Dopamine restores reward prediction errors in old age.

Senescence affects the ability to utilize information about the likelihood of rewards for optimal decision-making. Using functional magnetic resonance imaging in humans, we found that healthy older adults had an abnormal signature of expected value, resulting in an incomplete reward prediction error (RPE) signal in the nucleus accumbens, a brain region that receives rich input projections from substantia nigra/ventral tegmental area (SN/VTA) dopaminergic neurons. Structural connectivity between SN/VTA and striatum, measured by diffusion tensor imaging, was tightly coupled to inter-individual differences in the expression of this expected reward value signal. The dopamine precursor levodopa (L-DOPA) increased the task-based learning rate and task performance in some older adults to the level of young adults. This drug effect was linked to restoration of a canonical neural RPE. Our results identify a neurochemical signature underlying abnormal reward processing in older adults and indicate that this can be modulated by L-DOPA

Biosimilars in Belgium: a proposal for a more competitive market

More than ten years after the first biosimilars were authorized for use in the European Union, Belgium still experiences limited competition from biosimilars, as exemplified by low market shares. Achieving high biosimilar market shares is not necessarily a goal in itself, as cost savings are also realized by mandatory price reductions on originator medicines in Belgium. However, we believe that biosimilars play a role in ensuring the long-term sustainability of the off-patent biologicals market. It is therefore crucial to list what has been done and what is needed to support the Belgian government in establishing a policy framework for a competitive off-patent biologicals market. We provide a comprehensive overview of the Belgian biosimilar market, including existing hurdles for biosimilar use in Belgium. Based on these hurdles and supplemented with learnings from other European countries, we propose practical recommendations that can be implemented to overcome them. Several Belgian stakeholders had the opportunity to comment on these recommendations. Specifically, we suggest to evolve towards a long-term consistent, integrated policy framework via i) the creation of a proactive and transparent climate supporting a level playing field for both biosimilar and reference product, including public dissemination of how savings at the level of the Belgian healthcare system are used, ii) investment in educational activities, including raising awareness of societal responsibility, iii) enforcement of the practical implementation of public procurement law, and iv) the development of incentives for physicians, who are key stakeholders in the Belgian off-patent biologicals market

An overview of patents on therapeutic monoclonal antibodies in Europe: are they a hurdle to biosimilar market entry?

As patents on many high-selling biological medicines are expiring, non-innovator versions, such as biosimilars, may enter this multi-billion dollar market. This study aims to map patents and patent applications for innovator as well as biosimilar monoclonal antibodies in Europe, and investigates legal challenges associated with patenting the innovator product and alleged infringing activities, focusing on consequences for biosimilar developers. Via an exploratory literature review in PubMed and a database analysis in Darts-ip, Derwent Innovation, and Espacenet, an overview of basic patents and exclusivity rights for some of the best-selling biologicals is given, supplemented with a detailed analysis of patents taken during the medicine’s life cycle via three specific case studies (trastuzumab, bevacizumab, cetuximab). Case law was used to determine which patents were viewed by biosimilar developers as blocking market entry. For the selected monoclonal antibodies, the key protection instruments appeared to be the basic patent and the additional protection provided by a supplementary protection certificate. We observed that additional patents filed after the basic patent are hard to obtain and often insufficient in blocking market entry of biosimilars, but can in some cases be a substantial hurdle for biosimilar developers to overcome in patent litigation cases or to invent around, creating uncertainty on the launch date of a biosimilar on the market. These hurdles, however, seem to be surmountable, given that many cases were won by biosimilar developers. Also, biosimilars can be protected by filing new patents and these mainly pertain to new formulations

The effects of life stress and neural learning signals on fluid intelligence.

