Neuromodulation Treatments of Pathological Anxiety in Anxiety Disorders, Stressor-Related Disorders, and Major Depressive Disorder: A Dimensional Systematic Review and Meta-Analysis

BackgroundPathological anxiety is responsible for major functional impairments and resistance to conventional treatments in anxiety disorders (ADs), posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Focal neuromodulation therapies such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS) are being developed to treat those disorders.MethodsWe performed a dimensional systematic review and meta-analysis to assess the evidence of the efficacy of TMS, tDCS and DBS in reducing anxiety symptoms across ADs, PTSD and MDD. Reports were identified through systematic searches in PubMed/Medline, Scopus and Cochrane library (inception to November 2020), followed by review according to the PRISMA guidelines. Controlled clinical trials examining the effectiveness of brain stimulation techniques on generic anxiety symptoms in patients with ADs, PTSD or MDD were selected.ResultsNineteen studies (RCTs) met inclusion criteria, which included 589 participants. Overall, focal brain activity modulation interventions were associated with greater reduction of anxiety levels than controls [SMD: −0.56 (95% CI, −0.93 to−0.20, I2 = 77%]. Subgroup analyses revealed positive effects for TMS across disorders, and of focal neuromodulation in generalized anxiety disorder and PTSD. Rates of clinical responses and remission were higher in the active conditions. However, the risk of bias was high in most studies.ConclusionsThere is moderate quality evidence for the efficacy of neuromodulation in treating pathological anxiety.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=233084, identifier: PROSPERO CRD42021233084. It was submitted on January 29th, 2021, and registered on March 1st, 2021. No amendment was made to the recorded protocol. A change was applied for the subgroup analyses based on target brain regions, we added the putative nature (excitatory/inhibitory) of brain activity modulation

First-Line Pharmacotherapies and Survival among Patients Diagnosed with Non-Resectable NSCLC: A Real-Life Setting Study with Gender Prospective

(1) Purpose: To describe first-line pharmacotherapy and overall survival in non-resectable non-small cell lung cancer (nrNSCLC) patients by gender. (2) Methods: Incident cases of nrNSCLC recorded between 2009 and 2019 (cohort entry) in the pathology registry of the regional administrative healthcare database of Tuscany were identified. Records of antineoplastic therapies delivered up to 4 months following cohort entry were classified as chemotherapy, target therapies, immunotherapies, and undefined monoclonal antibodies. First-line treatment and survival of patients receiving drug treatment was described. Analyses were stratified according to histology, gender, and cohort entry year. (3) Results: 4393 incident cases of nrNSCLC were included. Women with non-squamous-NSCLC received target-therapy more frequently than men (14.9% vs. 6.5%). Immunotherapy incidence of use varied between 3.8% (2017) and 9.1% (2019). The 2-year survival rate increased over time: for non-squamous-NSCLC, it was 22.3% (2009-2011) and 30.6% (2018-2019), while for squamous-NSCLC, it was 13.5% and 22.5%, respectively. After multivariate analysis, a low reduction in mortality risk in 2018-2019 vs. 2009-2011 was found (non-squamous: HR: 0.95 CI95%: 0.92-0.98; squamous: HR: 0.94 CI95%: 0.90-0.98). Among non-squamous NSCLC, median survival was longer in women than in men (389 vs. 276 days). (4) Conclusion: In light of sex-related biomolecular differences, among non-squamous NSCLC, women received target-therapy more frequently than men. Survival seemed to slightly improve over the study period for both histologies, despite a poor reduction in mortality risk was still observed

Mésusage des médicaments : caractérisation et évaluation. Cas des benzodiazépines et opiacés faibles.

