What drives the rise of antidepressant consumption? Evidence from Switzerland

Antidepressant (AD) consumption has been steadily increasing in the last decade in most countries. The explanations suggested by researchers for this increment are still under scrutiny. This study attempts to identify the determinants of AD consumption by exploiting small area variations from Switzerland between 2003 and 2014. We observe that two specific drugs - Citalopram and Escitalopram - within the Selective Serotonin Re-uptake Inhibitors (SSRI) category are mainly responsible for the increasing trend in AD consumption. Socio-economic, demographic, cultural, and geographical characteristics of the area are included in multiple regression models with random and fixed effects of AD consumption per capita. While most of these factors contribute to explain cross-area variations in AD use, they provide little explanation for the temporal trend in overall AD consumption. Conversely, we find that the time trend in AD consumption is explained at least partially by the density of prescribing physicians. More precisely, generic AD turn out to be positively associated with adverse local economic conditions, while branded AD are negatively associated with adverse economic conditions and positively related to the presence of neurologists and psychiatrists in the area. This may suggest that generic AD drugs are more likely prescribed in accordance to need, whereas branded AD are more likely to respond to preferences and financial incentives affecting suppliers

The effect of local growth in antidepressant consumption on mental health outcomes

Despite growing skepticism regarding the efficacy of antidepressants, global consumption is increasing at an unprecedented path with unknown implications for society. We estimate the causal effect of this increase on mental health outcomes using an IV strategy that exploits detailed drug sales data from Switzerland between 2002 and 2014. Our instrument, a modified version of the popular shift-share instrument, relies on the national growth in antidepressant sales for pharmaceutical companies (the shift) - mainly due to product innovation - and assigns it locally using regional non-antidepressant market shares. Our estimates show that an increase in antidepressants sales does not significantly affect suicide rates but cause an increase of hospital admissions for mental disorder and for depression. The causal effects prove to be resistant to several robustness checks

Evaluation der Offshore-ArbZV

Die Verordnung über die Arbeitszeit bei Offshore-Tätigkeiten (Offshore-ArbZV) ist am 1. August 2013 in Kraft getreten. Mit der in § 17 Offshore-ArbZV vorgesehenen Evaluation sollen die Umsetzung und Anwendung der Verordnung analysiert, potenzielle Wirkungskanäle der Offshore-ArbZV identifiziert und, sofern möglich, Wirkungsmechanismen und Wirkungen der Verordnung ermittelt werden. Die beiden zentralen Leitfragen sind die Untersuchung der Angemessenheit der vorgesehenen Ausgleichsmaßnahmen nach Art und Umfang sowie eine Prüfung, ob die Offshore-ArbZV den im § 1 Abs. 1 ArbZG garantierten Arbeits- und Gesundheitsschutz gewährleistet. Bereits im Vorfeld der Evaluation wurde darauf verwiesen, dass eine Beantwortung der Leitfragen aus methodischen Gründen nur mit Einschränkungen möglich ist. So ist das Fehlen geeigneter interner oder externer Referenzgrößen eine entscheidende Einschränkung. Für die Untersuchung der Fragestellung hat das Evaluationsteam auf eine Kombination unterschiedlicher empirischer Ansätze zurückgegriffen. Die Ergebnisse der Evaluation zeigen, dass die in der Offshore-ArbZV vorgesehenen Ausgleichsmaßnahmen vor dem Hintergrund der festgeschriebenen Ausnahmeregelungen nach Art und Umfang angemessen sind. Zwar lässt sich nicht abschließend klären, ob die Offshore-ArbZV ein Niveau des Arbeits- und Gesundheitsschutzes gewährleistet, wie ihn auch das ArbZG garantiert, aber sie leistet mit einem verbindlichen Rechtsrahmen zur Arbeitszeit einen wichtigen Beitrag zum sehr hohen Arbeits- und Gesundheitsschutzniveau in der Offshore-Branche.The Offshore Working Time Ordinance (Offshore-ArbZV) entered into force on 1 August 2013. According to § 17 Offshore-ArbZV an evaluation should analyse the implementation and application of the Offshore-ArbZV, identify potential impact channels and, if possible, determine the effects and impact mechanisms of the law. The two key questions are if the form and scope of the intended compensatory measures are adequate and whether the Offshore-ArbZV ensures the level of occupational health and safety protection guaranteed according to § 1 (1) ArbZG. It was already pointed out in advance of the study, that these key questions cannot be fully answered due to methodological reasons, e.g. the lack of suitable internal or external references is a crucial limitation. The evaluation team used a combination of different empirical approaches to analyse the issue. The results of the evaluation show that the intended compensatory measures of the Offshore-ArbZV are appropriate in type and scope. Although it cannot be conclusively clarified whether the Offshore-ArbZV guarantees a level of occupational health and safety, as ensured by the ArbZG, but the binding legal framework on working hours are an important contribution to the very high level of occupational health and safety in the offshore industry

Polyglutamine-expanded ataxin-3: a target engagement marker for spinocerebellar ataxia type 3 in peripheral blood