Fluid intelligence (fluid IQ), defined as the capacity for rapid problem solving and behavioral adaptation, is known to be modulated by learning and experience. Both stressful life events (SLES) and neural correlates of learning [specifically, a key mediator of adaptive learning in the brain, namely the ventral striatal representation of prediction errors (PE)] have been shown to be associated with individual differences in fluid IQ. Here, we examine the interaction between adaptive learning signals (using a well-characterized probabilistic reversal learning task in combination with fMRI) and SLES on fluid IQ measures. We find that the correlation between ventral striatal BOLD PE and fluid IQ, which we have previously reported, is quantitatively modulated by the amount of reported SLES. Thus, after experiencing adversity, basic neuronal learning signatures appear to align more closely with a general measure of flexible learning (fluid IQ), a finding complementing studies on the effects of acute stress on learning. The results suggest that an understanding of the neurobiological correlates of trait variables like fluid IQ needs to take socioemotional influences such as chronic stress into account

Challenges and Solutions to the Measurement of Neurocognitive Mechanisms in Developmental Settings

Identifying early neurocognitive mechanisms that confer risk for mental health problems is one important avenue as we seek to develop successful early interventions. Currently, however, we have limited understanding of the neurocognitive mechanisms involved in shaping mental health trajectories from childhood through young adulthood, and this constrains our ability to develop effective clinical interventions. In particular, there is an urgent need to develop more sensitive, reliable, and scalable measures of individual differences for use in developmental settings. In this review, we outline methodological shortcomings that explain why widely used task-based measures of neurocognition currently tell us little about mental health risk. We discuss specific challenges that arise when studying neurocognitive mechanisms in developmental settings, and we share suggestions for overcoming them. We also propose a novel experimental approach—which we refer to as “cognitive microscopy”—that involves adaptive design optimization, temporally sensitive task administration, and multilevel modeling. This approach addresses some of the methodological shortcomings outlined above and provides measures of stability, variability, and developmental change in neurocognitive mechanisms within a multivariate framework

The market of biopharmaceutical medicines: A snapshot of a diverse industrial landscape

Background: Biopharmaceutical medicines represent a growing share of the global pharmaceutical market, and with many of these biopharmaceutical products facing loss of exclusivity rights, also biosimilars may now enter the biopharmaceutical market. Objectives: This study aims to identify and document which investment and development strategies are adopted by industrial players in the global biopharmaceutical market. Methods: A descriptive analysis was undertaken of the investment and development strategies of the top 25 pharmaceutical companies according to 2015 worldwide prescription drug sales. Strategies were documented by collecting data on manufacturing plans, development programs, acquisition and collaboration agreements, the portfolio and pipeline of biosimilar, originator and next-generation biopharmaceutical products. Data were extracted from publicly available sources. Results: Various investment and development strategies can be identified in the global biopharmaceutical market: (a) development of originator biopharmaceuticals, (b) investment in biotechnology, (c) development of next-generation biopharmaceuticals, (d) development of biosimilars, (e) investment in emerging countries, and (f) collaboration between companies. In the top 25 pharmaceutical companies almost every company invests in originator biopharmaceuticals and in biotechnology in general, but only half of them develops next-generation biopharmaceuticals. Furthermore, only half of them invest in development of biosimilars. The companies' biosimilar pipeline is mainly focused on development of biosimilar monoclonal antibodies and to some extent on biosimilar insulins. A common strategy is collaboration between companies and investment in emerging countries. Conclusions: A snapshot of investment and development strategies used by industrial players in the global biopharmaceutical market shows that all top 25 pharmaceutical companies are engaged in the biopharmaceutical market and that this industrial landscape is diverse. Companies do not focus on a single strategy, but are involved in multiple investment and development strategies. A common strategy to market biopharmaceuticals is collaboration between companies. These collaborations can as well be used to gain access in regions the company has less experience with. With patents expiring for some of the highest selling monoclonal antibodies, this snapshot highlights the interest of companies to invest in the development of these molecules and/or enter into collaborations to create access to these molecules

Learnings from Regional Market Dynamics of Originator and Biosimilar Infliximab and Etanercept in Germany.

