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The ageing process is associated with an increased probability of accumulating health deficits, chronic conditions and geriatric syndromes, leading to a growing prevalence of multimorbidity, defined as the co-occurrence of two or more chronic conditions (of which, at least one physical condition). One of the most frequent and direct consequences of multimorbidity, especially amongst older adults, is polypharmacy, a condition characterized by the concomitant use of five or more drugs per day. Polypharmacy is one of the main risk factors for adverse clinical outcomes, including drug-drug interactions and adverse drug reactions, also resulting in increased hospitalizations, morbidity, and increased use of healthcare resources, with considerable implications for healthcare costs. Deprescribing is one of potential approaches to reduce inappropriate prescribing and it is defined as the stopping or dose reduction of medications that are either inappropriate or unnecessary, especially among patients with polypharmacy. In this review, the major issues associated with polypharmacy among older people, the current guidelines for the management of polypharmacy and the strategies to implement deprescribing in different settings (i.e., hospital setting, nursing homes and general practice) are discussed. [ABSTRACT FROM AUTHOR]

Spontaneous reporting systems remain pivotal for post-marketing surveillance and disproportionality analysis (DA) represents a recognized approach for early signal detection. Although DAs cannot be used per se as a standalone approach to assess a drug-related risk and cannot replace clinical judgment in the individual patient, their role remain irreplaceable for rapid detection of rare and unpredictable adverse drug reactions with strong drug-attributable component (e.g., designated medical events), especially when developed by a multidisciplinary team and combined with a careful case-by-case analysis (individual inspection of reports for causality assessment or to uncover reporting patterns and clinical features). In the recent past, a remarkable increase in publications of pharmacovigilance studies using DAs was observed, albeit the quality was debated: several publications contained "spin", namely, misinterpretation of results to infer causality, calculate incidence, or provide risk stratification, which may ultimately result in unjustified alarm. The development of dedicated Guidelines by the international READUS-PV project (https://readus-statement.org/) will allow reproducible and transparent publication of accurate DAs, thus supporting their real transferability and exploitation by regulators and clinicians. This review offered a perspective on methodological aspects (and understanding) of DAs, their rationale, design, reporting, and interpretation. [ABSTRACT FROM AUTHOR]

Aims: The aims of this study were to measure the prevalence of polypharmacy and describe the prescribing of selected medications known for overuse in older people with polypharmacy in primary care. Methods: This was a multinational retrospective cohort study across six countries: Belgium, France, Germany, Italy, Spain and the UK. We used anonymized longitudinal patient‐level information from general practice databases hosted by IQVIA. Patients ≥65 years were included. Polypharmacy was defined as having 5–9 and ≥10 distinct drug classes (ATC Level 3) prescribed during a 6‐month period. Selected medications were: opioids, antipsychotics, proton pump inhibitors (PPI), benzodiazepines (ATC Level 5). We included country experts on the healthcare context to interpret findings. Results: Age and gender distribution was similar across the six countries (mean age 75–76 years; 54–56% female). The prevalence of polypharmacy of 5–9 drugs was 22.8% (UK) to 58.3% (Germany); ≥10 drugs from 11.3% (UK) to 28.5% (Germany). In the polypharmacy population prescribed ≥5 drugs, opioid prescribing ranged from 11.5% (France) to 27.5% (Spain). Prescribing of PPI was highest with almost half of patients receiving a PPI, 42.3% (Germany) to 65.5% (Spain). Benzodiazepine prescribing showed a marked variation between countries, 2.7% (UK) to 34.9% (Spain). The healthcare context information explained possible underreporting for selected medications. Conclusions: We have found a high prevalence of polypharmacy with more than half of the older population being prescribed ≥5 drugs in four of the six countries. Whilst polypharmacy may be appropriate in many patients, worryingly high usage of PPIs and benzodiazepines supports current efforts to improve polypharmacy management across Europe. [ABSTRACT FROM AUTHOR]

