Two Studies Analyze Add-On Treatments for Schizophrenia

Two recent studies examined long-term effects of add-on treatments for patients with schizophrenia: one study found that antipsychotic polypharmacy was associated with fewer hospitalizations than monotherapy, while the other study found that adding an antidepressant generally provided best outcomes. Both studies were published February 20 in JAMA Psychiatry.

Anna Collsiöö

The first study found significantly reduced hospitalization rates when patients took more than one antipsychotic compared with times when they just took one antipsychotic, according Jari Tiihonen, M.D., Ph.D., a professor in the Department of Clinical Neuroscience at the Karolinska Institutet in Sweden, and colleagues.

Furthermore, researchers found no evidence that antipsychotic polypharmacy was associated with increased mortality rates or medical hospitalizations among more than 62,000 patients with schizophrenia in Finland. In fact, the study found that mortality rates were highest during medication-free periods. The combination of clozapine plus aripiprazole was associated with the lowest risk of psychiatric rehospitalization among patients, who were followed up to 20 years for the study.

Meanwhile, the other study examining 10 years of Medicaid data on some 82,000 U.S. patients with schizophrenia found that adjunctive treatment with an antidepressant was associated with a lower risk of psychiatric rehospitalization compared with adjunctive treatment with a second antipsychotic, according to the study by T. Scott Stroup, M.D., M.P.H., a professor of psychiatry and director of the Optimizing and Personalizing Interventions for Schizophrenia Across the Lifespan Center at the Columbia University Vagelos College of Physicians and Surgeons, and colleagues. Adjunctive benzo-diazepine was associated with an increase in the risk of rehospitalization and ED visits, whereas mood stabilizers were associated with an increased risk in mortality. Comparisons of relative rates of emergency department (ED) visits corroborated these findings.

Antipsychotic Polypharmacy May Reduce Rehospitalizations

Tiihonen and colleauges examined 22 antipsychotic combinations, excluding polypharmacy periods of shorter than 90 days, plus seven monotherapies. Researchers conducted within-individual analyses—comparing different time periods for the same individual—to minimize selection bias. They wrote that antipsychotic polypharmacy is considered controversial because of its lack of evidence of tolerability, safety, and efficacy.

Researchers analyzed data on all Finnish patients with schizophrenia treated in an inpatient setting from 1972 to 2014, following more than 62,000 patients for a median of 14 years. During that time 59 percent of participants were readmitted for psychiatric inpatient care.

The highlights from the Finnish study include the following:

• More than two-thirds of patients (68 percent) were exposed to antipsychotic combinations of at least 90 days. In general, this practice was associated with 10 percent lower relative risk of psychiatric rehospitalization compared with monotherapy. Antipsychotic combinations were also associated with lower risk of physical illness and mortality.

• The treatment associated with the best outcome was clozapine plus aripiprazole. Patients taking this combination had an 18 percent lower risk of psychiatric hospitalization than those taking clozapine alone, which was the monotherapy associated with the best outcome.

• Clozapine was the only monotherapy among the 10 best treatments.

• The advantage of the clozapine plus aripiprazole combination was greater for patients with first-episode schizophrenia, who were 23 percent less likely to be rehospitalized than those on clozapine monotherapy.

• Among the 29 therapies examined, quetiapine was the least successful monotherapy, as has also been observed in previous Swedish and Finnish studies. However, adding on another antipsychotic to quetiapine resulted in a better outcome.

“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 had some methodological limitations,” Tiihonen told Psychiatric News.

“One possible explanation for the superiority of polypharmacy is that, in the real-world setting, treatment adherence is poor, and if the patient has prescriptions for two antipsychotics, he or she may use at least one of them,” the researchers wrote. However, for the clozapine plus aripiprazole combination, “it is plausible that the different types of receptor profiles result in beneficial effects.”

Antidepressant Add-Ons Result in Lowest Rehospitalization Risk

In another study of patients with schizophrenia, Stroup and colleagues studied nearly 82,000 adults who were treated with a single antipsychotic for at least 90 days before adding on either benzodiazepine, an antidepressant, a mood stabilizer, or a second antipsychotic. Researchers found that adding an antidepressant was associated with substantially reduced rates of psychiatric rehospitalization and psychiatric ED visits compared with other adjunctive psychotropic strategies.

Researchers found that adding benzodiazepine was associated with a modest increase in the risk of psychiatric hospitalization and ED visits, compared with adding a second antipsychotic, whereas adding a mood stabilizer was associated with higher mortality. In fact, gabapentin was associated with more deaths than any other adjunctive treatment studied. No other mood stabilizer appeared to be associated with a higher rate of death than the others.

In an editorial published in JAMA Psychiatry, Donald Goff, M.D., pointed out that there are few high-quality randomized, controlled trials (RCTs) investigating outcomes of long-term adjunctive treatments for schizophrenia and that results of such studies are difficult to interpret. Goff is the director of the Nathan S. Kline Institute for Psychiatric Research and Professor of Psychiatry at the New York University Langone Medical Center.

As for these two studies, the results “should be considered preliminary until confirmed by RCTs,” Goff wrote. “If clinicians and patients choose to implement add-on treatment after weighing results from observational studies and RCTs, the limitations of the evidence should be acknowledged and outcomes should be carefully monitored.” ■