Introduction: Clopidogrel is commonly used after ischemic stroke, and acid-suppressive agents are often prescribed to reduce gastrointestinal complications. However, the effects of P-CABs and PPIs on clopidogrel-related outcomes remain uncertain.

Aims: This study evaluated the efficacy and safety of concomitant P-CAB or PPI use in patients with ischemic stroke receiving clopidogrel.

Methods: We conducted a retrospective cohort study using nationwide claims data from 2016 to 2022. Patients with first-recorded ischemic stroke were identified using prespecified criteria and grouped as clopidogrel only, clopidogrel with P-CAB, or clopidogrel with PPI. After propensity score matching, 6-month risks of major adverse cardiovascular events, recurrent stroke, and gastrointestinal bleeding were compared.

Results: Among 65,180 patients with newly identified stroke between 2017 and 2021, 40,752 (62.5%) received clopidogrel. Of these, 6680 (16.4%) received clopidogrel alone, 578 (1.4%) received clopidogrel with P-CAB, and 8806 (21.6%) received clopidogrel with PPI. Recurrent stroke occurred in 268 (4.0%), 26 (4.5%), and 431 (4.9%) patients, respectively. In matched analyses, P-CAB use was associated with increased risks of major adverse cardiovascular events (HR, 2.40 [95% CI, 1.18–4.85]) and recurrent stroke (HR, 2.64 [95% CI, 1.27–5.47]) versus clopidogrel alone. PPI use was also associated with higher risks of major adverse cardiovascular events (HR, 1.38 [95% CI, 1.17–1.63]) and recurrent stroke (HR, 1.41 [95% CI, 1.20–1.67]). Esomeprazole showed similar associations, whereas gastrointestinal bleeding did not differ significantly among groups.

Conclusions: Concomitant use of P-CABs or PPIs with clopidogrel was associated with worse ischemic outcomes in patients with ischemic stroke. These agents should be prescribed cautiously in this population.

Keywords: Ischemic stroke, Clopidogrel, Potassium-competitive acid blockers.

Introduction: Migraine is associated with up to a six-fold increased risk of major depressive disorder, yet comparative evidence on depression risk between oral prophylactics and CGRP-targeted injections remains limited. Prospective studies have only evaluated changes in depressive symptom severity among patients with pre-existing depression instead of incident depression.

Aims: We compared depression incidence among migraine or headache patients continuing/initiating oral prophylactics versus those switching/initiating to CGRP-targeted injections.

Methods: We conducted a retrospective cohort study using the JMDC claims database up to February 2025. A prevalent new-user (PNU) design compared patients switching from oral prophylactics (propranolol, amitriptyline, valproate, lomerizine, verapamil, and dimetotiazine) to CGRP injections (erenumab, fremanezumab, and galcanezumab) versus those continuing oral prophylactics. An active-comparator new-user (ACNU) design was restricted to incident new users. All patients had migraine/headache diagnosis and no depression at baseline. Incident depression was the primary outcome. Adjusted HRs with 95% CIs were estimated from stratified Cox models with 1:4 time-conditional propensity score matching (PNU), and from IPTW Cox models (ACNU).

Results: In the PNU cohort (19,469 continued-oral, 3,783 switch-to-CGRP), switching to CGRP was not associated with a difference in incident depression versus continuing oral prophylactics (incidence rate: 7.79 vs 7.61 per 100 person-years; adjusted HR: 1.00; 95% CI: 0.87-1.16). In the ACNU cohort (137,152 oral initiators, 2,032 CGRP injection initiators), initiating CGRP was associated with a 47% lower risk of incident depression versus initiating oral prophylactics (incidence rate: 4.97 vs. 8.28 per 100 person-years; adjusted HR: 0.53; 95% CI: 0.40-0.70). Sensitivity analyses yielded consistent results.

Conclusions: Initiating CGRP injections as first-line preventive therapy was associated with a substantially lower risk of incident depression compared with initiating oral prophylactics. However, this protective association was not observed when CGRP injections were used as a later-line option after prior oral therapy.

