Exploring venlafaxine pharmacokinetic variability with a phenotyping approach, a multicentric french-swiss study (MARVEL study).

It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the "in vivo" measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis. The goal of this project is to explore the relationship between the activity of drug-metabolizing enzymes (DME), assessed by a phenotypic approach, and the concentrations of Venlafaxine (VLX) + O-demethyl-venlafaxine (ODV), the efficacy and tolerance of VLX. This study is a multicentre prospective non-randomized open trial. Eligible patients present a major depressive episode, MADRS over or equal to 20, treatment with VLX regardless of the dose during at least 4 weeks. The Phenotype Visit includes VLX and ODV concentration measurement. Following the oral absorption of low doses of omeprazole, midazolam, dextromethorphan, and fexofenadine, drug metabolizing enzymes activity is assessed by specific metabolite/probe concentration ratios from a sample taken 2 h after cocktail administration for CYP2C19, CYP3A4, CYP2D6; and by the determination of the limited area under the curve from the capillary blood samples taken 2-3 and 6 h after cocktail administration for CYP2C19 and P-gp. Two follow-up visits will take place between 25 and 40 days and 50-70 days after inclusion. They include assessment of efficacy, tolerance and observance. Eleven french centres are involved in recruitment, expected to be completed within approximately 2 years with 205 patients. Metabolic ratios are determined in Geneva, Switzerland. By showing an association between drug metabolism and VLX concentrations, efficacy and tolerance, there is a hope that testing drug metabolism pathways with a phenotypical approach would help physicians in selecting and dosing antidepressants. The MARVEL study will provide an important contribution to increasing the knowledge of VLX variability and in optimizing the use of methods of personalized therapy in psychiatric settings. ClinicalTrials.gov NCT02590185 (10/27/2015). This study is currently recruiting participants

Low- vs High-Frequency Repetitive Transcranial Magnetic Stimulation as an Add-On Treatment for Refractory Depression

Objectives: Repetitive transcranial magnetic stimulation (rTMS) seems to be effective as an antidepressant, however, some confusion remains about the best parameters to apply and the efficacy of its association with pharmacological antidepressant treatments. Method: In a single blind randomized study 14 patients with unipolar resistant depression to one antidepressant treatment were enrolled to receive, in combination with venlafaxine (150 mg), either 20 sessions of 10 Hz rTMS (2000 pulses per session) applied over the left dorsolateral prefrontal cortex (DLPFC) or 20 sessions of 1 Hz rTMS (120 stimulations per sessions) applied over the right DLPFC. Results: A similar antidepressant effect was observed in both groups with a comparable antidepressant delay of action (2 weeks) and a comparable number of responders (MADRS < 15) after 4 weeks of daily rTMS sessions (66 vs 50%). Conclusion: Low- and high- frequency rTMS seems to be effective as an add-on treatment to venlafaxine as monotherapy in pharmacological refractory major depression (stage 1). Due to its short duration (one session of 1 Hz rTMS lasts 4 min vs 16 for 10 Hz rTMS) and its safety, low frequency rTMS may be a useful alternative treatment for patients with refractory depression

TREATMENT OF SHIZOPHRENIC PATIENTS AND rTMS

Introduction: Schizophrenia (SCH) is a heterogeneous syndrome characterized by positive and negative symptoms. Despite appropriate medication, about 1/4 of patients suffer for refractory positive and/or negative symptoms, which are associated with functional handicap, increase of duration and of the number of hospitalizations. Numerous studies have suggested that the pathophysiology of auditory hallucinations (AH) is related to a hyper activity of the left temporoparietal cortex (TPC). On the other hand, negative symptoms are associated with a prefrontal hypoactivity and the efficiency of pharmacological treatments is frequently partial. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation tool with excellent tolerability and safety. Given its hypothesized mechanisms of action and the clinical beneficial effects obtained in several types of pathology (Aleman et al. 2007), the efficacy of rTMS has been investigated for drug-resistant SCH symptoms. Objective: Our objective is to expose the knowledge concerning the rTMS use in the treatment of these symptoms and to purpose a critical analysis of these data. Method: a systematic review of the literature has been conducted using NIH Pubmed. The following search terms were used: TMS - rTMS - Schizophrenia - negative symptoms - hallucinations. Results: Concerning the treatment of AH, 16 publications and 4 meta analyses were selected. For the negative symptoms, we retained 16 studies and 3 meta analyses. The most extensively investigated application for rTMS in SCH is the use of low-frequency stimulation to the left TPC with the aim to improve AH symptomatology. When compared to sham, this type of acute course of rTMS has been proven to induce a substantial and significant reduction in AH. But this effect does not seem long-lasting and maintenance protocols must be developed. Concerning negative symptoms, the results are less solid but we find some works which demonstrate an improvement of these symptoms while various stimulation parameters were used. Recently, new parameters of stimulation in particular the theta burst stimulation have permitted us to obtain larger effects with longer duration. The interest of these new parameters will be discussed here. Conclusion: Overall, rTMS studies have demonstrated some promise in the treatment of SCH. However, more research is required to enhance rTMS efficacy and increase its beneficial effect duration and to test new therapeutic strategies in this topic

