Characterization and clinical prioritization of neurotoxicity-related safety signals associated with lithium and haloperidol co-administration: A pharmacovigilance study based on FAERS

The concurrent use of lithium carbonate and haloperidol is common in psychiatric practice, yet it remains unclear which neurotoxicity-related adverse events are specific to the combination rather than to either agent alone. This study aimed to identify and prioritize the neurotoxicity-related manifestations potentially associated with this drug combination.

Neurological and psychiatric adverse event reports were extracted from FAERS covering Q1 2004 through Q4 2025 and stratified into lithium reports without haloperidol, haloperidol reports without lithium, and combination co-administration reports. Drug-event-pair-based reporting odds ratios were used for signal estimation, while report-level dual-comparator screening was used to retain co-administration-associated signals. Retained signals were ranked using a semi-quantitative clinical prioritization system. Sensitivity analysis under a stricter exposure definition assessed robustness.

A total of 9745 target reports were included (combination co-administration: 429; lithium without haloperidol: 3688; haloperidol without lithium: 5628). Twenty-eight reporting signals were more frequently reported with co-administration than with reports involving either target drug without the other in the main analysis, with 14 retained after sensitivity analysis. Neuroleptic malignant syndrome, neurotoxicity, encephalopathy, and delirium remained moderate-priority signals in both analyses.

Neurotoxicity, neuroleptic malignant syndrome, encephalopathy, and delirium warrant prioritized clinical attention during lithium carbonate and haloperidol co-administration. These hypothesis-generating findings support targeted neurological and neuropsychiatric monitoring for patients receiving this combination.