Second-Generation Antipsychotics and VTE Risk

Introduction: It has been known for some time that antipsychotic medications are associated with an increased risk of venous thromboembolism (VTE) though mechanism of action has not yet been elucidated. However, it is not known if there are certain antipsychotics that are more associated with VTE than others, and with over 26 million prescriptions in 2020 of olanzapine, risperidone, aripiprazole and quetiapine combined the importance of identifying such an association, if it exists, is essential. To explore this a safety analysis was conducted of six second-generation antipsychotics using the FDA Adverse Event Reporting System (FAERS).

Methods: The FAERS system was searched using the reaction terms ‘venous thrombosis’, 'deep vein thrombosis,' and 'pulmonary embolism.' Events were included if they occurred prior to 2023 and contained one of the aforementioned terms. Events could also include symptoms that could be reasonably associated with such a reaction - for example, hypoxia from pulmonary embolism (PE). Events were then narrowed further to include only those associated with a single second-generation antipsychotic - aripiprazole, clozapine, olanzapine, quetiapine, and ziprasidone. Data was then analyzed for demographic differences in weight and age of the patients using ANOVA, as well as frequency of VTE events using the proportional reporting ratio (PRR).

Results: There were a total of 1155 VTE events amongst the six antipsychotics, out of 180824 total reported cases. Olanzapine (308) and quetiapine (273) had the most events overall as well as the most PEs (olanzapine 224, quetiapine 204), while risperidone had the most deep vein thromboses (DVT) (103). When analyzed using the PRR (for which ziprasidone was excluded due to low number of cases and events), olanzapine and quetiapine were disproportionally associated with an increased rate of VTE (2.57 and 2.22 respectively) and PE (2.71 and 2.42 respectively). Olanzapine and risperidone were associated with an increased rate of DVT (2.35 and 2.31 respectively). Though limited data was available on patient demographics, of that which was available (excluding ziprasidone), VTE patients on clozapine had significantly higher weights than those on quetiapine or olanzapine ( P = 0.01 and P = 0.004 respectively), while VTE patients on risperidone were significantly older than those taking aripiprazole or clozapine ( P = 0.003 and P = 0.03 respectively). There were otherwise no significant differences in age and weight among the different VTE antipsychotics groups.

Discussion: This data suggests that the rate of VTE as reported to the FDA is unexpectedly high for those taking olanzapine and quetiapine as compared with other second-generation antipsychotics. Limitations of the study include reliance on accurate and complete reporting of events and potential for duplication of reports. Further investigation is needed into the differences amongst the antipsychotics in relation to VTE risk as well as further research into potential mechanism of action. Given how frequently these medications are prescribed, antipsychotics may represent an underrecognized significant contributor to rates of thrombosis.