REVIEW OF: Taipale H et al, Am J Psychiatry 2023;180(5):377–385

STUDY TYPE: Retrospective cohort study

Patients with schizophrenia often take multiple antipsychotic medications, though treatment guidelines generally caution against polypharmacy due to safety concerns and unproven efficacy. However, observational studies suggest that polypharmacy might reduce the risk of psychiatric hospitalization compared to monotherapy. This raises a question: How does antipsychotic polypharmacy compare with monotherapy in terms of overall safety?

A Finnish register-based study addressed this issue by investigating the risk of nonpsychiatric and cardiovascular hospitalizations across different antipsychotic polypharmacy and monotherapy dosage categories. The study covered 61,889 patients with schizophrenia (average age 47 years) discharged from Finnish hospitals between 1972 and 2014. Antipsychotic dosages were calculated at each dispensing date and averaged to daily defined doses (DDDs/day).

Between 1996 and 2017, with a median follow-up of 14.8 years, patients received monotherapy 46% of the time, were on polypharmacy 34% of the time, and were off medication 20% of the time. About 46% were on high-dose (≥1.6 DDD/day) monotherapy, and 53% were on high-dose polypharmacy. Comparing any polypharmacy against monotherapy showed no significant differences in nonpsychiatric (hazard ratio [HR]=0.99) or cardiovascular hospitalization risks (HR=0.98). Interestingly, mid- to high-dose polypharmacy was associated with lower rates of nonpsychiatric and cardiovascular hospitalizations compared to similar monotherapy dosages (HR=0.82–0.91). Also, polypharmacy was associated with a 6% reduced risk of psychiatric hospitalization (HR=0.94). The most commonly used two-drug combinations were olanzapine and quetiapine, risperidone and quetiapine, and clozapine and aripiprazole.

The study’s limitations include its reliance on prescription data, which did not verify whether the medication was taken as prescribed. Additionally, the use of long-acting injectables was higher in the high-dose polypharmacy group (39% vs 22% in high-dose monotherapy), potentially influencing the reduced psychiatric hospitalization rates. Also, the study does not state what other psychiatric drugs the patients were being prescribed, such as antidepressants or mood stabilizers.

Carlat Take

This study found lower rates of nonpsychiatric and cardiovascular hospitalizations among patients receiving mid- to high-dose antipsychotic polypharmacy when compared to similar monotherapy dosages. The rate of psychiatric hospitalization was also slightly lower among the antipsychotic polypharmacy group. The results provide reassurance about the safety and efficacy of antipsychotic polypharmacy.