Showing papers by "Caroline Dubertret published in 2019"

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

Abstract: 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.

Prospective cohort study of early biosignatures of response to lithium in bipolar-I-disorders: overview of the H2020-funded R-LiNK initiative

Abstract: Lithium is recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need. The H2020-funded Response to Lithium Network (R-LiNK; http://www.r-link.eu.com/ ) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including omics, neuroimaging, and actigraphy, etc. Individuals will be followed up for 24 months and an independent panel will assess and classify each participants’ response to lithium according to predefined criteria that consider evidence of relapse, recurrence, remission, changes in illness activity or treatment failure (e.g. stopping lithium; new prescriptions of other mood stabilizers) and exposure to lithium. Novel elements of this study include the recruitment of a large, multinational, clinically representative sample specifically for the purpose of studying candidate biomarkers and biosignatures; the application of lithium-7 magnetic resonance imaging to explore the distribution of lithium in the brain; development of a digital phenotype (using actigraphy and ecological momentary assessment) to monitor daily variability in symptoms; and economic modelling of the cost-effectiveness of introducing biomarker tests for the customisation of lithium treatment into clinical practice. Also, study participants with sub-optimal medication adherence will be offered brief interventions (which can be delivered via a clinician or smartphone app) to enhance treatment engagement and to minimize confounding of lithium non-response with non-adherence. The paper outlines the rationale, design and methodology of the first study being undertaken by the newly established R-LiNK collaboration and describes how the project may help to refine the clinical response phenotype and could translate into the personalization of lithium treatment.

Tobacco smoking is associated with antipsychotic medication, physical aggressiveness, and alcohol use disorder in schizophrenia: results from the FACE-SZ national cohort.

Abstract: Tobacco smoking is common in schizophrenia and is one of the main causes of premature mortality in this disorder. Little is known about clinical correlates and treatments associated with tobacco smoking in patients with schizophrenia. Still, a better characterization of these patients is necessary, in a personalized care approach. Aggressiveness and childhood trauma have been associated with tobacco smoking in general population, but this association has never been explored in schizophrenia. Our study examines the clinical and therapeutic characteristics of tobacco smoking in schizophrenia. 474 stabilized patients (mean age = 32.2; 75.7% male gender; smokers n = 207, 54.6%) were consecutively included in the network of the FondaMental Expert centers for Schizophrenia and assessed with valid scales. Current tobacco status was self-declared. Aggressiveness was self-reported with Buss-Perry Aggressiveness Questionnaire and Childhood Trauma with Childhood Trauma Questionnaire. Ongoing treatment was reported. In univariate analysis, tobacco smoking was associated with lower education level (p < 0.01), positive syndrome (p < 0.01), higher physical aggressiveness (p < 0.001), alcohol dependence (p < 0.001), and First Generation Antipsychotics (FGAs) use (p = 0.018). In a multivariate model, tobacco smoking remained associated with physical aggressiveness (p < 0.05), current alcohol dependence (p < 0.01) and FGA use (p < 0.05). No association was observed with childhood trauma history, mood disorder, suicidal behavior, psychotic symptom, global functioning or medication adherence. Patients with tobacco use present clinical and therapeutic specificities, questioning the neurobiological links between tobacco and schizophrenia. They could represent a specific phenotype, with specific clinical and therapeutic specificities that may involve interactions between cholinergic-nicotinic system and dopaminergic system. Further longitudinal studies are needed to confirm the potential efficacy of second generation antipsychotics (SGAs) on tobacco use in schizophrenia and to develop effective strategies for tobacco cessation in this population.

Machine learning for predicting psychotic relapse at 2 years in schizophrenia in the national FACE-SZ cohort.

Abstract: 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 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.

Prevalence of and Risk Factors for Extrapyramidal Side Effects of Antipsychotics: Results From the National FACE-SZ Cohort.

Abstract: 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.

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

Abstract: 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.