Medicines misuse is often defined as the inappropriate use of medicines according to current guidelines or patients’ characteristics. Some medicines with a high potential for misuse, such as benzodiazepines or opioids, are subject to close monitoring. The aim of this thesis was to characterise medicines misuse and to assess it on the basis of two therapeutic classes: benzodiazepines and weak opioids. Firstly, we carried out a systematic review of the literature aiming at characterise and classify misuse definitions and identify the most appropriate ones. This review allowed us to identify the most appropriate definitions to assess medicine misuse according to the type of data available. Secondly, we studied the use and misuse of weak opioids using French medico-administrative databases: the national health data system (SNDS). This study revealed that among new users of weak opioids more than a third used them as a firstline treatment and that their misuse at one year, ranging from 2% to 3%, could involve at less 270,000 users per year in France. Finally, we investigated the determinants associated with general practitioners’ (GPs) non-compliance with benzodiazepine discontinuation guidelines as GPs have a central role in patients’ care. This work highlighted that GPs’ perceptions of the drug benefit-risk ratio and patients’ preferences were as important as their socio-demographic characteristics for explaining their deprescribing practices. These results provide a global picture of misuse through its characterisation, quantification and determinants. They underline the need for further awareness-raising measures on psychoactive medicines in France.Le mésusage des médicaments est souvent défini comme l’utilisation inappropriée des médicaments au regard des recommandations en vigueur, ou des caractéristiques de l’individu. Certains médicaments à fort potentiel de mésusage, tels que les benzodiazépines ou les opioïdes, font l’objet d’une surveillance rapprochée. L’objectif de ce travail de thèse était de caractériser le mésusage, et de l’évaluer à partir de deux classes médicamenteuses : les benzodiazépines et les opiacés faibles. Dans un premier temps, nous avons réalisé une revue systématique de la littérature ayant pour objectifs de caractériser et classer les définitions de mésusage, et d’en identifier les plus appropriées. Cette revue a permis d’identifier les définitions les plus adaptées à l’évaluation du mésusage selon le type de données disponibles pour son évaluation. Dans un deuxième temps, nous avons étudié l’utilisation et le mésusage des opiacés faibles à partir des bases de données médico-administratives françaises : le système national des données de santé (SNDS). Cette étude a mis en évidence que, parmi les nouveaux utilisateurs d’opiacés faibles, plus d’un tiers les utilisaient en première intention et que leur mésusage à un an, variant de 2 à 3 %, pouvait concerner au moins 270 000 utilisateurs par an en France. Enfin, nous nous sommes intéressés aux déterminants associés au non-respect des recommandations d’arrêt des benzodiazépines en médecine générale, le médecin généraliste ayant un rôle central dans la prise en charge des patients. Ce travail a souligné que les perceptions des médecins généralistes vis-à-vis de la balance bénéfice-risque des médicaments ou encore des préférences des patients étaient aussi importantes que leurs caractéristiques sociodémographiques pour expliquer leurs pratiques lors de l’arrêt d’un traitement. Ces résultats permettent l’obtention d’une vision globale du mésusage passant par sa caractérisation, sa quantification et ses déterminants. Ils soulignent la nécessité de poursuivre les mesures de sensibilisation à l’usage des médicaments psychoactifs en France

Medicines misuse : characterization and assessment. Cases of benzodiazepines and weak opioids.

Le mésusage des médicaments est souvent défini comme l’utilisation inappropriée des médicaments au regard des recommandations en vigueur, ou des caractéristiques de l’individu. Certains médicaments à fort potentiel de mésusage, tels que les benzodiazépines ou les opioïdes, font l’objet d’une surveillance rapprochée. L’objectif de ce travail de thèse était de caractériser le mésusage, et de l’évaluer à partir de deux classes médicamenteuses : les benzodiazépines et les opiacés faibles. Dans un premier temps, nous avons réalisé une revue systématique de la littérature ayant pour objectifs de caractériser et classer les définitions de mésusage, et d’en identifier les plus appropriées. Cette revue a permis d’identifier les définitions les plus adaptées à l’évaluation du mésusage selon le type de données disponibles pour son évaluation. Dans un deuxième temps, nous avons étudié l’utilisation et le mésusage des opiacés faibles à partir des bases de données médico-administratives françaises : le système national des données de santé (SNDS). Cette étude a mis en évidence que, parmi les nouveaux utilisateurs d’opiacés faibles, plus d’un tiers les utilisaient en première intention et que leur mésusage à un an, variant de 2 à 3 %, pouvait concerner au moins 270 000 utilisateurs par an en France. Enfin, nous nous sommes intéressés aux déterminants associés au non-respect des recommandations d’arrêt des benzodiazépines en médecine générale, le médecin généraliste ayant un rôle central dans la prise en charge des patients. Ce travail a souligné que les perceptions des médecins généralistes vis-à-vis de la balance bénéfice-risque des médicaments ou encore des préférences des patients étaient aussi importantes que leurs caractéristiques sociodémographiques pour expliquer leurs pratiques lors de l’arrêt d’un traitement. Ces résultats permettent l’obtention d’une vision globale du mésusage passant par sa caractérisation, sa quantification et ses déterminants. Ils soulignent la nécessité de poursuivre les mesures de sensibilisation à l’usage des médicaments psychoactifs en France.Medicines misuse is often defined as the inappropriate use of medicines according to current guidelines or patients’ characteristics. Some medicines with a high potential for misuse, such as benzodiazepines or opioids, are subject to close monitoring. The aim of this thesis was to characterise medicines misuse and to assess it on the basis of two therapeutic classes: benzodiazepines and weak opioids. Firstly, we carried out a systematic review of the literature aiming at characterise and classify misuse definitions and identify the most appropriate ones. This review allowed us to identify the most appropriate definitions to assess medicine misuse according to the type of data available. Secondly, we studied the use and misuse of weak opioids using French medico-administrative databases: the national health data system (SNDS). This study revealed that among new users of weak opioids more than a third used them as a firstline treatment and that their misuse at one year, ranging from 2% to 3%, could involve at less 270,000 users per year in France. Finally, we investigated the determinants associated with general practitioners’ (GPs) non-compliance with benzodiazepine discontinuation guidelines as GPs have a central role in patients’ care. This work highlighted that GPs’ perceptions of the drug benefit-risk ratio and patients’ preferences were as important as their socio-demographic characteristics for explaining their deprescribing practices. These results provide a global picture of misuse through its characterisation, quantification and determinants. They underline the need for further awareness-raising measures on psychoactive medicines in France