From 2009 to 2015, the IMI PROTECT conducted rigorous studies addressing questions about optimal implementation and significance of disproportionality analyses, leading to the development of Good Signal Detection Practices. The ensuing period witnessed the independent exploration of research paths proposed by IMI PROTECT, accumulating valuable experience and insights that have yet to be seamlessly integrated. This state-of-the-art review integrates IMI PROTECT recommendations with recent acquisitions and evolving challenges. It deals with defining the object of study, disproportionality methods, subgrouping, masking, drug-drug interaction, duplication, expectedness, the debated use of disproportionality results as risk measures, integration with other types of data. Despite the ongoing skepticism regarding the usefulness of disproportionality analyses and individual case safety reports, their ability to timely detect safety signals regarding rare and unpredictable adverse reactions remains unparalleled. Moreover, recent exploration into their potential for characterizing safety signals revealed valuable insights concerning potential risk factors and the patient's perspective. To fully realize their potential beyond hypothesis generation and achieve a comprehensive evidence synthesis with other kinds of data and studies, each with their unique limitations and contributions, we need to investigate methods for more transparently communicating disproportionality results and mapping and addressing pharmacovigilance biases. [ABSTRACT FROM AUTHOR]

The article discusses the process of peer review in pharmacovigilance, specifically focusing on disproportionality analysis (DA) of individual case safety reports (ICSR) systems. It highlights the challenges and limitations of the current peer review process, such as lack of standardization and potential bias. The article emphasizes the importance of complementing DA with careful case-by-case analysis and the need for clear reporting and interpretation of results. It also suggests proposals to improve the peer review process, including standardized reporting, reviewer engagement, and reviewer training. The article concludes by calling for a more effective and innovative model of peer review in pharmacovigilance. [Extracted from the article]

Aims Methods Results Conclusion In this reflection paper, the authors, based on their experience as teachers and students of the courses of Pharmacology at the University of Bologna, reflect on their specific roles towards innovation in the teaching of Clinical Pharmacology.Strengths, weaknesses and challenges are presented as identified during the teaching and learning experience in the currently evolving medical degree programmes of the University in light of current trends in medical education.Keeping in mind the identified challenges together with the features proposed for the model prescriber (knowledgeable, contemporary, communicative and safe), we indicate some ways to improve the students' experience and make sure they develop up‐to‐date skills in Clinical Pharmacology taking advantage of recent ongoing collaborations at European level. International collaboration is indeed necessary to adequately address the current challenges of teaching clinical pharmacology.Our shared conclusion is that empowering students with a scientifically sound method to retrieve relevant information and developing their skills to communicate in an interprofessional and, wherever possible, international environment is the key to prepare future prescribers and, ultimately, to improve patient safety. [ABSTRACT FROM AUTHOR]

Finally, data transformation plays a significant role, such as the loss of information in the FAERS public dashboard's coding of reporter type. In today's data-driven world, where the value of information derived from data is crucial for health-related decision making, a deeper understanding of the data sources we use and the decisions that shape them is a desirable step. For this reason, various ready-made and user-friendly open products or proprietary products have been developed to offer researchers convenient access to FAERS data without the need to manage the pre-processing procedure. [Extracted from the article]

Purpose: Communication atypicalities are considered promising markers of a broad range of clinical conditions. However, little is known about the mechanisms and confounders underlying them. Medications might have a crucial, relatively unknown role both as potential confounders and offering an insight on the mechanisms at work. The integration of regulatory documents with disproportionality analyses provides a more comprehensive picture to account for in future investigations of communication-related markers. The aim of this study was to identify a list of drugs potentially associated with communicative atypicalities within psychotic and affective disorders. Method: We developed a query using the Medical Dictionary for Regulatory Activities to search for communicative atypicalities within the FDA Adverse Event Reporting System (updated June 2021). A Bonferroni-corrected disproportionality analysis (reporting odds ratio) was separately performed on spontaneous reports involving psychotic, affective, and non-neuropsychiatric disorders, to account for the confounding role of different underlying conditions. Drug--adverse event associations not already reported in the Side Effect Resource database of labeled adverse drug reactions (unexpected) were subjected to further robustness analyses to account for expected biases. Results: A list of 291 expected and 91 unexpected potential confounding medications was identified, including drugs that may irritate (inhalants) or desiccate (anticholinergics) the larynx, impair speech motor control (antipsychotics), or induce nodules (acitretin) or necrosis (vascular endothelial growth factor receptor inhibitors) on vocal cords; sedatives and stimulants; neurotoxic agents (anti-infectives); and agents acting on neurotransmitter pathways (dopamine agonists). Conclusions: We provide a list of medications to account for in future studies of communication-related markers in affective and psychotic disorders. The current test case illustrates rigorous procedures for digital phenotyping, and the methodological tools implemented for large-scale disproportionality analyses can be considered a road map for investigations of communication-related markers in other clinical populations. Supplemental Material: https://doi.org/10.23641/asha.23721345 [ABSTRACT FROM AUTHOR]