Background: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. Objective: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF). Methods: Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials. Results: Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases. Conclusions: The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyFunding agencies: This project is supported by the EU Joint Programme—Neurodegenerative Disease Research (JPND) through the following funding organizations under the aegis of JPND: Germany, Federal Ministry of Education and Research (BMBF; funding codes 01ED1602A/B); Netherlands, The Netherlands Organisation for Health Research and Development; Portugal, Foundation for Science and Technology (FCT, grant number JPCOFUND/0001/2015), and Regional Fund for Science and Technology of the Azores; and United Kingdom, Medical Research Council. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 643417. In addition, support has been received by the BIONIC project (number 733050822, which has been made possible by ZonMW as part of “Memorabel,” the research and innovation program for dementia, as part of the Dutch national “Deltaplan for Dementia”: zonmw.nl/dementiaresearch), the CAF[1]E project (the National Institutes of Health, USA, grant number 5R01NS104147-02), and a grant from the Selfridges Group Foundation (NR170024). The BIONIC project is a consortium of Radboudumc, LUMC, ADX Neurosciences, and Rhode Island University

Missense variants in ANO4 cause sporadic encephalopathic or familial epilepsy with evidence for a dominant-negative effect

Anoctamins are a family of Ca$^{2+}$-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure. Four variants are localized close to the Ca$^{2+}$ binding sites of ANO4, suggesting impaired protein function. Variant mapping to the protein topology suggests a preliminary genotype-phenotype correlation. Moreover, the observation of a heterozygous ANO4 deletion in a healthy individual suggests a dysfunctional protein as disease mechanism rather than haploinsufficiency. To test this hypothesis, we examined mutant ANO4 functional properties in a heterologous expression system by patchclamp recordings, immunocytochemistry, and surface expression of annexin A5 as a measure of phosphatidylserine scramblase activity. All ANO4 variants showed severe loss of ion channel function and DEE/EE associated variants presented mild loss of surface expression due to impaired plasma membrane trafficking. Increased levels of Ca$^{2+}$-independent annexin A5 at the cell surface suggested an increased apoptosis rate in DEE-mutant expressing cells, but no changes in Ca$^{2+}$-dependent scramblase activity were observed. Co-transfection with ANO4 wild-type suggested a dominant-negative effect. In summary, we expand the genetic base for both encephalopathic sporadic and inherited fever-sensitive epilepsies and link germline variants in ANO4 to a hereditary disease

Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection

Innate immune cells detect pathogens via pattern recognition receptors (PRRs), which signal for initiation of immune responses to infection. Studies with Dectin-1, a PRR for fungi, have defined a novel innate signaling pathway involving Syk kinase and the adaptor CARD9, which is critical for inducing Th17 responses to fungal infection. We show that another C-type lectin, Dectin-2, also signals via Syk and CARD9, and contributes to dendritic cell (DC) activation by fungal particles. Unlike Dectin-1, Dectin-2 couples to Syk indirectly, through association with the FcRγ chain. In a model of Candida albicans infection, blockade of Dectin-2 did not affect innate immune resistance but abrogated Candida-specific T cell production of IL-17 and, in combination with the absence of Dectin-1, decreased Th1 responses to the organism. Thus, Dectin-2 constitutes a major fungal PRR that can couple to the Syk–CARD9 innate signaling pathway to activate DCs and regulate adaptive immune responses to fungal infection

What drives the rise of antidepressant consumption? Evidence from Switzerland

Antidepressant (AD) consumption has been steadily increasing in the last decade in most countries. The explanations suggested by researchers for this increment are still under scrutiny. This study attempts to identify the determinants of AD consumption by exploiting small area variations from Switzerland between 2003 and 2014. We observe that two specific drugs - Citalopram and Escitalopram - within the Selective Serotonin Re-uptake Inhibitors (SSRI) category aremainly responsible for the increasing trend in AD consumption. Socio-economic, demographic, cultural, and geographical characteristics of the area are included in multiple regression modelswith random and fixed effects of AD consumption per capita. While most of these factors contribute to explain cross-area variations in AD use, they provide little explanation for the temporal trend in overall AD consumption. Conversely, we find that the time trend in AD consumption is explained at least partially by the density of prescribing physicians. More precisely, generic AD turn out to be positively associated with adverse local economic conditions, while branded AD are negatively associated with adverse economic conditions and positively related to the presence of neurologists and psychiatrists in the area. This may suggest that generic AD drugs are more likely prescribed in accordance to need, whereas branded AD are more likely to respond to preferences and financial incentives affecting suppliers

The effect of local growth in antidepressant consumption on mental health outcomes

Despite growing skepticism regarding the efficacy of antidepressants, global consumption is increasing at an unprecedented path with unknown implications for society. We estimate the causal effect of this increase on mental health outcomes using an IV strategy that exploits detailed drug sales data from Switzerland between 2002 and 2014. Our instrument, a modified version of the popular shift-share instrument, relies on the national growth in antidepressant sales for pharmaceutical companies (the shift) - mainly due to product innovation - and assigns it locally using regional non-antidepressant market shares. Our estimates show that an increase in antidepressants sales does not significantly affect suicide rates but cause an increase of hospital admissions for mental disorder and for depression. The causal effects prove to be resistant to several robustness checks