Medicines misuse : characterization and assessment. Cases of benzodiazepines and weak opioids.

Le mésusage des médicaments est souvent défini comme l’utilisation inappropriée des médicaments au regard des recommandations en vigueur, ou des caractéristiques de l’individu. Certains médicaments à fort potentiel de mésusage, tels que les benzodiazépines ou les opioïdes, font l’objet d’une surveillance rapprochée. L’objectif de ce travail de thèse était de caractériser le mésusage, et de l’évaluer à partir de deux classes médicamenteuses : les benzodiazépines et les opiacés faibles. Dans un premier temps, nous avons réalisé une revue systématique de la littérature ayant pour objectifs de caractériser et classer les définitions de mésusage, et d’en identifier les plus appropriées. Cette revue a permis d’identifier les définitions les plus adaptées à l’évaluation du mésusage selon le type de données disponibles pour son évaluation. Dans un deuxième temps, nous avons étudié l’utilisation et le mésusage des opiacés faibles à partir des bases de données médico-administratives françaises : le système national des données de santé (SNDS). Cette étude a mis en évidence que, parmi les nouveaux utilisateurs d’opiacés faibles, plus d’un tiers les utilisaient en première intention et que leur mésusage à un an, variant de 2 à 3 %, pouvait concerner au moins 270 000 utilisateurs par an en France. Enfin, nous nous sommes intéressés aux déterminants associés au non-respect des recommandations d’arrêt des benzodiazépines en médecine générale, le médecin généraliste ayant un rôle central dans la prise en charge des patients. Ce travail a souligné que les perceptions des médecins généralistes vis-à-vis de la balance bénéfice-risque des médicaments ou encore des préférences des patients étaient aussi importantes que leurs caractéristiques sociodémographiques pour expliquer leurs pratiques lors de l’arrêt d’un traitement. Ces résultats permettent l’obtention d’une vision globale du mésusage passant par sa caractérisation, sa quantification et ses déterminants. Ils soulignent la nécessité de poursuivre les mesures de sensibilisation à l’usage des médicaments psychoactifs en France.Medicines misuse is often defined as the inappropriate use of medicines according to current guidelines or patients’ characteristics. Some medicines with a high potential for misuse, such as benzodiazepines or opioids, are subject to close monitoring. The aim of this thesis was to characterise medicines misuse and to assess it on the basis of two therapeutic classes: benzodiazepines and weak opioids. Firstly, we carried out a systematic review of the literature aiming at characterise and classify misuse definitions and identify the most appropriate ones. This review allowed us to identify the most appropriate definitions to assess medicine misuse according to the type of data available. Secondly, we studied the use and misuse of weak opioids using French medico-administrative databases: the national health data system (SNDS). This study revealed that among new users of weak opioids more than a third used them as a firstline treatment and that their misuse at one year, ranging from 2% to 3%, could involve at less 270,000 users per year in France. Finally, we investigated the determinants associated with general practitioners’ (GPs) non-compliance with benzodiazepine discontinuation guidelines as GPs have a central role in patients’ care. This work highlighted that GPs’ perceptions of the drug benefit-risk ratio and patients’ preferences were as important as their socio-demographic characteristics for explaining their deprescribing practices. These results provide a global picture of misuse through its characterisation, quantification and determinants. They underline the need for further awareness-raising measures on psychoactive medicines in France