Background and Aim: Disproportionality analysis is traditionally used in spontaneous reporting systems to generate working hypotheses about potential adverse drug reactions: the so-called disproportionality signals. We aim to map the methods used by researchers to assess and increase the validity of their published disproportionality signals. Methods: From a systematic literature search of published disproportionality analyses up until 1 January 2020, we randomly selected and analyzed 100 studies. We considered five domains: (1) rationale for the study, (2) design of disproportionality analyses, (3) case-by-case assessment, (4) use of complementary data sources, and (5) contextualization of the results within existing evidence. Results: Among the articles, multiple strategies were adopted to assess and enhance the results validity. The rationale, in 95 articles, was explicitly referred to the accrued evidence, mostly observational data (n = 46) and regulatory documents (n = 45). A statistical adjustment was performed in 34 studies, and specific strategies to correct for biases were implemented in 33 studies. A case-by-case assessment was complementarily performed in 35 studies, most often by investigating temporal plausibility (n = 26). Complementary data sources were used in 25 articles. In 78 articles, results were contextualized using accrued evidence from the literature and regulatory documents, the most important sources being observational (n = 45), other disproportionalities (n = 37), and case reports (n = 36). Conclusions: This meta-research study highlighted the heterogeneity in methods and strategies used by researchers to assess the validity of disproportionality signals. Mapping these strategies is a first step towards testing their utility in different scenarios and developing guidelines for designing future disproportionality analysis. [ABSTRACT FROM AUTHOR]

Drug-drug interaction of the sodium glucose co-transporter 2 inhibitors with statins and myopathy: a disproportionality analysis using adverse events reporting data. Keywords: disproportionality analysis; drug-drug interactions; pharmacovigilance; SGLT2 inhibitors; spontaneous reporting system; statins EN disproportionality analysis drug-drug interactions pharmacovigilance SGLT2 inhibitors spontaneous reporting system statins 2365 2368 4 07/21/23 20230801 NES 230801 Drug-drug interactions (DDIs) represent an important cause of serious adverse drug reactions: this results from various guidelines promoting upfront combined pharmacological approaches and relevant polypharmacy with increasing age. Spotlight commentary: The value of spontaneous reporting systems to detect (the lack of) clinically relevant drug-drug interactions in clinical practice. [Extracted from the article]

Pharmaceuticals can reach the environment at all stages of their lifecycle and accumulate in the ecosystem, potentially reaching toxic levels for animals and plants. In recent years, efforts have been made to map and control this hazard. Assessing country‐specific environmental risks could drive regulatory actions towards eco‐friendlier drug utilization and disposal practices. By starting from a list of 25 environmentally hazardous pharmaceuticals developed by Region Stockholm, we integrated eco‐toxicological and 2019–2021 Italian drug utilization data to estimate the environmental impact of pharmaceuticals in Italy. We calculated the risk as the ratio between the predicted environmental concentration (PEC) and the predicted no‐effect concentration (PNEC). We found a high risk for levonorgestrel, ciprofloxacin, amoxicillin, azithromycin, venlafaxine, sertraline and diclofenac and a moderate risk for ethinyloestradiol, oestradiol and clarithromycin. This analysis can be periodically performed to identify the pharmaceuticals with the highest risk for the environment and ascertain if containment measures should be implemented. [ABSTRACT FROM AUTHOR]

Aims: Impulse control disorders (ICDs) are iatrogenic and idiopathic conditions with psychosocial and economic consequences for the affected individuals and their families (e.g. bankruptcy and divorce). However, the definition of ICDs has changed over time, and ICDs are not consistently included within existing taxonomies. We discuss the origins of the ICD diagnostic construct and its unsolved tensions. Methods: To contextualize the ICD diagnostic construct, we provided an overview of its origins in past centuries and followed its development across multiple editions of the Diagnostic and Statistical Manual and the International Classification of Diseases, as well as its definition within emerging ontologies. Results: Two independent roots of the ICD construct emerged: (a) the interest in behavioral excess as expressed in encyclopedic compilations (18th century) and (b) the juridical debate on disruptive conduct and responsibility (19th–20th centuries). These roots underlie the repeated taxonomic remodeling observed throughout the 20th and 21st centuries and three critical issues persisting in both clinical practice and research. First, the number of ICDs keeps increasing across the spectrum of human behaviors, disregarding common pathogenetic and phenomenological grounds. Secondly, ICDs substantially overlap with other mental conditions. Impulsivity is often neglected as a minor inconvenience or side effect when co‐occurring with major diagnoses (e.g. depression) and therefore inadequately managed. Finally, ICDs' definitions display an unsolved tension between being conceived as hobby, moral fault or pathological drive, which may be responsible for stigma and delayed intervention. Conclusion: The reasons that made impulse control disorders (ICDs) difficult to define from their first conceptualization are the same reasons that now complicate taxonomic efforts and diagnosis. Tracing back ICDs' roots and criticalities can help to define a common and less ambiguous theoretical framework, which may also result in the demise of the ICD construct and a move towards more clearly defined and more useful ontologies. [ABSTRACT FROM AUTHOR]

