Prodromal or mild Alzheimer's disease: Influence of neuropsychiatric symptoms and premordid personality on caregivers' burden.

OBJECTIVE: In Alzheimer's disease (AD), the burden on caregivers is influenced by various factors, including the stage of disease progression and neuropsychiatric symptoms (NPS). To date, there has been limited research examining how patient's premorbid personality could affect this burden. The objective of this study was to investigate the impact of both premorbid personality and NPS in individuals with prodromal to mild AD on their caregivers' burden. METHOD: One hundred eighty participants with prodromal or mild AD drown from the PACO (in French: Personnalité Alzheimer COmportement) cohort were included. Personality was assessed by the Revised NEO Personality Inventory (NEO-PI-R). Neuropsychiatric symptoms were measured with the short version of the Neuropsychiatric Inventory (NPI-Q), and caregiver burden was evaluated with the Zarit burden scale. Relationships between personality, Neuro-Psychiatric Inventory (NPI) scores, and caregiver burden were determined using multivariate linear regressions controlled for age, sex, educational level, and Mini Mental State Examination. RESULTS: The total NPI score was related to increased burden (beta = 0.45; p < 0.001). High level of neuroticism (beta = 0.254; p = 0.003) et low level of conscientiousness (beta = - 0.233; p = 0.005) were associated higher burden. Extraversion (beta = -0.185; p = 0.027) and conscientiousness (beta = -0.35; p = 0.006) were negatively associated with burden. In contrast, neuroticism, openness and agreeableness were not correlated with burden. When adjusted on total NPI score, the relationship between extraversion and conscientiousness didn't persist. CONCLUSION: Our results suggest that premorbid personality of patients with prodromal to mild Alzheimer influence caregivers's burden, with a protective effect of a high level of extraversion and conscientiousness.

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.

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.

Clinical guidelines for the management of treatment-resistant depression: French recommendations from experts, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental.

BACKGROUND: Clear guidance for successive antidepressant pharmacological treatments for non-responders in major depression is not well established. METHOD: Based on the RAND/UCLA Appropriateness Method, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental developed expert consensus guidelines for the management of treatment-resistant depression. The expert guidelines combine scientific evidence and expert clinicians' opinions to produce recommendations for treatment-resistant depression. A written survey comprising 118 questions related to highly-detailed clinical presentations was completed on a risk-benefit scale ranging from 0 to 9 by 36 psychiatrist experts in the field of major depression and its treatments. Key-recommendations are provided by the scientific committee after data analysis and interpretation of the results of the survey. RESULTS: The scope of these guidelines encompasses the assessment of pharmacological resistance and situations at risk of resistance, as well as the pharmacological and psychological strategies in major depression. CONCLUSION: The expert consensus guidelines will contribute to facilitate treatment decisions for clinicians involved in the daily assessment and management of treatment-resistant depression across a number of common and complex clinical situations.

Clinical guidelines for the management of depression with specific comorbid psychiatric conditions French recommendations from experts (the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental).

BACKGROUND: Recommendations for pharmacological treatments of major depression with specific comorbid psychiatric conditions are lacking. METHOD: The French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental developed expert consensus guidelines for the management of depression based on the RAND/UCLA Appropriatneness Method. Recommendations for lines of treatment are provided by the scientific committee after data analysis and interpretation of the results of a survey of 36 psychiatrist experts in the field of major depression and its treatments. RESULTS: The expert guidelines combine scientific evidence and expert clinician's opinion to produce recommendations for major depression with comorbid anxiety disorders, personality disorders or substance use disorders and in geriatric depression. CONCLUSION: These guidelines provide direction addressing common clinical dilemmas that arise in the pharmacologic treatment of major depression with comorbid psychiatric conditions.

[The serotonin syndrome: An updated literature review]. / Le syndrome sérotoninergique : une revue actualisée de la littérature.