Neuromodulation Treatments of Pathological Anxiety in Anxiety Disorders, Stressor-Related Disorders, and Major Depressive Disorder: A Dimensional Systematic Review and Meta-Analysis

International audienceBackgroundPathological anxiety is responsible for major functional impairments and resistance to conventional treatments in anxiety disorders (ADs), posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Focal neuromodulation therapies such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS) are being developed to treat those disorders.Methods: We performed a dimensional systematic review and meta-analysis to assess the evidence of the efficacy of TMS, tDCS and DBS in reducing anxiety symptoms across ADs, PTSD and MDD. Reports were identified through systematic searches in PubMed/Medline, Scopus and Cochrane library (inception to November 2020), followed by review according to the PRISMA guidelines. Controlled clinical trials examining the effectiveness of brain stimulation techniques on generic anxiety symptoms in patients with ADs, PTSD or MDD were selected.ResultsNineteen studies (RCTs) met inclusion criteria, which included 589 participants. Overall, focal brain activity modulation interventions were associated with greater reduction of anxiety levels than controls [SMD: −0.56 (95% CI, −0.93 to−0.20, I2 = 77%]. Subgroup analyses revealed positive effects for TMS across disorders, and of focal neuromodulation in generalized anxiety disorder and PTSD. Rates of clinical responses and remission were higher in the active conditions. However, the risk of bias was high in most studies.Conclusions: There is moderate quality evidence for the efficacy of neuromodulation in treating pathological anxiety

General practitioners' compliance with benzodiazepine discontinuation guidelines in patients treated with long-term lorazepam: A case-vignette cross-sectional survey

AIM: To study determinants associated with GPs' compliance with benzodiazepine discontinuation guidelines through a case-vignette of a patient with multimorbidity treated with long-term lorazepam for insomnia. METHODS: This cross-sectional survey was performed in a sample of French GPs. The questionnaire included items on their characteristics and questions related to the management of a case-vignette with long-term lorazepam use consulting for a prescription renewal. GPs who proposed a dedicated consultation to discuss discontinuation or progressive discontinuation were considered as "following guidelines", while they were considered as "out-of-guidelines" if they proposed immediate discontinuation or decided not to discontinue lorazepam. A backward selection process was used to select factors to be included in the final logistic regression model. The probabilities of out-of-guidelines practice and their 95% confidence interval (95% CI) were then plotted using a heatmap graph. RESULTS: Of 1,177 GPs, the majority (92.2%) were aware of the necessity to discontinue lorazepam and reported practice consistent with good practice guidelines. Women GPs aged under 50 years had the lowest estimated probability of out-of-guidelines practice. Conversely, men aged over 58 years with high consideration of patient preferences and low concern about the benefit-risk ratio of lorazepam had the highest probability of out-of-guidelines practice (27.3% [18.7%; 34.7%]). CONCLUSION: GPs largely reported practice compliant with benzodiazepine discontinuation guidelines, although some GPs, mainly older men who overemphasise patient preferences, were more likely to adopt out-of-guidelines practice

Br J Clin Pharmacol

AIMS: Although medicine misuse is a public health issue, it has multiple meanings in the medical literature. This study aimed to characterize, classify and identify the most appropriate definitions of medicine misuse. METHODS: A systematic review was performed in Medline, ISI Web of Science, SocINDEX, PsycInfo, PsycArticles and Psychological and Behavioral Sciences Collection, using keywords related to "misuse", "appropriateness" and "medicine" between 1 November 2008 and 25 August 2020. Additional searches were conducted in websites of regulatory agencies and public health institutions. Two authors independently selected studies providing both definitions and examples of misuse, while a third resolved disagreements. Definitions were used to propose a hierarchical classification based on initiator, intent, purpose and context of medicine misuse. The study is registered on PROSPERO: CRD42018115789. RESULTS: Of 3404 identified records, 51 were included. A total of 71 definitions and 74 examples of misuse were retrieved. When the prescriber is initiator and according to intent, potential medicine misuse referred to "intentional or unintentional prescribing not in line with clinical evidence". Based on context, they could prescribe medicines not clinically justified, i.e. overprescribing, or prescribe indicated medicines incorrectly, i.e. misprescribing. Among other groups of definitions, those overlapping with drug abuse or medication use errors were considered out-of-scope. CONCLUSION: This systematic review provides a comprehensive overview of the terms and definitions used to characterize medicine misuse and could serve as a basis for a terminology that makes clear distinctions between misuse, abuse and errors

