Antipsychotic polypharmacy in patients with schizophrenia between 1999 and 2024 in Denmark: Prevalence, time trends, and combinations

Antipsychotic polypharmacy (APP) remains common in the treatment of schizophrenia despite increased risk of adverse events and limited evidence of additional efficacy compared to antipsychotic monotherapy (APM). We conducted a nationwide, register-based cohort study to characterize APP among patients with schizophrenia in Denmark, 1997-2021. Patients were followed from year 3 after the schizophrenia diagnosis and onwards. APP was defined as treatment with ≥2 antipsychotics lasting ≥60 days. Of 29,696 patients with schizophrenia (55 % males; median age 29 years [interquartile range (IQR) = 22-41 years]; median follow-up 10.5 years [IQR 5.1-16.3]), 51 % of patients were exposed to APP at some point during follow-up. The one-year prevalence of APP decreased from 44 % in 2005 to 29 % in 2024. In 2024, 58 % of APP regimens involved quetiapine, and 52 % involved clozapine and/or partial dopamine receptor agonists. Median total dose of antipsychotics was significantly higher with APP than with APM (1.4 vs. 0.7 WHO-defined daily doses;p < 0.001). In 2024, 43 % of APP included chlorprothixene or quetiapine (≤100mg/day). Use of APP was associated with male sex, more and longer hospitalizations, suicide attempts/self-harm, alcohol/substance use, use of antidepressants, mood stabilizers, hypnotics, or benzodiazepines (all p < 0.001). Although the prevalence of APP in schizophrenia decreased from 2005 to 2024, one-third of patients with schizophrenia remained exposed to APP. Only half of APP included potentially evidence-based combinations with clozapine and/or partial dopamine-receptor agonists. APP was associated with higher total antipsychotic doses, but also with more severe schizophrenia illness. These findings can inform future studies to investigate the comparative efficacy and safety of specific APP combinations and potential opportunities for deprescribing APP.