Objective: Due to significant risks to the offspring after intrauterine exposure, the European Medicines Agency issued recommendations in 2014 and 2018 restricting the use of valproate (VPA) in women of childbearing age (WOCA). We aimed to evaluate their impact in the Emilia‐Romagna region (ERR) of Northern Italy. Methods: Using administrative databases, we identified all the ERR residents who received antiseizure medication (ASM) prescriptions from 2010 to 2020. Time series of incidence rates by sex and age group were evaluated for all ASMs. Focusing on VPA, an interrupted time series analysis was applied to assess the impact of the restrictions in WOCA with epilepsy (WOCA‐E) and WOCA with psychiatric disorders (WOCA‐P). We then evaluated the chronological order of ASM prescriptions with regard to the position of VPA. Results: Incidence rates of VPA prescriptions overall decreased over time. A significant decrease was observed only for females. The effect was stronger for WOCA, after both the first (incidence rate ratio [IRR] =.85, 95% confidence interval [CI] =.75–.96) and the second restriction (IRR =.67, 95% CI =.55–.82). The decrease was significant after the second restriction both for WOCA‐E (IRR =.43, 95% CI =.27–.68) and for WOCA‐P (IRR =.49, 95% CI =.35–.70), as well as VPA as a first prescription in both populations. VPA prescriptions as further choice did not show the same trend. Significance: After the regulatory restrictions, an overall significant decline in the use of VPA in WOCA was observed in ERR. The second restriction has been effective in consolidating the prescription trend. However, VPA appears still to be a commonly used drug in WOCA when other ASMs have failed. [ABSTRACT FROM AUTHOR]

Introduction: Impulse control disorders (e.g. pathological gambling, hypersexuality) may develop as adverse reactions to drugs. Pathogenetic hypotheses have mainly focused on D3‐receptor agonism, and switching to alternatives with different pharmacologic mechanisms represents a common management strategy. Nonetheless, treatment failure is common and gaining pathophysiological insights is needed. Aim: We aimed to identify targets potentially contributing to pathologic impulsivity. Method: We performed a pharmacovigilance‐pharmacodynamic study on dopamine agonists and antipsychotics using the Food and Drug Administration Adverse Event Reporting System (January 2004–December 2021). We estimated disproportionate reporting using the Bayesian information component. Using online public databases (IUPHAR, ChEMBL, PDSP, DrugBank), we calculated drug occupancies. To identify the targets potentially contributing to impulsivity, we fitted univariate regression models interpolating information components and occupancies within dopamine agonists and antipsychotics. Sensitivity analyses were performed to check for the robustness of the results. Results: Among 19 887 reports of impulsivity, 5898 recorded an antipsychotic, and 3100 a dopamine agonist. The more robust signals concerned aripiprazole (N = 3091; median information component [95% confidence interval] = 4.51[4.45–4.55]) and brexpiprazole (229; 4.00[3.78–4.16]) for antipsychotics, pergolide (105; 5.82[5.50–6.06]) and pramipexole (2009; 5.43[5.36–5.48]) for dopamine agonists. Robust, significant positive associations between drug occupancy and impulsivity reporting were found for D3 within dopamine agonists (beta = 1.52; P‐value = 0.047) and 5‐HT1a within antipsychotics (1.92, 0.029). Conclusion: Our results supported the role of D3‐receptor agonism in inducing impulsivity in dopamine receptor agonists and identified a potential role of 5‐HT1a receptor agonism in antipsychotics. Investigating these receptors may drive towards a better management of drug‐induced impulsivity. [ABSTRACT FROM AUTHOR]