Keywords: CGRP-targeting therapy; oral prophylactics; migraine

Introduction. Epilepsy is associated with substantial economic burden and increased risks of psychiatric comorbidities, including depression. However, pharmacovigilance evidence regarding drug-associated epilepsy remains limited.
Aims. We aimed to identify the top 10 drugs associated with epilepsy-related adverse events using FAERS and to estimate the global burden of idiopathic epilepsy using GBD 2023 data.
Methods. This study utilized the United States Food and Drug Administration Adverse Event Reporting System (FAERS) to identify the top 10 drugs associated with epilepsy. Epilepsy was defined using preferred terms based on the Medical Dictionary for Regulatory Activities. Pharmacovigilance signals were identified using disproportionality analyses with the information component and reporting odds ratio (ROR), along with corresponding 95% confidence intervals (CIs). We also assess the global burden of idiopathic epilepsy between 1990 and 2023, using data from the Global Burden of Disease Study 2023. Burden of idiopathic epilepsy was assessed using disability-adjusted life years (DALYs), with 95% uncertainty intervals (UIs).
Results. Among 3,843 reported epilepsy-related adverse events, females accounted for 55.45%. Although Adalimumab was the most frequently reported drug (n=706), disproportionality signals were not significant. Imipenem/cilastatin showed the strongest signals (IC 6.24 [IC0.25, 6.11]; ROR 96.96 [95% CI, 89.13-105.49]), with disproportionality signals progressively increasing with age and peaking among individuals aged ≥70 years. Reporting trends for Natalizumab and Bupropion declined over time. In 2023, Sub-Saharan Africa had the highest age-standardized DALY rates for idiopathic epilepsy. DALY rates showed a U-shaped age distribution, peaking among children aged <5 years, and were consistently higher in males than in females.
Discussion. Several drugs showed strong pharmacovigilance signals for epilepsy, particularly imipenem/cilastatin, with disproportionately elevated risks observed among older adults. Given the substantial burden of idiopathic epilepsy across vulnerable populations and regions, enhanced neurological safety monitoring and targeted prevention strategies may be warranted.
Keywords. Pharmacovigilance, epilepsy, DALY.

Introduction: Dyslipidemia represents a major health burden and shares complex pathophysiological mechanisms with bone metabolism. Antiresorptive medications are the cornerstone of osteoporosis management, but their pleiotropic effects on lipid profiles remain controversial. The comparative impact of denosumab versus bisphosphonates on the incidence of lipid disorders is currently poorly understood.

Aims: This study aims to compare the real-world effectiveness of denosumab and bisphosphonates in reducing the risk of incident dyslipidemia. We also sought to evaluate these metabolic effects across various high-risk clinical subgroups.

Methods:We conducted a retrospective active-comparator, new-user cohort study using a large federated electronic health record network. Participants included osteoporotic patients aged 50 years and older, excluding those with baseline lipoprotein disorders to minimize confounding by indication. Incident dyslipidemia was assessed using Cox regression after a 183-day landmark period within 1:1 propensity score-matched cohorts.

Results: After matching, 62,671 patient pairs (mean age 71.2 years, 91% female) were analyzed. Denosumab initiation was associated with a significantly lower risk of incident dyslipidemia compared to bisphosphonate therapy (HR 0.92, 95% CI 0.90-0.94, p<0.001). This protective effect demonstrated strong robustness to unmeasured confounding (E-value 1.33). The lipid-lowering benefit was significantly amplified in patients with baseline diabetes (HR 0.786, p for interaction=0.005). Furthermore, concurrent statin utilization synergistically enhanced this metabolic protection (HR 0.826, p for interaction<0.001). Conversely, concomitant systemic steroid use completely neutralized denosumab’s advantages (HR 0.987, p for interaction=0.027).

Conclusions: Denosumab therapy significantly lowers incident dyslipidemia risk in osteoporosis, especially among patients with concurrent diabetes or statin use. These findings advocate for personalizing osteoporosis treatments based on underlying cardiometabolic risks. Future prospective trials should elucidate the specific molecular mechanisms driving this benefit.

Keywords: Denosumab, Bisphosphonates, Dyslipidemia

Introduction:
Conventional pharmacovigilance focuses on the suspected drug recorded in each adverse drug reaction (ADR) report. In polypharmacy, however, a serious outcome may reflect the full set of concurrent medications rather than any single suspected agent. We asked whether class-level profiles built from all concomitant medications capture seriousness-related patterns that are attenuated when only suspected drugs are analyzed.

