Polypharmacy May Cut Rehospitalization Risk in Schizophrenia

Deborah Brauser

March 11, 2019

Some antipsychotic polypharmacy protocols may lower the risk for schizophrenia-related rehospitalization in adult patients more so than monotherapy, new research suggests.

In a study of more than 62,000 patients in Finland who had schizophrenia and were followed for up to 20 years, the risk for psychiatric rehospitalization was 7% to 13% lower for those who received any antipsychotic polypharmacy therapy than for those who received any monotherapy.

Within the entire cohort, the patients at lowest risk for rehospitalization were those who received clozapine (multiple brands) plus aripiprazole (multiple brands). Although clozapine was the monotherapy that was associated with the best outcomes, it was bested by 14% by the clozapine plus aripiprazole combination.

Dr Jari Tiihonen

"The results suggest that certain antipsychotic combinations, such as clozapine plus aripiprazole, may be useful," lead author Jari Tiihonen, MD, PhD, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden, told Medscape Medical News.

"The relatively good outcome with polypharmacy was not that surprising since it is in line with the results from previous observational studies — although the previous studies have had some methodological limitations," he added.

The findings were published online February 20 in JAMA Psychiatry.

Controversial Treatment

"The effectiveness of antipsychotic polypharmacy in schizophrenia relapse prevention is controversial, and use of multiple agents is generally believed to impair physical well-being," the investigators write.

Still, it's estimated that up to 30% of patients with schizophrenia receive antipsychotic polypharmacy, they add.

The researchers note that meta-analyses of randomized controlled trials (RCTs) "have shown mixed results" and that observational studies using large electronic databases may be more helpful.

They add that no previous observational studies have compared the effectiveness of antipsychotic monotherapies vs combinations using within-individual analyses.

"Antipsychotic polypharmacy is widely used, although treatment guidelines discourage its use since short-term RCTs have not shown any substantial benefit in efficacy," Tiihonen said. "However, very little has been known about the effectiveness of polypharmacy in long-term use in relapse prevention."

For the current study, the investigators assessed data from discharge, prescription, and death registers from January 1996 through December 2015 for 62,250 patients with schizophrenia (50.2% men; mean age, 45.6 years). All participants were in Finland, and 29 different antipsychotics were used singly and/or in combination.

The primary outcome measure was risk for psychiatric rehospitalization "during use of polypharmacy vs during monotherapy within the same individual," note the researchers.

Polypharmacy Feasibility

Results showed that the only monotherapy among the 10 best treatments for decreasing risk for psychiatric rehospitalization was clozapine. Of all the protocols, the lowest risk for rehospitalization was with clozapine plus aripiprazole.

The hazard ratios (HRs) for this protocol vs clozapine alone were 0.86 in analysis that included all polypharmacy periods (95% confidence interval [CI], 0.79 – 0.94) and 0.82 "in the conservatively defined polypharmacy analysis excluding periods shorter than 90 days" (95% CI, 0.75 – 0.89; P < .001).

Differences were even greater between the two protocols for patients with a first episode of schizophrenia — with HRs of 0.78 and 0.77 for all polypharmacy periods and in the conservative polypharmacy analysis, respectively.

"At the aggregate level," HRs for rehospitalization ranged from 0.87 to 0.93 for any antipsychotic polypharmacy vs any monotherapy, the researchers report.

In addition, findings on "all-cause and somatic hospitalization, mortality, and other sensitivity analyses were in line with the primary outcomes," they write.

Overall, the results indicate that "certain types of polypharmacy may be feasible" when treating schizophrenia.

"Because add-on treatments are started when monotherapy is no longer sufficient to control for worsening of symptoms, it is likely that the effect sizes for polypharmacy are underestimates," the investigators write.

They note that although the findings do not suggest benefit from all types of polypharmacy, "the current treatment guidelines should modify their categorical recommendations discouraging all antipsychotic polypharmacy in the maintenance treatment of schizophrenia."

Confounding by Indication?

In an accompanying editorial, Donald C. Goff, MD, Nathan Kline Institute for Psychiatric Research, New York University School of Medicine, New York City, notes that the study applied "sophisticated statistical methods to large administrative databases" to assess outcomes.

"Observational data contained in these databases may yield valuable information about treatment response, but this approach has important limitations. Of primary concern is confounding by indication, which occurs when the clinical indication for selecting a particular add-on treatment also may influence outcome," Goff writes.

In this study, "the investigators were faced with the problem of not knowing whether patients receiving a specific drug were similar in their risk for hospitalization to patients who did not receive the drug," he adds.

"Contrary to most treatment guidelines, Tiihonen and colleagues found that antipsychotic polypharmacy was associated with better outcomes than monotherapy and that addition of aripiprazole uniquely improved outcomes in patients treated with clozapine," he writes

However, these should be considered preliminary results until RCTs can confirm the findings, Goff notes.

"If clinicians and patients choose to implement add-on treatments after weighing results from...observational studies and RCTs, the limitations of the evidence should be acknowledged and outcomes should be carefully monitored," he concludes.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and state research funding. Tiihonen reports having participated in research projects funded by grants from Janssen-Cilag and Eli Lilly; receiving personal fees from the Finnish Medicines Agency, the European Medicines Agency, Eli Lilly, Janssen-Cilag, Lundbeck, and Otsuka; and receiving grants from the Stanley Foundation and the Sigrid Jusélius Foundation. Disclosures for the other study authors are fully listed in the original article. Goff reports having received grants from Avanir Pharmaceuticals.

JAMA Psychiatry. Published online February 20, 2019. Abstract, Editorial

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