Centres Experts Schizophrénie, un outil pour le soin et la recherche : retour sur 10 ans d’expérience

Abstract: Resume Objectifs Le present article propose de faire un retour sur les 10 ans d’experience du reseau national des 10 centres experts schizophrenie Francais, a travers une revue des principales publications scientifiques qui en sont issues. Methodes A ce jour, les donnees de plus de 700 patients ont pu etre analysees. Globalement, cette population est composee de trois quarts d’hommes, est âgee en moyenne de 32 ans, la duree moyenne de maladie est d’environ 11 ans, l’âge moyen de debut de maladie est de 21 ans, la duree de psychose non traitee est d’environ un an et demi. 55 % des sujets sont consommateurs de tabac au moment de l’evaluation. Enfin, un focus sera fait sur les projets de recherche multicentriques collaboratifs deployes au sein de ce reseau. Resultats Les principales donnees obtenues peuvent etre resumees comme suit : le syndrome metabolique reste deux fois plus frequent dans la schizophrenie qu’en population generale et n’est pas correctement pris en charge ; des troubles cognitifs specifiques ont ete identifies chez les patients consommateurs de benzodiazepines et chez les patients presentant une inflammation peripherique. Des specificites liees au sexe ont egalement ete observees ; la depression comorbide reste tres frequente, elle est associee a une diminution de la qualite de vie et a une augmentation de la dependance nicotinique chez les fumeurs. Prendre en charge la depression et les symptomes negatifs pourraient fortement ameliorer la qualite de vie des patients ; le delai a l’instauration du traitement est plus long pour les schizophrenies se declenchant avant 19 ans et chez les consommateurs de cannabis. L’adhesion au traitement est diminuee chez les patients rapportant un ressenti subjectif negatif du traitement, independamment de la prise de poids ou d’un syndrome extrapyramidal. Enfin, l’akathisie est tres frequente et fortement associee a la polytherapie antipsychotique. Conclusions Ces resultats conduisent a formuler plusieurs recommandations. Le depistage du trouble et le traitement devraient etre renforces chez les adolescents et les consommateurs de cannabis. Tous les patients devraient beneficier d’une evaluation neuropsychologique au debut de leur trouble, apres stabilisation sous traitement, puis de facon plus espacee au cours de leur suivi. La prise en charge des parametres metaboliques, de l’alimentation et de l’activite physique devrait etre renforcee. La balance benefice/risque de la prescription de benzodiazepines doit etre reevaluee regulierement au regard de son impact notamment sur la cognition. La monotherapie antipsychotique est recommandee autant que possible pour limiter les effets indesirables. La depression reste sous-diagnostiquee et doit faire l’objet d’une evaluation systematique et d’un traitement specifique. La remediation cognitive doit egalement etre plus largement proposee chez les patients presentant des troubles cognitifs.

Validation and refinement of the clinical staging model in a French cohort of outpatient with schizophrenia (FACE-SZ).

Abstract: 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.

Modeling the Longitudinal Effects of Insight on Depression, Quality of Life and Suicidality in Schizophrenia Spectrum Disorders: Results from the FACE-SZ Cohort.

Abstract: Background: Up to half of the patients with schizophrenia attempt suicide during their lifetime. Better insight is associated with better functioning but also with increased suicidality. The direction of the relationship between insight and suicidality is not clear, hence we aimed to provide new elements using structural equation modeling. Methods: Insight, quality of life (QoL), depression, and suicidality were measured at baseline and at 12 months in individuals with schizophrenia spectrum disorders. The relationships between these variables were investigated by latent difference score models, controlling for chlorpromazine doses, positive and negative symptoms, and general psychopathology. Results: 738 patients were included, and 370 completed the study. Baseline levels of insight predicted changes in suicidality, whereas baseline levels of suicidality did not predict changes in insight, suggesting that better insight underlies suicidality and predicts its worsening. Our results suggest this temporal sequence: better insight → worse QoL → increased depression → increased suicidality, while insight also affects the three variables in parallel. Conclusion: Better insight predicts a worsening of QoL, depression and suicidality. These findings contribute to our global understanding of the longitudinal influence of insight on suicidality. We advocate that insight-targeted interventions should not be proposed without the monitoring of depression and suicide prevention.

Sexual dysfunctions are associated with major depression, chronic inflammation and anticholinergic consumption in the real-world schizophrenia FACE-SZ national cohort.