Objectives:
To characterize medication class profiles in polypharmacy ADR reports and to test whether restricting analysis to suspected drugs underestimates the association between medication complexity and serious outcomes.

Methods:
We analyzed a Korean national spontaneous ADR reporting database (2020–2024), retaining reports with five or more concomitant medications. ATC third-level classes with at least 100 reports were profiled using medication-complexity and reporting-context variables (e.g., age, sex). We applied principal component analysis, factor analysis, and Ward clustering. Sensitivity analyses compared profiles derived from all concomitant medications against those derived from suspected drugs only.

Results:
Profiling identified three dimensions: medication complexity, age-related reporting, and sex-related reporting. Although seriousness was not used to build the profiles, the complexity dimension was associated post hoc with serious-event rate, hospitalization, and death. Restricting the analysis to suspected drugs substantially weakened these associations, indicating that suspected-drug-only profiles retained less of the seriousness-related structure present in the full concomitant profile. The complexity gradient persisted across age and sex strata, arguing against a simple reflection of patient demographics. Clustering separated classes into interpretable groups with distinct complexity and seriousness gradients.

Conclusion:
Seriousness-related signals in polypharmacy ADR reports were expressed more strongly in the full concomitant medication class profile than in suspected drugs alone. Suspected-drug-centered surveillance may therefore overlook context-level risk that arises from the medication environment as a whole. Routinely profiling all concomitant medications could give pharmacovigilance an additional, scalable lens for flagging high-risk polypharmacy reports that current workflows leave underexamined.

Introduction: Prior studies link high anticholinergic burden to increased cardiovascular risk in older adults, but burden scores aggregate diverse drug classes, leaving unclear whether this risk reflects cumulative burden or specific drug-class exposures. Moreover, prior studies have failed to capture the dynamic, time-varying nature of real-world anticholinergic use.

Aims: To identify multi-trajectory subtypes of anticholinergic medication-class use among older adults and evaluate their association with cardiovascular outcomes by frailty status.

Methods: Using nationwide claims database, we identified adults aged ≥65 years newly initiating Anticholinergic Cognitive Burden (ACB) Scale-listed medication in 2012. Individuals with 4-point major adverse cardiovascular events (4p-MACE) or death before or during the 3-year exposure period were excluded. Exposure across six drug categories (cardiovascular, psychotropic, antihistamine, overactive bladder, gastrointestinal, and theophylline/other) was measured quarterly and analyzed using group-based multi-trajectory modeling. Cox proportional hazards models, adjusted for age, sex, ACB score, cardiovascular risk factors, and multimorbidity frailty index (mFI), estimated hazard ratios for 4p-MACE and all-cause mortality over 9 years, with mFI-stratified subgroup analyses.

Results: Among 55,675 eligible participants (mean age 74.0± 6.4 years; 52.5% female), four subtypes were identified: transient (57.1%) and three persistent subtypes－CV-dominant (14.5%), psychotropic-dominant (16.0%), and theophylline/antihistamine-dominant (12.5%). Relative to transient users, CV-dominant and theophylline/antihistamine-dominant trajectories showed significantly higher 4p-MACE risk (aHR 1.22, 95% CI, 1.16-1.27; aHR 1.08, 95% CI, 1.03-1.13) and all-cause mortality (aHR 1.21, 95% CI, 1.16-1.26; aHR 1.15, 95% CI, 1.11-1.20). The psychotropic-dominant group showed no significant association with 4p-MACE (aHR 0.99, 95% CI, 0.94-1.04) but a significantly higher mortality risk (aHR 1.11, 95% CI, 1.07-1.16). Risks attenuated to non-significance in the severely frail stratum (CV-dominant 4p-MACE: aHR 1.00, 95% CI, 0.81-1.24).

Conclusions: Associations between anticholinergic medications and cardiovascular or mortality outcomes are drug-class specific and frailty-dependent, supporting composition-based rather than purely cumulative risk assessment.

Keywords: anticholinergic burden, multi-trajectory modeling, cardiovascular risk