The serotonin syndrome is a potentially deadly complication resulting from drug adverse effect, drug-drug interaction or overdose involving one or more serotonergic molecules, e.g., antidepressants, psychostimulants and sometimes an "ignored" serotonergic compound. The serotonin syndrome typically consists of a clinical triad including cognitive/behavioral, neurovegetative and neuromuscular features. However, this syndrome is characterized by major clinical heterogeneity, making the diagnosis difficult in practice. Moreover, many practitioners are quite unaware of this syndrome. Available scores and classifications can help physicians in their diagnosis approach. Knowing the responsible molecules, their potential interactions and mechanisms of action can help preventing this complication allowing therapeutic education among patients. This updated article reviews the clinical presentation, prevention, management, and pathophysiology of the serotonin syndrome, and addresses the most recent advances in pharmacogenetics regarding this syndrome.

Childhood trauma, depression and negative symptoms are independently associated with impaired quality of life in schizophrenia. Results from the national FACE-SZ cohort.

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 (ß=-0.21, p<0.0001), psychotic negative symptoms (ß=-0.11, p=0.04), current depression (ß=-0.0.38, p<0.0001) and male gender (ß=-0.16, p<0.0001). CONCLUSION: Impaired QoL is independently associated with negative symptoms, depression and childhood trauma in schizophrenia.

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.

Differential effects of childhood trauma and cannabis use disorders in patients suffering from schizophrenia.

BACKGROUND: Childhood trauma (CT) and cannabis use are both environmental and modifier risk factors for schizophrenia. However, little is known about how they interact in schizophrenia. We examined the main effect of each of these two environmental factors on the clinical expression of the disease using a large set of variables, and we tested whether and how cannabis and CT interact to influence the course and the presentation of the illness. METHODS: A sample of 366 patients who met the DSM-IV-TR criteria for schizophrenia was recruited through the FACE-SCZ (Fondamental Advanced Centre of Expertise - Schizophrenia) network. Patients completed a large standardized clinical evaluation including Structured Clinical Interview for DSM Disorders-I (SCID-I), Positive and Negative Symptoms Scale (PANSS), Columbia-Suicide Severity Rating Scale (C-SSRS), Global Assessment of Functioning (GAF), Short-Quality of Life-18 (S-QoL-18), and Medication Adherence Rating Scale (MARS). We assessed CT with the Childhood Trauma Questionnaire and cannabis status with SCID-I. RESULTS: CT significantly predicted the number of hospitalizations, GAF, and S-QoL-18 scores, as well as the PANSS total, positive, excitement, and emotional distress scores. Cannabis use disorders significantly predicted age of onset, and MARS. There was no significant interaction between CT and cannabis use disorders. However, we found evidence of a correlation between these two risk factors. CONCLUSIONS: CT and cannabis both have differential deleterious effects on clinical and functional outcomes in patients with schizophrenia. Our results highlight the need to systematically assess the presence of these risk factors and adopt suitable therapeutic interventions.

Medication and aggressiveness in real-world schizophrenia. Results from the FACE-SZ dataset.

INTRODUCTION: The primary objective of this study was to determine if second-generation antipsychotic (SGA) administration was associated with lower aggressiveness scores compared to first-generation (FGA) in schizophrenia (SZ). The secondary objective was to determine if antidepressants, mood stabilizers, and benzodiazepines administration were respectively associated with lower aggressiveness scores compared to patients who were not administered these medications. METHODS: Three hundred thirty-one patients with schizophrenia (N = 255) or schizoaffective disorder (N = 76) (mean age = 32.5 years, 75.5 % male gender) were systematically included in the network of FondaMental Expert Center for Schizophrenia and assessed with the structured clinical interview for DSM-IV Axis I disorders and validated scales for psychotic symptomatology, insight, and compliance. Aggressiveness was measured by the Buss-Perry Aggression Questionnaire (BPAQ) score. Ongoing psychotropic treatment was recorded. RESULTS: Patients who received SGA had lower BPAQ scores than patients who did not (p = 0.01). More specifically, these patients had lower physical and verbal aggression scores. On the contrary, patients who received benzodiazepines had higher BPAQ scores than patients who did not (p = 0.04). No significant difference was found between BPAQ scores of patients respectively being administered mood stabilizers (including valproate), antidepressant, and the patients who were not. These results were found independently of socio-demographical variables, psychotic symptomatology, insight, compliance into treatment, daily-administered antipsychotic dose, the way of antipsychotic administration (oral vs long acting), current alcohol disorder, and daily cannabis consumption. CONCLUSION: The results of the present study are in favor of the choice of SGA in SZ patients with aggressiveness, but these results need further investigation in longitudinal studies. Given the potent side effects of benzodiazepines (especially dependency and cognitive impairment) and the results of the present study, their long-term prescription is not recommended in patients with schizophrenia and aggressive behavior.

