Comparative Pharmacovigilance of Quetiapine, Clozapine, and Pimavanserin in Dementia With Lewy Bodies: A FAERS Analysis

Background: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer’s disease. There are currently no FDA-approved drugs specifically indicated for DLB, but several medications are used off-label with varying levels of efficacy and tolerance. The FDA Adverse Event Reporting System (FAERS) Database contains adverse event reports submitted by consumers, healthcare professionals, and manufacturers in support of the FDA’s post-marketing safety surveillance program. This study compares adverse event reporting profiles between three antipsychotic medications—quetiapine (Seroquel®), clozapine (Clozaril®), and pimavanserin (Nuplazid®)—in patients with DLB to generate real-world evidence for future confirmatory research in Lewy body dementia and DLB pharmacotherapy.

Methods: A retrospective pharmacovigilance study was conducted using the FAERS Database. Included reports were those received between 2016 and 2026 that listed DLB as Reason for Use; listed quetiapine, clozapine, and/or pimavanserin as Suspect Product Active Ingredient; and resulted in Serious Outcomes as defined by the database. Data was manually deduplicated and cleaned according to the inclusion criteria. Baseline characteristics were summarized using descriptive statistics. Logistic regression models were used to compare reported mortality and reported hospitalization, disability, or life-threatening outcomes among mutually-exclusive study drug group reports. Both unadjusted and age- and sex-adjusted odds ratios (ORs) with 95% confidence intervals were estimated. Adjusted analyses were restricted to complete cases because age was missing for a substantial proportion of reports.

Results: 595 unique FAERS reports were included in the final analysis (clozapine, n=149; quetiapine, n=140; pimavanserin, n=306). In unadjusted analyses for mutually-exclusive study drug groups, pimavanserin was associated with higher odds of reported mortality (OR 1.89, 95% CI 1.26–2.85, p = 0.002), while quetiapine was associated with lower odds (OR 0.30, 95% CI 0.16–0.54, p < 0.001) compared with clozapine. After adjustment for age and sex, these associations persisted, with pimavanserin demonstrating higher odds of mortality (adjusted OR 3.40, 95% CI 1.85–6.36, p < 0.001) and quetiapine lower odds (adjusted OR 0.28, 95% CI 0.14–0.55, p < 0.001). Pimavanserin's lower unadjusted odds of hospitalization, disability, or life-threatening events were no longer significant after adjustment, whereas quetiapine was associated with higher adjusted odds of morbidity metrics (adjusted OR 1.91, 95% CI 1.10–3.35, p < 0.022).

Conclusion: This retrospective analysis presents statistically significant disproportionalities in both mortality and morbidity. Mortality and morbidity ORs between the respective drugs are inversely proportional, where pimavanserin simultaneously carries the greatest odds for mortality and the lowest odds for morbidity. Quetiapine resulted in the inverse correlation. Crucial to note is that this data represents safety signals rather than true clinical incidence or direct causality. Potential channeling and adoption bias may illustrate context where pimavanserin is preferentially utilized monotherapeutically in an inherently more vulnerable or disease-progressed patient subpopulation, rather than reflecting direct drug-class toxicity. Future prospective clinical trials or large-scale electronic health record reviews incorporating exposure-adjusted tracking are required to calculate true incidence rates and fully isolate drug-specific safety risks from baseline neurodegenerative disease severity across distinct DLB populations.