Real-world effectiveness of antipsychotic monotherapy vs. polypharmacy in schizophrenia: to switch or to combine? A nationwide study in Hungary

Background: Leading guidelines recommend antipsychotic (AP) monotherapy for schizophrenia, nonetheless the combination of antipsychotics (polypharmacy) is common practice worldwide. We conducted a nationwide population-based study to investigate the comparative effectiveness of monotherapy versus polypharmacy in schizophrenia and other psychotic disorders.

Methods: Data was collected from the Hungarian National Health Insurance Fund's database and a non-interventional retrospective-prospective parallel arm study was designed with a monotherapy arm (MA, switch to a new antipsychotic after >60 days of monotherapy, N=5480) and a polypharmacy arm with two APs (PA, addition of a second antipsychotic after >60 days of monotherapy, N=7901). The analyses focused on therapy changers, who started a new monotherapy or added a new AP to the existing one. Polypharmacy combinations with more than two APs were not investigated. Fourteen APs were investigated representing the majority of marketed antipsychotics of Hungary in the period of 1/2007-12/2009. The principal endpoint was the time to all-cause treatment discontinuation during a one-year observation period. Kaplan-Meier survival analysis and Cox proportional hazards model were applied with propensity score adjustment.

Results: The principal outcome measure time to all-cause discontinuation indicated superiority for monotherapy over polypharmacy for the majority of (oral and depot) second generation APs (SGAs). For first generation APs (FGAs), oral formulations did not show a difference between monotherapy and polypharmacy, while depot formulations exhibited polypharmacy advantage. For the four most frequently used oral SGAs, the median times to all-cause discontinuation for monotherapy and polypharmacy, respectively, were 192 and 100 days for aripiprazole; 222 and 86 days for olanzapine; 176 and 91 days for quetiapine; and 157 and 93 days for risperidone. For mortality and hospitalization, a significant overall advantage of polypharmacy was detected.

Conclusions: Our study provides evidence for the superiority of monotherapy over polypharmacy for SGAs in terms of all-cause treatment discontinuation in schizophrenia. Polypharmacy, however, was associated with a lower likelihood of mortality and hospitalizations. The finding that MA is superior to PA for long-term sustained treatment whereas polypharmacy has advantage in mortality and psychiatric hospitalizations suggests that combination treatments may be more efficacious during exacerbation of psychotic symptoms.