Predictors of mental well-being over the first lockdown period due to the COVID-19 pandemic in France. A repeated cross-sectional study

IntroductionNumerous studies have investigated the positive and negative effects of potential predictors of well-being during lockdowns due to COVID-19. Yet, little is known on whether these effects significantly changed with time spent in lockdown. In the current study, we described the association of mental well-being with a large number of background characteristics (e.g., socio-demographic or health-related factors), COVID-related factors, and coping strategies, over the duration of the first lockdown due to COVID-19 in France.MethodsA nationwide online survey was conducted over 7 of the 8 weeks of the 1st lockdown in France, i.e., from 25 March 2020 to 10 May 2020. The level of mental well-being was reported using the Warwick-Edinburgh Mental Well-Being Scale (WEMWBS). We also measured various background characteristics (e.g., age, sex, education, health issues), COVID-related factors (e.g., health and economic risks, agreement with lockdown), and coping strategies. Our analytical strategy enabled us to disentangle effects aggregated over the study period from those that linearly vary with time spent in lockdown.ResultsOur final dataset included 18,957 participants. The level of mental well-being dropped gradually from the third to the eighth week of lockdown [49.7 (sd 7.9) to 45.5 (sd 10.6)]. Time in lockdown was associated with a decrease in well-being (for each additional 10 days of lockdown: B = −0.30, 95%CI: −0.62, −0.15). Factors that showed significantly negative and positive effects on well-being as time in lockdown progressed were (for each additional 10 days of lockdown): having current psychiatric problems (B = −0.37; 95%CI: −0.63, −0.04), worries about having access to personal protective equipment (B = −0.09; 95%CI: −0.18, −0.01), coping by having positive beliefs about the future of the pandemics (B = 0.29; 95%CI: 0.04, 0.62), being supported by neighbors (B = 0.24; 95%CI: 0.04, 0.44), and being involved in collective actions (B = 0.23; 95%CI: 0.04, 0.46).DiscussionParticipants from our sample saw a drop in their mental well-being throughout the first period of COVID-19 lockdown. Policymakers should be mindful of factors contributing to greater deterioration of mental well-being over time, such as having current psychiatric issues. Promoting collective actions and local support from neighbors may alleviate the deterioration of mental well-being over time

Clinical and Prognostic Value of Immunogenetic Characteristics in Anti-LGI1 Encephalitis

OBJECTIVE: Antibodies against leucine-rich glioma-inactivated 1 (LGI1-Abs) characterize a limbic encephalitis (LE) strongly associated with HLA-DRB1*07:01, although some patients lack LGI1-Abs in CSF or do not carry this allele. Whether they represent a different subtype of disease or have different prognoses is unclear. METHODS: Retrospective analysis of clinical features, IgG isotypes, and outcome according to LGI1-Ab CSF positivity and DRB1*07:01 in a cohort of anti-LGI1 LE patients. RESULTS: Patients with LGI1-Abs detected in both CSF and serum (105/134, 78%) were compared with those who were CSF negative (29/134, 22%). Both groups had similar clinical features and serum levels, but CSF-positive patients had shorter diagnostic delay, more frequently hyponatremia, inflammatory CSF, and abnormal MRI (p 0.05). HLA and IgG isotypes were not associated with poor outcome (mRS >2 at last follow-up) in univariate analyses; CSF positivity was only identified as a poor outcome predictor in the multivariate analysis including the complete follow-up, whereas age and female sex also remained when just the first year was considered. CONCLUSIONS: LE without CSF LGI1-Abs is clinically indistinguishable and likely reflects just a lesser LGI1-Ab production. HLA association is sex and age biased and presents clinical particularities, suggesting subtle differences in the immune response. Long-term outcome depends mostly on demographic characteristics and the intensity of the intrathecal synthesis

Adolescents with Cystic Fibrosis Expressing their Possible Selves through Photovoice: A Longitudinal Interpretative Phenomenological Analysis to Prepare a Peer Support Intervention for Healthcare Transition

peer reviewe

Design and content validation of a survey questionnaire assessing the determinants of human papillomavirus (HPV) vaccine hesitancy in France: A reactive Delphi study.

