A. Zinetti-Bertschy

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.

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.

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 (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.

Influence of Venus and Mars in the cognitive sky of schizophrenia. Results from the first-step national FACE-SZ cohort

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.

Cigarette smoking and schizophrenia: a specific clinical and therapeutic profile? Results from the FACE-Schizophrenia cohort

BACKGROUND Tobacco use is common in patients with schizophrenia (SZ) but little is known on the role of tobacco in the physiopathology or on the course of the disease. Only few studies embrace an extensive examination of clinical and therapeutic characteristics in stabilized patients. The objective of the present study was to determine the prevalence of tobacco smoking in stabilized SZ outpatients and the clinical and treatment characteristics associated with daily tobacco use in a large community-dwelling sample of patients. METHODS Three-hundred-and-sixty-one patients were included in the network of the FondaMental Expert Centers for Schizophrenia. Current tobacco status was self-declared. RESULTS 53.7% were smokers. Mean age at tobacco onset was 17.2years old. In multivariate analyses, after adjustment for confounding factors, positive symptoms and mean daily antipsychotic dose were associated with a higher frequency of tobacco use (OR=1.06 95%IC[1.02-1.12], for positive symptoms, OR=1.1, 95%IC[1.02-1.18] for daily antipsychotic dose). Education level, negative symptoms, anticholinergic agents, clozapine or aripiprazole administration were independently associated with a lower frequency of tobacco use (respectively OR=0.87, 95%IC [0.79, 0.95], OR=0.95, 95%IC[0.91-0.98], OR=0.41, 95%IC[0.22-0.76], OR=0.56, 95%IC=[0.32, 0.99] and OR=0.49, 95%IC [0.26-0.91]). CONCLUSION The prevalence of current tobacco smoking in a French community-dwelling SZ patients is higher that observed in the general population. Patients with tobacco use present clinical and therapeutic specificities that may involve interaction between cholinergic-nicotinic and dopaminergic systems. The present study suggests that some therapeutics may improve daily smoking behavior in smokers. These results should be confirmed in longitudinal studies.

Psychiatric disability as mediator of the neurocognition-functioning link in schizophrenia spectrum disorders: SEM analysis using the Evaluation of Cognitive Processes involved in Disability in Schizophrenia (ECPDS) scale

The functional outcome in schizophrenia spectrum disorders is affected by multiple factors such as cognitive performance and clinical symptoms. Psychiatric disability may be another important determinant of functional outcome. The purpose of this study was to test whether schizophrenia symptoms and psychiatric disability mediated the association between cognition and functioning. Between April 2013 and July 2017, we included 108 community-dwelling adults with stable schizophrenia spectrum disorder in a multicenter study. Psychiatric disability was assessed with the Evaluation of Cognitive Processes involved in Disability in Schizophrenia (ECPDS) scale by relatives of patients. ECPDS focused on the broad array of motivational, neurocognitive, sociocognitive, and metacognitive impairments that result in activity restrictions. We used a battery of tests to assess seven cognition domains (processing speed, attention/vigilance, working, verbal and visual memory, reasoning and problem solving, and executive functioning) and cross-sectional structural equation modeling (SEM) for the mediation analyses. We estimated the one-year temporal stability of ECPDS scores in 45 participants. The model provided showed good fit and explained 43.9% of the variance in functioning. The effect of neurocognition on functioning was fully mediated by symptoms (proportion mediated: 36.5%) and psychiatric disability (proportion mediated: 31.3%). The ECPDS score had acceptable one-year temporal stability. The ECPDS scale has satisfactory psychometric properties, and shows significant convergence with neurocognition and functioning, suggesting a role for this tool in the routine evaluation of cognitive remediation needs. Our model validates psychiatric disability as a crucial step from cognitive impairment to restricted participation in life situations.

Latent toxoplasma infection in real-world schizophrenia: Results from the national FACE-SZ cohort

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.

A multi-dimensional approach to the relationship between insight and aggressiveness in schizophrenia: Findings from the FACE-SZ cohort.

BACKGROUND Aggressiveness is a stigma frequently associated with schizophrenia. The role of insight as a risk factor of aggressiveness remains contradictory; mainly because single measures of these states mask their complexity and heterogeneity. METHODS This study was conducted on 666 patients aged 15 and above with a DSM-IV-TR diagnosis of schizophrenia spectrum disorder, drawn from the French national network of schizophrenia expert center database. Collected data comprised socio-demographics and standardized psychiatric assessments. Aggressiveness was evaluated using the Buss-Perry Aggression Questionnaire and insight using the Scale to assess Unawareness of Mental Disorder (SUMD) and Birchwood Insight Scale (BIS). RESULTS Hostility was the aggressiveness dimension the most strongly associated with SUMD insight dimensions. Patients aware of their illness were nearly twice as likely to show hostility than those seriously unaware (OR = 1.95, 95% CI.: 1.08-3.5), but not when further adjusting for depression. Similarly, those aware of the consequences of their illness and of their symptoms were more hostile. Patients moderately aware of illness consequences had a higher risk of both anger and physical aggressiveness than those unaware (OR = 2.63, 95% CI.: 1.42-4.86, OR = 2.47, 95% CI.: 1.33-4.60, respectively), even when adjusting for depression for anger. CONCLUSION Our study confirms that a multi-dimensional approach to insight and aggressiveness is essential to understand the types of links between these clinical states. Insight may trigger the expression of an underlying hostile tendency, maybe via depression and self-stigmatisation. This should be taken into account in therapeutic approaches to improve insight.

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

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

Risk factors for increased duration of untreated psychosis. Results from the FACE-SZ dataset

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.