Off-label Antipsychotic Use and Cardiometabolic Effects: Real-World Evidence from Long-term Low-dose Use

Abstract

Antipsychotic medicines are increasingly used off-label at low doses to treat chronic non-psychotic disorders. They can cause cardiovascular and metabolic adverse effects at recommended doses, with lack of evidence at lower doses and off-label. This research characterised antipsychotic use patterns and associated cardiometabolic burden in Australia.

This research used pharmacoepidemiologic methods to address the aims. A systematic review of published literature quantified the cardiometabolic adverse effects of long-term off-label antipsychotic use. We then used national medicines dispensing claims data and general practitioner prescribing data to delineate trends in antipsychotic utilisation. Additionally, we examined the prevalence of cardiometabolic medicine use among antipsychotic-users compared with non-users, and the influence of their past antipsychotic treatment patterns.

Overall, evidence was limited in literature, with high study heterogeneity. Long-term antipsychotic use was associated with weight gain, hyperglycaemia and dyslipidaemia in both children and adults, while there was a weak association of ischaemic heart disease and cardiometabolic mortality among adults.

Both incidence and prevalence rates of antipsychotic use increased between 2005–2021, with 27% being off-label and commonly at lower median daily doses. Quetiapine had the highest utilisation, with around 35% low-dose dispensings. Cardiometabolic medicine use was more prevalent among antipsychotic-users in a dose- and duration-dependent manner, with onset occurring at younger ages and even with low doses (including quetiapine).

Despite policy initiatives to restrict low-dose and presumably off-label use, the trend has continued in Australia. Contrary to prevailing perceptions, higher cardiometabolic medicine use among low-dose users reinforces the need for greater scrutiny, especially for quetiapine, regular metabolic monitoring and safer prescribing practices.