longitudinal study.

OBJECTIVE: To examine which characteristics predict the time to a first mood recurrence at three years in Bipolar Disorder type I (BD-I) and type II (BD-II). METHODS: Individuals with BD were followed up to 3 years. Turbull's extension of the Kaplan-Meier analysis for interval-censored data was used to estimate the cumulative probability of recurrence over time. Separate models were performed according to BD subtype to determine which baseline factors were predictive of recurrences and were adjusted for age, gender and educational level. RESULTS: We included 630 individuals with BD-I and 505 with BD-II. The first recurrence of any polarity occurred earlier in BD-II (p = 0.03). The first depressive recurrence occurred earlier in BD-II (p < 0.0001), whereas the first (hypo)manic recurrence occurred earlier in BD-I (p = 0.0003). In BD-I, the clinical variables that were associated to the time to a first mood recurrence were depressive symptoms, lifetime rapid cycling, global activation and the number of psychotropic medications at baseline. In BD-II, the time to a first recurrence was associated with a younger age at onset of BD and a higher number of lifetime mood episodes. The Areas Under the Curve for both models were moderate. CONCLUSION: Predictors of recurrences showed few specificities to BD-I or BD-II. The ability to predict recurrences in BD based on socio-demographic and clinical variables remained too moderate for a transfer in daily practice. This study highlights the need for further studies that would include other types of predictors, such as molecular, cognitive or neuro-imaging ones, to achieve an accurate level of prediction of recurrences in BD.

Towards precision medicine: What are the stratification hypotheses to identify homogeneous inflammatory subgroups.

Diverse lines of research testify a link, presumably causal, between immune dysregulation and the development, course and clinical outcome of psychiatric disorders. However, there is a large heterogeneity among the patients' individual immune profile and this heterogeneity prevents the development of precise diagnostic tools and the identification of therapeutic targets. The aim of this review was to delineate possible subgroups of patients on the basis of clinical dimensions, investigating whether they could lead to particular immune signatures and tailored treatments. We discuss six clinical entry points; genetic liability to immune dysregulation, childhood maltreatment, metabolic syndrome, cognitive dysfunction, negative symptoms and treatment resistance. We describe the associated immune signature and outline the effects of anti-inflammatory drugs so far. Finally, we discuss advantages of this approach, challenges and future research directions.

Redefining peripheral inflammation signature in schizophrenia based on the real-world FACE-SZ cohort.

BACKGROUND: Peripheral inflammation is associated with impaired prognosis in schizophrenia (SZ). Highly sensitive C-reactive protein (hs-CRP) is the most used inflammatory biomarker in daily practice. However, no consensual cut-off has been determined to date to discriminate patients with peripheral inflammation from those without. AIMS: To determine if patients with peripheral inflammation between 1 and 3 mg/L had poorer outcomes compared to those with undetectable CRP (<1 mg/L). METHOD: Consecutive participants of the FACE-SZ cohort with a hs-CRP < 3 mg/L were included in 10 expert academic centers with a national geographical distribution between 2010 and 2018. Potential sources of inflammation, socio-demographics, illness characteristics, current illness severity, functioning and quality of life and were reported following the FACE-SZ standardized protocol. RESULTS: 580 patients were included, of whom 226 (39%) were identified with low-grade inflammation defined by a hs-CRP between 1 and 3 mg/L. Overweight and lack of dental care were identified as potential sources of inflammation. After adjustment for these factors, patients with inflammation had more severe psychotic, depressive and aggressive symptomatology and impaired functioning compared to the patients with undetectable hs-CRP. No association with tobacco smoking or physical activity level has been found. CONCLUSIONS: Patients with schizophrenia with hs-CRP level between 1 and 3 mg/L should be considered at risk for inflammation-associated disorders. Lowering weight and increasing dental care may be useful strategies to limit the sources of peripheral inflammation. Hs-CRP > 1 mg/L is a reliable marker to detect peripheral inflammation in patients with schizophrenia.

Recommendations of the schizophrenia expert center network for the screening prevention and treatment of sleep disorders based on the results from the real-world schizophrenia FACE-SZ national cohort.

BACKGROUND: Sleep disorders associated factors are under explored in schizophrenia while the literature suggests high and heterogeneous frequency. AIMS: The objective of the present study was to determine the prevalence and risk factors of sleep disorders in the real-world FACE-SZ national cohort. METHOD: Stabilized schizophrenic outpatients were recruited in 10 expert centers for schizophrenia. Sleep quality was explored with the Pittsburgh Sleep Quality Index (PSQI) and sleep disorders was defined by a PSQI score > 5. Psychosis severity was measured with the Positive and Negative Syndrome Scale, current major depressive episode with the Calgary Depression Scale for Schizophrenia, verbal aggressiveness with the Buss-Perry Aggression Questionnaire, adherence to treatment with the Medication Adherence Rating Scale, akathisia with the Barnes Akathisia Scale. Current somatic comorbidities and body mass index were reported. Variables with P values <0.20 in univariate analysis were included in a multivariate regression model. RESULTS: Of the 562 included patients, 327 subjects (58.2%, IC95% [54.1% - 62.3%]) reported having sleep disorders. After adjustment, sleep disorders were significantly associated with migraine (adjusted odds ratio aOR = 2.23, p = 0.041), major depressive disorder (aOR 1.79, p = 0.030), poor adherence to treatment (aOR = 0.87, p = 0.006), akathisia (aOR = 1.29, p = 0.042) and verbal aggressiveness (aOR = 1.09, p = 0.002). CONCLUSIONS: More than one on two stabilized real-life outpatients with schizophrenia have been identified with sleep disorders. Combined with the literature data, we have yielded expert recommendations for the treatment and prevention of sleep disorders including treating undiagnosed comorbid depression and migraine and managing antipsychotic treatment to improve adherence and akathisia.