Tsuyoshi Nakai

Background: Anti-amyloid-β (Aβ) monoclonal antibodies are disease-modifying treatments for early Alzheimer's disease but are associated with amyloid-related imaging abnormalities (ARIA) and intracranial hemorrhage (ICH). However, the safety of concomitant antithrombotic use remains unclear.Objective: To evaluate potential drug-drug interaction (DDI) signals between anti-Aβ antibodies and antithrombotic drugs for ARIA and ICH using the FDA Adverse Event Reporting System (FAERS; JAPIC AERS).Methods: FAERS reports from 1997 to 2024 were analyzed. The anti-Aβ antibodies evaluated were aducanumab, lecanemab, and donanemab. Antithrombotics were aspirin, P2Y12 inhibitors, direct oral anticoagulants, warfarin, and tissue-type plasminogen activators (tPAs). Outcomes were any ARIA, ARIA with edema or effusion (ARIA-E), ARIA with hemosiderin deposition (ARIA-H), and ICH. Individual-drug signals were assessed using reporting odds ratios and information components; DDIs were evaluated using four complementary models.Results: All three antibodies showed positive signals for all outcomes. When the three antibodies were analyzed together, aspirin showed positive DDI signals for any ARIA, ARIA-E, and ARIA-H in three models. Lecanemab-aspirin also showed signals for any ARIA and ARIA-H in multiple models. For ICH, tPAs showed signals in all four models with lecanemab and in the analysis combining all anti-Aβ antibodies. Both analyses were based on the same five lecanemab reports.Conclusions: DDI signals were detected for anti-Aβ antibody-aspirin combinations for ARIA and anti-Aβ antibody-tPA combinations for ICH, particularly with lecanemab. These findings may warrant careful review of aspirin indications and baseline hemorrhagic risk and caution with thrombolysis during anti-Aβ antibody treatment, although prospective validation is needed.

Background: Clozapine is associated with a high risk of central nervous system abnormalities. However, seizure risk related to interactions between clozapine and other antipsychotics remains poorly characterized, and the pharmacological mechanisms underlying these seizures are unclear. Objectives: We aimed to evaluate safety signals for seizures associated with clozapine augmentation by other antipsychotics and analyze the relationship between these signals and neurotransmitter receptor occupancy profiles. Design: A pharmacovigilance–pharmacodynamic analysis using a spontaneous reporting system. Methods: This pharmacovigilance study used VigiBase, an adverse drug reaction database maintained by the World Health Organization. Drug–drug interactions (DDIs) between clozapine and other antipsychotics were assessed using the Ω shrinkage measure model. The association between DDI signals and neurotransmitter receptor occupancy was evaluated using linear regression. Robustness was tested using four frequency statistical models: additive, multiplicative, combination risk ratio, and chi-square statistic models. Results: Of 38,758,077 reports in VigiBase between 1990 and 2024, 230,371 involved clozapine. Among antipsychotics classified under ATC code N05A, DDIs with clozapine were detected for amisulpride, chlorpromazine, haloperidol, lurasidone, olanzapine, penfluridol, risperidone, sulpiride, zotepine, and zuclopenthixol. A significant association between dopamine D ₄ receptor occupancy and the point estimates of signal values was observed in the Ω shrinkage measure model (β = 0.295, 95% confidence interval: 0.119–0.471, p  = 0.002) and replicated across all frequency statistical models. Conclusions: These findings suggest a potential role of dopamine D ₄ receptor occupancy in seizures associated with clozapine augmentation by other antipsychotics. Further large-scale epidemiological studies are needed to validate these findings.