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Introduction Evidence is lacking on withdrawal syndrome related to individual antidepressants and relevant risk factors for severe reactions. Objective To ascertain whether antidepressants are associated with an increased reporting of withdrawal syndrome as compared with other medications, and to investigate risk factors for severe reactions. Methods This is a case/non-case pharmacovigilance study, based on the VigiBase ® , the WHO global database of individual case safety reports of suspected adverse drug reactions. We performed a disproportionality analysis of reports of antidepressant-related withdrawal syndrome (calculating reporting odds ratio [ROR] and Bayesian information component [IC]). We compared antidepressants to all other drugs, to buprenorphine (positive control), and to each other within each class of antidepressants (selective serotonin reuptake inhibitors [SSRIs], tricyclics and other antidepressants). Antidepressants with significant disproportionate reporting were ranked in terms of clinical priority. Serious versus non-serious reactions were compared. Results There were 31,688 reports of antidepressant-related withdrawal syndrome were found. A disproportionate reporting was detected for 23 antidepressants. The estimated ROR for antidepressants altogether, compared to all other drugs, was 14.26 (95% CI 14.08–14.45), 17.01 for other antidepressants (95% CI 16.73–17.29), 13.65 for SSRIs (95% CI 13.41–13.90) and 2.8 for tricyclics (95% CI 2.59–3.02). Based on clinical priority ranking, the strongest disproportionate reporting was found for paroxetine, duloxetine, venlafaxine and desvenlafaxine, being comparable to buprenorphine. Withdrawal syndrome was reported as severe more often in males, adolescents, persons in polypharmacy, and with a longer antidepressant treatment duration ( p < 0.05). Conclusions Antidepressants are associated with an increased reporting of withdrawal syndrome compared with other drug classes. When prescribing and discontinuing antidepressants, clinicians should be aware of the potentially different proclivity of withdrawal syndrome across individual antidepressants, and the liability to experience more severe withdrawal symptoms in relation to specific patient characteristics.

The presence of pesticides in aquatic ecosystems has become an increasing concern. Contamination of ground and surface water results from substances escaping wastewater treatment plants (WWTP) and leaching from soil. Pesticides pose a significant threat to the aquatic environment, as even trace concentrations can damage the central nervous systems (CNS) of animals and humans. Rotenone (ROT), an electron transport chain inhibitor, causes selective dopaminergic (DA) degeneration, while deltamethrin (DM), a widely used type II pyrethroid insecticide, is known for its neurotoxic effect. We assessed the impact of chronic exposure to ROT (2 µg/L, 4 weeks) and DM (1 and 2.5 µg/L, 15 days) on the central nervous system of adult zebrafish. TUNEL assay analysis ( n  = 15 in total) revealed both pesticides triggered cell death in different brain regions of fish, including areas involved in sensory, motor, and cognitive processes. DM additionally affected regions associated with complex behaviors such as learning, memory, and decision-making. Immunohistological analyses ( n  = 12 in total) showed loss of DA neurons in the areas involved in the motor control of animals exposed to both pesticides. These neurotoxic effects were further supported by behavioral changes ( n  = 38 in total) in the Novel Tank Test (NTT), indicating alterations in movement and anxiety-like behavior. Our findings confirm that chronic sub-threshold exposure to chemicals present in environmental waters causes significant damage to cerebral tissue, leading to apoptosis and behavioral alterations.