Therapie

AIM OF THE STUDY: Post-mRNA coronavirus diseases 2019 (COVID-19) vaccines myocarditis emerged as a rare adverse effect, particularly in adolescents and young adults, and was labeled as such for both vaccines in the summer of 2021. This study aims to summarize the timeline and process of signal detection, substantiation, and quantification of myocarditis cases related to mRNA vaccines in France. METHODS: The intensive monitoring plan for COVID-19 vaccine safety was based on case-by-case analysis of all cases collected in the French spontaneous reporting database (Base nationale de pharmacovigilance, BNPV). Cases were evaluated by drug safety medical professionals and discussed at a national level for signal detection purposes. Reported cases were compared to the number of vaccine-exposed persons up to September 30th, 2021. Reporting rates (Rr) of myocarditis per 100,000 injections were calculated and stratified according to age, gender, and injection rank of BNT162b2 and mRNA-1273 vaccines. Poisson distribution was used to compute Rrs 95% Confidence Interval (95% CI). RESULTS: The case-by-case analysis detected a possible cluster of myocarditis in April 2021 (5 cases, 4 after the 2nd injection). In June 2021, the signal was substantiated with 12 cases (9 related to BNT162b2, and 3 to mRNA-1273). As of September 2021, almost 73 million BNT162b2 and 10 million mRNA-1273 doses had been injected. The Rr per 100,000 injections was 0.5 (0.5-0.6) for BNT162b2 and 1.1 (95% CI 0.9-1.3) for mRNA-1273. The difference among vaccines was more pronounced after the second injection, particularly in men aged 18-24 years (4.3 [3.4-5.5] for BNT162b2 vs. 13.9 [9.2-20.1] for mRNA-1273) and aged 25-29 years (1.9 [1.2-2.9] vs. 7.0 [3.4-12.9]). CONCLUSION: The study highlighted the role of the spontaneous reporting system in the detection, assessment, and quantification of myocarditis related to m-RNA vaccines. It suggested from September 2021 that mRNA-1273 was reasonably related to a higher risk of myocarditis than BNT162b2 in people under 30, particularly after the second injection

Adverse Drug Reaction-Related to Drug Shortage: A Retrospective Study on the French National Pharmacovigilance Database

International audienceAIM: Drug shortage is a growing global health issue. The aim of the study was to evaluate the consequences of drug shortages on patient safety based on data recorded in the French Pharmacovigilance Database. METHODS: All cases involving drug shortages reported from 1985 to the end of 2019 were extracted from the database. RESULTS: Following the selection process, 462 cases were included. The number of cases increased significantly from 2004 to 2019. Cases mainly involved drugs from the nervous system (22.1%, CI95[17.5;27.0]), the cardiovascular system (16.4%, CI95[11.9;21.4]), and anti-infectives for systemic use (14.3%, CI95[9.7;19.2]) ATC classes. Most of the cases reported an adverse drug reaction (ADR) belonging to the SOC nervous system (21%, CI95[18;24]), skin and subcutaneous (14%, CI95[11;17]), general (13%, CI95[10;17]), and gastrointestinal (8%, CI95[5;11]) disorders. Disease worsening was observed in 15.9% of the cases, mostly related to a lack of efficacy of the replacement drug. Half of the cases were considered as serious. Evolution was favourable in 79.4% of the cases. Death and/or life-threatening situations were reported in 5.8% of the cases. Medication errors (ME) were identified in 51 cases (11%), mostly occurring at the administration step and involving a human factor. CONCLUSION: This study emphasises the clinical impact of drug shortage in terms of ADRs, ME and inefficiency. These observations underline the importance of a global health policy programme to limit the occurrence of drug shortages and to reinforce the information provided to patients and health care professionals in this context to limit risk