Editor’s Note: The Perils of Polypharmacy

Norman Sussman, MD, DFAPA

Editor, Primary Psychiatry and Psychiatry Weekly , Professor of Psychiatry, New York University School of Medicine

Few disorders are as challenging to treat as schizophrenia. Despite the introduction of numerous new treatments for the disorder, many patients fail to benefit fully from medication. In fact, poor response—or at least noncompliance—is the rule rather than the exception. This was underscored by the results of the CATIE study, published in the NEJM in 2005. That study looked at long-term completion rate of patients treated with several atypical antipsychotics as well as the conventional agent perphenazine. Overall, about 75% of patients failed to remain on medication. Also, there was no meaningful difference in completion rates between the older drug and the newer agents.

Many psychiatrists address the limitations of existing therapies by combining two different antipsychotics, even though there is no body of evidence guiding this practice and the benefits and risks of combining treatments are not known. In the February 2, 2006 issue of the NEJM , a paper from a group with another acronym—Clozapine and Risperidone Enhancement (CARE) Study Group—presents the results of a short-term study looking at real world patients demonstrating a poor response to antipsychotic drugs with clozapine. While remaining on clozapine, patients were randomly assigned to receive augmentation with risperidone or with placebo. This course of treatment was followed by an optional 18 weeks of augmentation with risperidone. In the double-blind phase there was no statistically significant difference between augmentation with risperidone and placebo: Overall, the incidence and severity of other side effects did not differ between the two groups, but there was evidence that an increase in fasting blood glucose levels was mildly greater in the risperidone group than in the placebo group Although the addition of risperidone to clozapine did not improve symptoms in patients with severe schizophrenia, the possibility remains that an occasional patient may benefit from combination treatment. Patients on clozapine tend to be among the sickest patients with schizophrenia. It may be that combinations of other agents may be more beneficial than add-ons to clozapine. There may also be a rationale for combining medications to overcome unwanted side effects. For example, using lower doses of drugs that have slightly different pharmacological profiles may lower the side effect burden of medication. Nevertheless, this study should give pause to those who routinely practice polypharmacy, especially those who have a favorite cocktail. Before resorting to use of multiple antipsychotic agents, clinicians should consider more careful diagnosis, and possibly a trial with a medication from another category, for example, a mood stabilizer.

To see the complete CARE study, go to http://clinicaltrials.gov/ct/show/NCT00272584