Peripheral sub-inflammation is associated with antidepressant consumption in schizophrenia. Results from the multi-center FACE-SZ data set.

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.

Akathisia: prevalence and risk factors in a community-dwelling sample of patients with schizophrenia. Results from the FACE-SZ dataset.

The main objective of this study was to determine the prevalence of akathisia in a community-dwelling sample of patients with schizophrenia, and to determine the effects of treatments and the clinical variables associated with akathisia. 372 patients with schizophrenia or schizoaffective disorder were systematically included in the network of FondaMental Expert Center for Schizophrenia and assessed with validated scales. Akathisia was measured with the Barnes Akathisia Scale (BAS). Ongoing psychotropic treatment was recorded. The global prevalence of akathisia (as defined by a score of 2 or more on the global akathisia subscale of the BAS) in our sample was 18.5%. Patients who received antipsychotic polytherapy were at higher risk of akathisia and this result remained significant (adjusted odd ratio=2.04, p=.025) after controlling the influence of age, gender, level of education, level of psychotic symptoms, substance use comorbidities, current administration of antidepressant, anticholinergic drugs, benzodiazepines, and daily-administered antipsychotic dose. The combination of second-generation antipsychotics was associated with a 3-fold risk of akathisia compared to second-generation antipsychotics used in monotherapy. Our results indicate that antipsychotic polytherapy should be at best avoided and suggest that monotherapy should be recommended in cases of akathisia. Long-term administration of benzodiazepines or anticholinergic drugs does not seem to be advisable in cases of akathisia, given the potential side effects of these medications.

Metabolic syndrome, abdominal obesity and hyperuricemia in schizophrenia: Results from the FACE-SZ cohort.

OBJECTIVE: Abdominal obesity was suggested to be a better predictor than Metabolic Syndrome (MetS) for cardiovascular mortality, however this is has not been extensively studied in schizophrenia. Hyperuricemia (HU) was also suggested to be both an independent risk factor for greater somatic comorbidity and a global metabolic stress marker in patients with schizophrenia. The aim of this study was to estimate the prevalence of MetS, abdominal obesity and HU, to examine the association between metabolic parameters with HU in a cohort of French patients with schizophrenia or schizo-affective disorder (SZ), and to estimate the prevalence rates of treatment of cardio-vascular risk factors. METHOD: 240 SZ patients (age=31.4years, male gender 74.3%) were systematically included. Metabolic syndrome was defined according to the International Diabetes Federation and HU if serum uric acid level was above 360µmol/L. RESULTS: MetS, abdominal obesity and HU were found respectively in 24.2%, 21.3% and 19.6% of patients. In terms of risk factors, multiple logistic regression showed that after taking into account the potential confounders, the risk for HU was higher in males (OR=5.9, IC95 [1.7-21.4]) and in subjects with high waist circumference (OR=3.1, IC95 [1.1-8.3]) or hypertriglyceridemia (OR=4.9, IC95 [1.9-13]). No association with hypertension, low HDL cholesterol or high fasting glucose was observed. Only 10% of patients with hypertension received a specific treatment, 18% for high fasting glucose and 8% for dyslipidemia. CONCLUSIONS: The prevalence of MetS, abdominal obesity and hyperuricemia is elevated in French patients with schizophrenia, all of which are considerably under-diagnosed and undertreated. HU is strongly associated with abdominal obesity but not with psychiatric symptomatology.