Myocarditis and pericarditis following the Coronavirus Disease 2019 (COVID-19) mRNA vaccines administration have been reported, but their frequency is still uncertain in the younger population. This study investigated the association between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccines, BNT162b2, and mRNA-1273 and myocarditis/pericarditis in the population of vaccinated persons aged 12 to 39 years in Italy. We conducted a self-controlled case series study (SCCS) using national data on COVID-19 vaccination linked to emergency care/hospital discharge databases. The outcome was the first diagnosis of myocarditis/pericarditis between 27 December 2020 and 30 September 2021. Exposure risk period (0 to 21 days from the vaccination day, subdivided in 3 equal intervals) for first and second dose was compared with baseline period. The SCCS model, adapted to event-dependent exposures, was fitted using unbiased estimating equations to estimate relative incidences (RIs) and excess of cases (EC) per 100,000 vaccinated by dose, age, sex, and vaccine product. Calendar period was included as time-varying confounder in the model. During the study period 2,861,809 persons aged 12 to 39 years received mRNA vaccines (2,405,759 BNT162b2; 456,050 mRNA-1273); 441 participants developed myocarditis/pericarditis (346 BNT162b2; 95 mRNA-1273). Within the 21-day risk interval, 114 myocarditis/pericarditis events occurred, the RI was 1.99 (1.30 to 3.05) after second dose of BNT162b2 and 2.22 (1.00 to 4.91) and 2.63 (1.21 to 5.71) after first and second dose of mRNA-1273. During the [0 to 7) days risk period, an increased risk of myocarditis/pericarditis was observed after first dose of mRNA-1273, with RI of 6.55 (2.73 to 15.72), and after second dose of BNT162b2 and mRNA-1273, with RIs of 3.39 (2.02 to 5.68) and 7.59 (3.26 to 17.65). The number of EC for second dose of mRNA-1273 was 5.5 per 100,000 vaccinated (3.0 to 7.9). The highest risk was observed in males, at [0 to 7) days after first and second dose of mRNA-1273 with RI of 12.28 (4.09 to 36.83) and RI of 11.91 (3.88 to 36.53); the number of EC after the second dose of mRNA-1273 was 8.8 (4.9 to 12.9). Among those aged 12 to 17 years, the RI was of 5.74 (1.52 to 21.72) after second dose of BNT162b2; for this age group, the number of events was insufficient for estimating RIs after mRNA-1273. Among those aged 18 to 29 years, the RIs were 7.58 (2.62 to 21.94) after first dose of mRNA-1273 and 4.02 (1.81 to 8.91) and 9.58 (3.32 to 27.58) after second dose of BNT162b2 and mRNA-1273; the numbers of EC were 3.4 (1.1 to 6.0) and 8.6 (4.4 to 12.6) after first and second dose of mRNA-1273. The main study limitations were that the outcome was not validated through review of clinical records, and there was an absence of information on the length of hospitalization and, thus, the severity of the outcome. This population-based study of about 3 millions of residents in Italy suggested that mRNA vaccines were associated with myocarditis/pericarditis in the population younger than 40 years. According to our results, increased risk of myocarditis/pericarditis was associated with the second dose of BNT162b2 and both doses of mRNA-1273. The highest risks were observed in males of 12 to 39 years and in males and females 18 to 29 years vaccinated with mRNA-1273. The public health implication of these findings should be considered in the light of the proven mRNA vaccine effectiveness in preventing serious COVID-19 disease and death.

Background: Drug-drug interactions (DDIs) are an important cause of adverse drug reactions (ADRs). In literature most of studies focus only on potential DDIs, while detailed data on serious ADRs associated with DDIs are limited. Our aim is to identify and characterize serious ADRs caused by DDIs using a spontaneous reporting database. Methods: All serious ADR reports, not related to vaccines and with a “definite”, “probable” or “possible” causality assessment, inserted into the National Pharmacovigilance database from Veneto Region (January 1, 2015 to May 31, 2020) were analyzed. A list of drug pairs was created by selecting the reports containing at least two suspected or concomitant drugs. We verified which drug pairs potentially interacted according to the online version of DRUGDEX ® system. For each potential DDI we controlled whether the ADR description in the report corresponded to the interaction effect as described in Micromedex. A detailed characterization of all serious reports containing an occurring DDI was performed. Results: In the study period a total of 31,604 reports of suspected ADRs from the Veneto Region were identified, of which 2,195 serious reports (6.9% of all ADR reports) containing at least two suspected or concomitant drugs were analyzed. We identified 1,208 ADR reports with at least one potential DDI (55.0% of 2,195) and 381 reports (17.4% of 2,195 reports) with an occurring ADR associated with a DDI. The median age of patients and the number of contraindicated or major DDIs were significantly higher in reports with an occurring DDI. Warfarin was the most frequently reported interacting drug and the most common ADRs were gastrointestinal or cerebral hemorrhagic events. The proton pump inhibitors/warfarin, followed by platelet aggregation inhibitors/warfarin were the drug-drug combinations most frequently involved in ADRs caused by DDIs. The highest proportion of fatal reports was observed with platelet aggregation inhibitors/warfarin and antidepressants/warfarin. Conclusion: Our findings showed that about one-third of patients exposed to a potential DDI actually experienced a serious ADR. Furthermore, our study confirms that a spontaneous reporting database could be a valuable resource for identifying and characterizing ADRs caused by DDIs and the drugs leading to serious ADRs and deaths.

There is appreciable utilisation of antihistamines (H1) in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine and astemizole underwent regulatory restrictions in '90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines. To investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries. We identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance. Antihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine) and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine). Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible. Some second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators and clinicians should consider risk-minimisation activities. Also antihistamines without signal but with peculiar use in a few Countries (e.g., levocetirizine) or with increasing consumption (e.g., rupatadine) deserve careful surveillance.

