Disproportionality Analysis of ‘‘Early-Onset’’ Tardive Dyskinesia Stratified by Time to Onset Using FAERS Database.

Introduction: Tardive dyskinesia (TD), a chronic and disabling syndrome, usually develops after at least 3 months of anti-dopaminergic treatment, but it can also appear after shorter periods or even after discontinuation of the medication1. Aim: To evaluate whether there is significant risk of reporting for early-onset TD (\60 days) for some specific drugs. Methods: We used data from the FDA’s Adverse Event Reporting System (FAERS) database from 2004 to 2022. We quantified for all drugs in the database, the number of drug-event pairs with the preferred term ‘‘Tardive Dyskinesia’’ (TD). Then, we counted those with Time to onset (TTO) B 60 days (cases). All other adverse events where classified as ‘‘non-cases’’. Finally, we calculate Reporting Odds Ratio (ROR) as a measure of disproportionality, for drugs with at least 3 cases of TD with a TTO B 60 days (index), using the entire database as reference. Results: Our dataset includes 66.461.955 drug-event pairs. We found that the overall number of TD-drug pairs reported in FAERS database was 10,352. The overall TD-drug pairs with available TTO information available was 1,871 (18.1%). The overall TD cases with TTO B 60 days was 1,269 (68.8% of TD cases with TTO defined). Sixtyseven drugs with at least 3 reports with TD with TTO B 60 days were listed. Valbenazine has the highest number of case (n = 445), but it was excluded from the analysis due to its primary use in treating TD (indication bias). Among the remaining drugs, the overall number of pairs was 824. Risperidone has the highest count with 317 pairs (38.5%), Aripiprazole follows with 226 pairs (27.4%), Olanzapine with 109 pairs (13.2%), Paliperidone with 77 pairs (9.3%), and Haloperidol with 62 pairs (7.5% ). The RORs for these drugs are as follows: Risperidone - 510.9 (95% CI 443.9 - 588.0), Aripiprazole - 331.1 (95% CI 284.1 - 385.9), Olanzapine - 192.1 (95% CI 157.0 - 235.3), Paliperidone - 203 (95% CI 160.8 - 257.3), Haloperidol - 44.7 (95% CI 34.5 - 57.9). Conclusions: For many drugs, especially antipsychotics, there is a reporting risk of early onset tardive dyskinesia. It is important to underline that the TTO can be calculated for a proportion of drugevent pairs of less than 20%. It is possible that cases for which information is not known are predominantly with later onset because it is more difficult to report therapy initiation dates for events occurring after years of treatment.