Abstract: Background Sexual dysfunctions (SD) are frequent in schizophrenia (SZ) and associated with treatment withdrawal, however they remain under-explored and under-treated. To date, most of the studies have focused on SD as antipsychotics' side effects in therapeutic trials. Aims The objectives of the present study were to determine the SD prevalence in stabilized SZ outpatients and their clinical, pharmacological and biological correlates. Method Two hundred and thirty-seven participants (61.2% men) were consecutively included and received a thorough 2 days- clinical assessment including the self-reported Sexual Functioning Questionnaire (SFQ). SD was defined by a SFQ score ≥ 8. Results Two hundred and thirty-seven subjects were recruited in the FACE-SZ cohort, 41% of them reported sexual dysfunctions. In multivariate analyses, SD have been associated with current major depressive disorder (adjusted odd ratio aOR = 2.29[1.08–4.85], p = .03), anticholinergic prescription (aOR = 2.65, p = .02) and chronic low-grade inflammation (aOR = 2.09, p = .03) independently of age, gender, current cannabis use disorder and olanzapine prescription. No antipsychotic has been associated with increased or decreased SD rate. Conclusions SD are frequent in SZ subjects. Major depression, anticholinergic prescription and chronic low-grade peripheral inflammation may be the three targets of interest for addressing this specific issue.

Confirmation of a Two-Factor Solution to the Questionnaire of Cognitive and Affective Empathy in a French Population of Patients With Schizophrenia Spectrum Disorders.

Abstract: The Questionnaire of Cognitive and Affective Empathy (QCAE) is a tool for self-assessing the cognitive and emotional components of empathy. A study showed that a two-factor model fits the data of patients with schizophrenia, whereas other reports on healthy subjects have suggested a five-factor decomposition. We aimed to replicate the model of Horan et al. in a French population with schizophrenia spectrum disorders (i.e., schizophrenia and schizoaffective disorders) participating in the EVACO Study (NCT02901015). In total, 133 patients were assessed with the QCAE, the Positive and Negative Symptom Scale (PANSS), the Personal and Social Performance Scale (PSP), and the Self rating Quality of Life Scale (S-QoL). The two-factor model demonstrated an adequate fit with the data, comparable to that reported by Horan et al. Males scored higher on the Affective subscore than females. After correction for multiple tests, psychopathology (PANSS) and functioning (PSP) did not correlate significantly with the QCAE subscores. However, quality of life (S-QoL) correlated positively with the Emotional Contagion subscore. Thus, the variability of empathetic disposition in schizophrenia may be considered through the cognitive versus affective dichotomy and properly investigated with the QCAE. The results support further investigation of the relationship between QCAE scores and subjective outcome measurements, such as quality of life, and emphasize the importance of cross-cultural comparisons.

Major Depressive Disorder (MDD) and Schizophrenia- Addressing Unmet Needs With Partial Agonists at the D2 Receptor: A Review.

Abstract: Second-generation antipsychotics are common candidates for the adjunctive treatment of major depressive disorder and for the treatment of schizophrenia. However, unmet needs remain in the treatment of both disorders. Considering schizophrenia, antipsychotics are the most common treatment and have demonstrated good efficacy. Still, side effects of these treatments are commonly reported and may impact adherence to the medication and functioning in patients with schizophrenia. Regarding major depressive disorder, despite the availability of several classes of antidepressants, many patients do not achieve remission. Adjunctive treatment with antipsychotics may improve clinical and functional outcomes. Compared with dopamine D2 receptor antagonism that is exhibited by most antipsychotics, partial agonism may result in improved outcomes in major depressive disorder and in schizophrenia. Aripiprazole, cariprazine, and brexpiprazole have partial agonism at the dopamine D2 receptor and could potentially overcome limitations associated with D2 antagonism. The objectives of this review were (1) to discuss the goal of treatment with second-generation antipsychotics in major depressive disorder and schizophrenia, and the clinical factors that should be considered, and (2) to examine the short- and long-term existing data on the efficacy and safety of D2 receptor partial agonists (aripiprazole, cariprazine, and brexpiprazole) in the adjunctive treatment of major depressive disorder and in the treatment of schizophrenia.