Antipsychotics (APs) have been associated with risk of torsade de Pointes (TdP). This has important public health implications. Therefore, (a) we exploited the public FDA Adverse Event Reporting System (FAERS) to characterize their torsadogenic profile; (b) we collected drug utilization data from 12 European Countries to assess the population exposure over the 2005-2010 period. FAERS data (2004-2010) were analyzed based on the following criteria: (1) ≥ 4 cases of TdP/QT abnormalities; (2) Significant Reporting Odds Ratio, ROR [Lower Limit of the 95% confidence interval>1], for TdP/QT abnormalities, adjusted and stratified (Arizona CERT drugs as effect modifiers); (3) ≥ 4 cases of ventricular arrhythmia/sudden cardiac death (VA/SCD); (4) Significant ROR for VA/SCD; (5) Significant ROR, combined by aggregating TdP/QT abnormalities with VA and SCD. Torsadogenic signals were characterized in terms of signal strength: from Group A (very strong torsadogenic signal: all criteria fulfilled) to group E (unclear/uncertain signal: only 2/5 criteria). Consumption data were retrieved from 12 European Countries and expressed as defined daily doses per 1,000 inhabitants per day (DID). Thirty-five antipsychotics met at least one criterium: 9 agents were classified in Group A (amisulpride, chlorpromazine, clozapine, cyamemazine, haloperidol, olanzapine, quetiapine, risperidone, ziprasidone). In 2010, the overall exposure to antipsychotics varied from 5.94 DID (Estonia) to 13.99 (France, 2009). Considerable increment of Group A agents was found in several Countries (+3.47 in France): the exposure to olanzapine increased across all Countries (+1.84 in France) and peaked 2.96 in Norway; cyamemazine was typically used only in France (2.81 in 2009). Among Group B drugs, levomepromazine peaked 3.78 (Serbia); fluphenazine 1.61 (Slovenia). This parallel approach through spontaneous reporting and drug utilization analyses highlighted drug- and Country-specific scenarios requiring potential regulatory consideration: levomepromazine (Serbia), fluphenazine (Slovenia), olanzapine (across Europe), cyamemazine (France). This synergy should be encouraged to support future pharmacovigilance activities.

Background Drug-induced torsades de pointes (TdP) and related clinical entities represent a current regulatory and clinical burden. Objective As part of the FP7 ARITMO (Arrhythmogenic Potential of Drugs) project, we explored the publicly available US FDA Adverse Event Reporting System (FAERS) database to detect signals of torsadogenicity for antipsychotics (APs). Methods Four groups of events in decreasing order of drug-attributable risk were identified: (1) TdP, (2) QT-interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. The reporting odds ratio (ROR) with 95 % confidence interval (CI) was calculated through a cumulative analysis from group 1 to 4. For groups 1+2, ROR was adjusted for age, gender, and concomitant drugs (e.g., antiarrhythmics) and stratified for AZCERT drugs, lists I and II ( http://www.azcert.org , as of June 2011). A potential signal of torsadogenicity was defined if a drug met all the following criteria: (a) four or more cases in group 1+2; (b) significant ROR in group 1+2 that persists through the cumulative approach; (c) significant adjusted ROR for group 1+2 in the stratum without AZCERT drugs; (d) not included in AZCERT lists (as of June 2011). Results Over the 7-year period, 37 APs were reported in 4,794 cases of arrhythmia: 140 (group 1), 883 (group 2), 1,651 (group 3), and 2,120 (group 4). Based on our criteria, the following potential signals of torsadogenicity were found: amisulpride (25 cases; adjusted ROR in the stratum without AZCERT drugs = 43.94, 95 % CI 22.82–84.60), cyamemazine (11; 15.48, 6.87–34.91), and olanzapine (189; 7.74, 6.45–9.30). Conclusions This pharmacovigilance analysis on the FAERS found 3 potential signals of torsadogenicity for drugs previously unknown for this risk.