INTRODUCTION: This study aimed to develop and undertake a preliminary validation of a French Survey Questionnaire for the Determinants of HPV Vaccine Hesitancy (FSQD-HPVH). METHODS: We undertook an electronic-based Delphi consultation among a panel of Francophone experts in two rounds. Round 1 consisted of the assessment of a structured questionnaire comprising of three parts ((i) Contextual influences, (ii) Individual and group influences, and (iii) Vaccine/vaccination-specific issues), in line with the WHO Strategic Advisory Group of Experts (SAGE) Vaccine Hesitancy (VH) Model of Determinants. Items included in this questionnaire were based on a literature review. Definitions of the factors included in the SAGE model were provided in the questionnaire. The panel of experts was asked to score each item using a 3-point Likert scale, in which 1 meant "Essential", 2 "Useful but not essential", and 3 "Not necessary". The panel was also invited to comment on the clarity/comprehension of the questions and suggest reformulations/additional items. Lawshe's Content Validity Ratio (CVR) was computed to assess the level of consensus for each statement. Only items upon which agreement was not reached in Round 1 (CVR < 0.6) and newly proposed items were submitted for evaluation in Round 2, using the same procedure. RESULTS: Fifteen experts completed the two rounds. Of 83 items evaluated in Round 1, 35 (42%) had a CVR ≥ 0.6 and were accepted without modification. In Round 2, 66 items were submitted to the same panel and consensus was reached for 22 (33%) items using the threshold of 0.6. The final FSQD-HPVH version includes 57 items. CONCLUSION: This study developed a survey instrument for the evaluation of HPV VH in France with good content validity. It will be used to assess the determinants of HPV VH, the first step towards an evidence-based approach to improving HPV vaccination rates in France

The interplay between executive functions and updating predictive representations

Modifying habits, particularly unwanted behaviors, is often challenging. Cognitive research has focused on understanding the mechanisms underlying habit formation and how habits can be rewired. A key mechanism is statistical learning, the continuous, implicit extraction of probabilistic patterns from the environment, which forms the basis of predictive processing. However, the interplay between executive functions (EF) and the rewiring – or updating – of these probabilistic representations remains largely unexplored. To address this gap, we conducted an experiment consisting of four sessions: (1) Learning Phase – acquisition of probabilistic representations, (2) Rewiring Phase – updating these probabilistic representations, (3) Retrieval Phase – accessing learned representations, and (4) EF assessment, targeting five key aspects: attentional control, inhibition, working memory, flexibility, and verbal fluency. We focused on the relationship between these EF measures and the updating of previously acquired knowledge using an interindividual differences approach. Our results revealed a positive relationship between rewiring and inhibition, suggesting that better inhibitory control may facilitate the adaptive restructuring of probabilistic predictive representations. Conversely, a negative relationship was identified between rewiring and semantic fluency, implying that certain underlying aspects of verbal fluency tasks, such as access to long-term memory representations, may hinder the updating process. We interpret this relationship through the lens of competitive memory network models. Our findings indicate that the rewiring of implicit probabilistic representations is a multifaceted cognitive process requiring both the suppression of proactive interference from prior knowledge through cognitive inhibition and a strong reliance on model-free functioning

Occupational, academic, and personal determinants of wellbeing and psychological distress in residents: results of a survey in Lyon, France

IntroductionThe mental health of residents is a growing significant concern, particularly with respect to hospital and university training conditions. Our goal was to assess the professional, academic, and psychological determinants of the mental health status of all residents of the academy of Lyon, France.Materials and methodsThe Health Barometer of Lyon Subdivision Residents (BASIL) is an initiative which consists in proposing a recurrent online survey to all residents in medicine, pharmacy, and dentistry, belonging to the Lyon subdivision. The first of these surveys was conducted from May to July 2022. Participants should complete a series of validated questionnaires, including the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS), and the Kessler Psychological Distress Scale (K6), respectively, and ad-hoc questions assessing their global health and hospital and academic working conditions. A Directed Acyclic Graph (DAG) analysis was conducted prior to multivariable analyses, to explore the determinants associated with low wellbeing (WEMWBS &lt;43) and high psychological distress (K6 ≥ 13).ResultsA total of 904 residents (response rate: 46.7%) participated in the survey. A low level of wellbeing was observed in 23% of participants, and was significantly associated to job strain (OR = 2.18; 95%CI = [1.32–3.60]), low social support (OR = 3.13; 95%CI = [2.05–4.78]) and the experience of very poor university teaching (OR = 2.51; 95%CI = [1.29–4.91]). A high level of psychological distress was identified for 13% of participants, and associated with low social support (OR = 2.41; 95%CI = [1.48–3.93]) and the experience of very poor university teaching (OR = 2.89, 95%CI = [1.16–7.21]).ConclusionHospital working conditions, social support, and the perception of teaching quality, were three major determinants of wellbeing and psychological distress among health profession residents. Demographic determinants, personal life and lifestyle habits were also associated. This supports a multilevel action in prevention programs aiming to enhance wellbeing and reduce mental distress in this specific population and local organizational specificities