Antipsychotic Polypharmacy With Risperidone and Olanzapine for the Treatment of Refractory Schizophrenia

Darren J. Hein, PharmD


August 08, 2017


Given high rates of treatment failure for initial therapy of schizophrenia, is combining risperidone and olanzapine an appropriate approach to improve clinical response while also limiting potential adverse effects?

Response from Darren J. Hein, PharmD
Assistant Professor, Department of Pharmacy Practice, Creighton University School of Pharmacy and Health Professions, Omaha, Nebraska

Combination Therapy With Multiple Antipsychotics

Initial therapy for acute episodes of schizophrenia generally includes antipsychotic monotherapy with a second-generation antipsychotic (SGA) other than clozapine.[1] However, while many patients experience a significant reduction in symptoms of schizophrenia with antipsychotic monotherapy, 20%-40% fail to respond or respond only partially.[2,3] For patients who are refractory to initial treatment approaches, clinical practice guidelines recommend switching to another SGA or to clozapine. Only after these options have been exhausted should antipsychotic polypharmacy be considered.[1,4,5]

Despite guidelines reserving combination therapy with multiple antipsychotics as a last-ditch approach, the practice is well documented, with around 10%-30% of patients with schizophrenia in the United States being treated with more than one antipsychotic.[6] Additionally, some clinical evidence supports combination therapy. One meta-analysis examined antipsychotic combination therapy versus monotherapy, and another examined augmentation by adding a second antipsychotic to initial antipsychotic therapy versus continued antipsychotic monotherapy. These two pooled analyses showed some benefit with combination or augmentation therapy versus monotherapy; however, the low quality of the included trials suggests that larger and more rigorous, controlled clinical trials should be conducted in this area.[7,8]

A majority of the studies included in these pooled analyses evaluated combination therapy with clozapine and another antipsychotic, which appears to be the most common combination used in clinical practice.[7,8] However, combination therapy with two second-generation agents, such as risperidone and olanzapine, is also being used.[6] This article reviews the available evidence to determine whether risperidone and olanzapine can be safely and effectively used in combination for the treatment of refractory schizophrenia.


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