Background and Aims Patient and public involvement and engagement (PPIE) in research is crucial for producing knowledge that is meaningful to the participating community. Sharing PPIE principles into practical tools and strategies enriches the development of participatory research methodologies. This article describes the co‐creation process of ProSafe, a Community‐Based Participatory Research (CBPR) project conducted in Italy, which explores community perspectives on the reorganization of territorial healthcare toward proximity care. The aims are: (1) to describe the co‐creation process, (2) to examine its successes and challenges, and (3) to propose strategies and practical recommendations for fostering partnerships and engagement throughout all research stages. Methods The project is based on an explanatory sequential mixed‐method design. A Patient Safety Council (PSC) acted as a co‐researcher. The five‐level spectrum of public engagement developed by the International Association for Public Participation (IAP2) guided the analysis of the decision‐making power balance between academics and the PSC at each phase. Emphasis was given to the process of survey co‐creation. A SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis was performed to identify strategies and practical recommendations to strengthen engagement. Results The SWOT analysis results informed the development of OPERA‐PACT (Opening a Participatory and Equitable Research Agreement based on Partnership, Awareness, Collaboration, and Trust), a framework co‐created with the PSC to formalize shared principles, values, and attitudes that sustain collaborative partnerships. The framework also includes a commitment to continuous monitoring, verification, and feedback to reinforce partnership over time. Conclusions All instruments, strategies, and methodological insights proposed in the article may serve as practical support tools to strengthen the voice of communities in research and to contribute to the production of valid and translational results. Implementing the OPERA‐PACT framework may further help align team members with PPIE principles and lay the foundation for effective and sustainable collaboration.

Background Angiotensin II receptor blockers (ARBs) are widely used to treat hypertension and heart failure. Photosensitivity reactions are cutaneous adverse events due to exposure to a drug and either ultraviolet or visible radiation. Among the ARB class, this type of adverse drug reaction is labeled only for losartan. Objective The aim of this study was to provide a descriptive evaluation of photosensitivity reports with ARBs in the World Health Organization Global Individual Case Safety Report database, VigiBase ® . Methods All reports of photosensitivity reported with ARBs were identified from VigiBase ® . All variables contained in the reports were analyzed. Information component (IC) and its lower limit of a 95 % credibility interval (IC 025 ) values were considered as measures of disproportionality for the assessment of photosensitivity cases reported with ARBs. VigiGrade completeness score ( C ) was used as a measure of quality of each report. Well-documented reports ( C  > 0.8) were fully described and analyzed. Results Up to December 2014, a total of 203 reports on photosensitivity reported with ARBs and submitted by 25 different countries had been recorded in VigiBase ® . Among them, 25.1 % involved losartan, 23.1 % involved irbesartan, and 21.7 % involved valsartan. In 126 cases, the ARB was the only suspected drug and in 10 % of them the reaction was serious. IC and IC 025 values indicated a possible positive correlation between photosensitivity and both irbersartan and losartan. A focus on well-documented reports, after excluding those with a co-prescription of other drugs known to cause photosensitivity, showed that out of 18 cases, six were related to losartan, four to olmesartan, three to irbesartan, two to valsartan and to candesartan, and one to telmisartan. Causality assessment was ‘probable’ in ten cases and ‘possible’ in eight cases. Moreover, positive dechallenge was reported in ten cases and positive rechallenge in one case. Conclusions Photosensitivity reactions have been reported with almost all ARBs in VigiBase ® with a positive disproportionality for irbesartan and losartan. Considering that ARBs share the same chemical structure, which may have the same response to sunlight, it is plausible to consider photosensitivity as a possible class effect. Physicians and patients should be aware of potentially serious photosensitivity reactions related to treatment with ARBs.

Background: Evidence on whether the influenza vaccine could exacerbate immune-related adverse events, including myopericarditis (MP), in patients treated with immune checkpoint inhibitors (ICIs), is still conflicting. We explored this issue through a global real-world approach. Methods: We queried the Vaccine Adverse Event Reporting System (VAERS) and VigiBase to retrieve cases of MP in which the influenza vaccine and ICIs were recorded as suspect and were concomitantly reported. For the included cases, causality assessment and Drug Interaction Probability Scale (DIPS) algorithms were applied. Results: There were 191 and 399 reports of MP with the influenza vaccine that were retrieved (VAERS and VigiBase, respectively). No case of MP reporting the concomitant use of ICIs and the influenza vaccine was found in VAERS, while three cases of myocarditis were retrieved in VigiBase. All of the cases were unclassifiable for a causality assessment because of the lack of data concerning latency. According to the DIPS, one report was categorized as possible and two as doubtful. Conclusion: The paucity of cases coupled with the doubtful causality assessment make the potential interaction between influenza vaccines and ICIs in cancer patients negligible from clinical and epidemiological standpoints. These findings support the cardiovascular safety of the influenza vaccination, which remains strongly recommended in cancer patients, especially in the current COVID-19 era.