Summary: A new study reports combining antipsychotic medications could help to prevent relapse and hospitalization for those with schizophrenia. Combining aripiprazole and clozapine resulted in a 23% lower risk of rehospitalization than with clozapine alone, researchers report.
Source: Karolinska Institute.
Combining certain types of two antipsychotic agents in the maintenance treatment of schizophrenia is associated with a lower risk of relapse than using monotherapy. This is suggested in a paper published by researchers at Karolinska Institutet in the journal JAMA Psychiatry. The current treatment guidelines should modify their categorical recommendations discouraging all antipsychotic polypharmacy, according to the researchers.
The effectiveness of antipsychotic combination therapy in schizophrenia relapse prevention is controversial, and use of multiple agents is generally believed to impair physical well-being. But the evidence for this is weak and antipsychotic polypharmacy is widely used.
Now researchers at Karolinska Institutet in Sweden have conducted a large registry based study to see if there is any difference in the risk of relapse in schizophrenia when patients use antipsychotic polypharmacy compared to monotherapy.
Studied 62,000 patients
The study was based on more than 62,000 patients; all persons with schizophrenia treated in the inpatient setting during 1972-2014 in Finland. The researchers then followed the patients to see to what extent they were rehospitalised for psychiatric care, which was used as a marker for relapse. The median follow-up time was 14.1 years and to avoid bias each patient was used as his or her own control (so called within-individual analysis).
The results show that antipsychotic polypharmacy in general was associated with a slightly lower risk of psychiatric rehospitalisation than monotherapy. They do however not indicate that all types of polypharmacy are beneficial. Combining aripiprazole with clozapine was associated with the best outcome, with a 14-23 per cent lower risk of rehospitalisation compared to clozapine alone; which was the monotherapy associated with the best outcomes.
Possible update of treatment guidelines
Current treatment guidelines state that antipsychotic monotherapy should be preferred and polypharmacy should be avoided if possible. This study should change that view, according to first author of the study, Jari Tiihonen, specialist doctor and professor at Karolinska Institutet’s Department of Clinical Neuroscience.
”Our results indicate that the current treatment guidelines should tone down their categorical recommendations discouraging all antipsychotic polypharmacy. The evidence of superiority of polypharmacy might be sparse, and should be replicated in other countries, but there is no evidence at all on superiority of monotherapy over polypharmacy in the maintenance treatment of schizophrenia”, says Jari Tiihonen.
Researchers affiliated to the University of Eastern Finland, Niuvanniemi Hospital, EPID research Oy, Hofstra Northwell School of Medicine, The Zucker Hillside Hospital, Charité Universitätsmedizin and National Institute for Health and Welfare, Finland, also contributed to the study.
Funding: The study was funded by the Finnish Ministry of Social Affairs and the Academy of Finland. No company has financed this study, but several of the authors have previously received funding/fees from pharmaceutical companies in different contexts. Two of the authors are employed by the contract research organisation EPID Research. The scientific article provides more detailed information about potential conflicts of interest.
Source: Karolinska Institute
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Original Research: Abstract for “Association of Antipsychotic Polypharmacy vs Monotherapy With Psychiatric Rehospitalization Among Adults With Schizophrenia” by Jari Tiihonen, Heidi Taipale, Juha Mehtälä, Pia Vattulainen, Christoph U. Correll and Antti Tanskanen in JAMA Psychiatry. Published February 20 2019.
Association of Antipsychotic Polypharmacy vs Monotherapy With Psychiatric Rehospitalization Among Adults With Schizophrenia
The effectiveness of antipsychotic polypharmacy in schizophrenia relapse prevention is controversial, and use of multiple agents is generally believed to impair physical well-being.
To study the association of specific antipsychotic combinations with psychiatric rehospitalization.
Design, Setting, and Participants
In this nationwide cohort study, the risk of psychiatric rehospitalization was used as a marker for relapse among 62 250 patients with schizophrenia during the use of 29 different antipsychotic monotherapy and polypharmacy types between January 1, 1996, and December 31, 2015, in a comprehensive, nationwide cohort in Finland. We conducted analysis of the data from April 24 to June 15, 2018. Rehospitalization risks were investigated by using within-individual analyses to minimize selection bias.
Main Outcomes and Measures
Hazard ratio (HR) for psychiatric rehospitalization during use of polypharmacy vs during monotherapy within the same individual.
In the total cohort, including 62 250 patients, 31 257 individuals (50.2%) were men, and the median age was 45.6 (interquartile range, 34.6-57.9) years. The clozapine plus aripiprazole combination was associated with the lowest risk of psychiatric rehospitalization in the total cohort, being superior to clozapine, the monotherapy associated with the best outcomes, with a difference of 14% (HR, 0.86; 95% CI, 0.79-0.94) in the analysis including all polypharmacy periods, and 18% in the conservatively defined polypharmacy analysis excluding periods shorter than 90 days (HR, 0.82; 95% CI, 0.75-0.89; P < .001). Among patients with their first episode of schizophrenia, these differences between clozapine plus aripiprazole vs clozapine monotherapy were greater (difference, 22%; HR, 0.78; 95% CI, 0.63-0.96 in the analysis including all polypharmacy periods, and difference, 23%; HR, 0.77; 95% CI, 0.63-0.95 in the conservatively defined polypharmacy analysis). At the aggregate level, any antipsychotic polypharmacy was associated with a 7% to 13% lower risk of psychiatric rehospitalization compared with any monotherapy (ranging from HR, 0.87; 95% CI, 0.85-0.88, to HR, 0.93; 95% CI, 0.91-0.95; P < .001). Clozapine was the only monotherapy among the 10 best treatments. Results on all-cause and somatic hospitalization, mortality, and other sensitivity analyses were in line with the primary outcomes.
Conclusions and Relevance
Combining aripiprazole with clozapine was associated with the lowest risk of rehospitalization, indicating that certain types of polypharmacy may be feasible in the treatment of 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. Although the results do not indicate that all types of polypharmacy are beneficial, the current treatment guidelines should modify their categorical recommendations discouraging all antipsychotic polypharmacy in the maintenance treatment of schizophrenia.