Drug budget and prescription control measures are implemented regionally in Germany, meaning that the uptake of pharmaceuticals, including biosimilars, can vary by region. We examine regional market dynamics of tumor necrosis factor alpha (TNFα) inhibitor originators and biosimilars in Germany and studied the influence of biosimilar policies on these dynamics. This study is based on: (1) a literature review in which German biosimilar policies are identified, (2) the analysis of dispensing data (2010-2018) for the class of TNFα inhibitors, and (3) ten semi-structured interviews investigating prescribers' and insurers' views on factors potentially influencing biosimilar uptake. The analysis of biosimilar market shares of infliximab and etanercept revealed wide variations across the 17 German Regional Associations of Statutory Health Insurance Accredited Physicians (PA regions). Quantitative analyses indicated that biosimilar market shares for infliximab and etanercept were significantly lower in former East Germany when compared to former West Germany regions. Through qualitative interview analyses, this study showed that the use of infliximab and etanercept biosimilars across Germany is primarily influenced by (1) the regional-level implementation of biosimilar quotas and the presence of monitoring/sanctioning mechanisms to ensure adherence to these quotas, (2) the different insurer-manufacturer discount contracts, and (3) gainsharing arrangements established at the insurer-prescriber level

The relationship between resting-state functional connectivity, antidepressant discontinuation and depression relapse

The risk of relapsing into depression after stopping antidepressants is high, but no established predictors exist. Resting-state functional magnetic resonance imaging (rsfMRI) measures may help predict relapse and identify the mechanisms by which relapses occur. rsfMRI data were acquired from healthy controls and from patients with remitted major depressive disorder on antidepressants. Patients were assessed a second time either before or after discontinuation of the antidepressant, and followed up for six months to assess relapse. A seed-based functional connectivity analysis was conducted focusing on the left subgenual anterior cingulate cortex and left posterior cingulate cortex. Seeds in the amygdala and dorsolateral prefrontal cortex were explored. 44 healthy controls (age: 33.8 (10.5), 73% female) and 84 patients (age: 34.23 (10.8), 80% female) were included in the analysis. 29 patients went on to relapse and 38 remained well. The seed-based analysis showed that discontinuation resulted in an increased functional connectivity between the right dorsolateral prefrontal cortex and the parietal cortex in non-relapsers. In an exploratory analysis, this functional connectivity predicted relapse risk with a balanced accuracy of 0.86. Further seed-based analyses, however, failed to reveal diferences in functional connectivity between patients and controls, between relapsers and non-relapsers before discontinuation and changes due to discontinuation independent of relapse. In conclusion, changes in the connectivity between the dorsolateral prefrontal cortex and the posterior default mode network were associated with and predictive of relapse after open-label antidepressant discontinuation. This fnding requires replication in a larger dataset

Low predictive power of clinical features for relapse prediction after antidepressant discontinuation in a naturalistic setting

The risk of relapse after antidepressant medication (ADM) discontinuation is high. Predictors of relapse could guide clinical decision-making, but are yet to be established. We assessed demographic and clinical variables in a longitudinal observational study before antidepressant discontinuation. State-dependent variables were re-assessed either after discontinuation or before discontinuation after a waiting period. Relapse was assessed during 6 months after discontinuation. We applied logistic general linear models in combination with least absolute shrinkage and selection operator and elastic nets to avoid overfitting in order to identify predictors of relapse and estimated their generalisability using cross-validation. The final sample included 104 patients (age: 34.86 (11.1), 77% female) and 57 healthy controls (age: 34.12 (10.6), 70% female). 36% of the patients experienced a relapse. Treatment by a general practitioner increased the risk of relapse. Although within-sample statistical analyses suggested reasonable sensitivity and specificity, out-of-sample prediction of relapse was at chance level. Residual symptoms increased with discontinuation, but did not relate to relapse. Demographic and standard clinical variables appear to carry little predictive power and therefore are of limited use for patients and clinicians in guiding clinical decision-making