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Trial Fails to Support Polypharmacy in Refractory Schizophrenia

9 February 2006. The prescription of multiple antipsychotic drugs, or "polypharmacy," is a common practice in the treatment of schizophrenia, particularly in patients who fail to improve after attempts with several different drugs. The hope is that drugs with slightly different profiles—differential receptor activities and effectiveness in different symptom domains—might augment each other. However, most of this prescribing is being done on sparse evidence for its effectiveness and with concerns about the additive side effects of these expensive drugs, especially on metabolic systems (see SRF related news story on the CATIE trial).

A new study published February 2, 2006, in the New England Journal of Medicine casts doubts on this practice, at least with two drugs, in one particular subgroup of patients. William Honer of the University of British Columbia, Vancouver, and colleagues at a number of institutions report that in a multicenter, international trial, the addition of risperidone to clozapine produced no benefits over placebo in treatment-resistant schizophrenia.

This particular polypharmacy strategy has a logic, namely that risperidone (Risperdal, Janssen), which occupies a high percentage of dopamine D2 receptors at clinical doses, might occupy any D2 receptors left vacant by clozapine (Clozaril, Novartis), which occupies a lower percentage of D2 receptors (Kapur et al., 1999). Binding affinity to D2 receptors has been shown to correlate with antipsychotic drug effectiveness, particularly for psychosis and other positive symptoms. There are also hints that risperidone might have greater benefits for working memory (Woodward et al., 2005). However, previous, smaller studies of the risperidone/clozapine combination have been contradictory on the value of this approach.

The researchers randomized 68 patients in Canada, Germany, China, and the United Kingdom to receive either risperidone (3 mg/day) or placebo on top of clozapine in a double-blind design for 8 weeks. The manufacturer of risperidone supplied the medication for the trial, but was not otherwise involved in it, according to the authors. Patients were, on average, in their late thirties, with a duration of illness of about 15 years. They had tried, on average, three antipsychotic drugs over the previous 5 years, ending up on clozapine at an average dose of 490 mg per day.

Honer and colleagues found that both groups improved significantly from baseline on a battery of measures, including the Positive and Negative Syndrome Scale (PANSS) and neurocognitive tests, but there was no benefit of risperidone over placebo. The authors report that nine of 34 patients in the placebo group improved on PANSS scores, versus six of 34 in the risperidone group (p = 0.038). Indeed, the placebo-treated patients had a slight improvement in working memory over the risperidone group (p = 0.02). Fasting blood glucose levels increased significantly more in the risperidone-treated group, though the authors emphasize that this finding should be viewed as preliminary.

In an editorial accompanying the article, John Davis of the University of Illinois, Chicago, and the Maryland Psychiatric Research Center in Baltimore, cautions that too low a dose of risperidone may have been used. Davis noted that the previous, industry-funded trials that showed a benefit of this polypharmacy had found that daily doses of over 4 mg were more effective than lower doses. "Nonetheless, the Honer trial was carefully conducted, and its negative findings introduce palpable doubt about the efficacy of augmentation therapy in refractory schizophrenia. Given the contradictory results among these studies, more industry-funded and independently funded trials are needed," Davis writes. This editorial is also worth reading for Davis's thoughts on antipsychotic prescribing in general, and the CATIE trial in particular.—Hakon Heimer.

Davis JM. The choice of drugs for schizophrenia. N Engl J Med. 2006 Feb 2;354(5):518-20. Abstract

Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, Falkai P, Pomarol-Clotet E, McKenna PJ, Stip E, Williams R, MacEwan GW, Wasan K, Procyshyn R; Clozapine and Risperidone Enhancement (CARE) Study Group. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med. 2006 Feb 2;354(5):472-82. Abstract

Comments on News and Primary Papers
Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 15 February 2006 Posted 15 February 2006
  I recommend the Primary Papers

Evaluating the effect of adding risperidone to clozapine is an example of clinical practice getting out ahead of evidence and theory. It has become common practice, so we need to know the answer. The combination surely will add adverse effects, but what hypothesis supports the notion of increased efficacy? Clozapine has superior efficacy for psychosis in treatment-resistant patients and low occupancy (fast on/off) at the dopamine 2 receptor. Is this important for diminished motor adverse effects or for superior efficacy? If so, adding risperidone will terminate this advantage. I think this may be the case for adverse effects, but we tested the partial occupancy hypothesis and the D2/5HT ratio hypothesis for clozapine (Carpenter et al., 1998) and found that full D2 occupancy did not interfere with clozapine superiority. But in this analysis, we found no evidence that being on a drug with high affinity for the D2 receptor combined with clozapine gave any efficacy advantage and recommended against the...  Read more

View all comments by William Carpenter

Comment by:  Herbert Meltzer (Disclosure)
Submitted 16 February 2006 Posted 17 February 2006
  I recommend the Primary Papers

The paper by Honer et al., which reported a lack of benefit from augmentation of clozapine by risperidone in patients with schizophrenia who were partial responders to clozapine, is consistent with our previous report which had the same design but was of somewhat shorter duration (Anil Yagcioglu et al., 2005), with the exception that we found that improvement in psychopathology after the addition of placebo was superior to risperidone. A second paper from our double-blind, randomized trial has been submitted which showed that improvement in cognition with placebo was often, but not always, greater than that with risperidone as well. Honer et al. explicitly stated that their results were consistent with ours. We proposed, based upon my hypothesis that more potent blockade of 5-HT2A than D2 receptors contributed to the beneficial effects of...  Read more

View all comments by Herbert Meltzer

Comment by:  William Honer
Submitted 15 May 2006 Posted 16 May 2006
  I recommend the Primary Papers

Our paper (Honer et al., 2006) and the associated editorial by Dr. John M. Davis (Davis, 2006) concerning augmentation of risperidone with clozapine drew some commentary in this Forum, and recently, three letters to the Editor of the New England Journal of Medicine. The April 27 issue of the NEJM also includes our response, and a response from Dr. Davis. The first of the letters, from Grass and colleagues (Grass et al., 2006) concerns the broader issues of the confidence with which we can conclude that risperidone augmentation of clozapine offers no benefit, and the degree to which the results of this approach to antipsychotic polypharmacy can be generalized to other combinations of antipsychotic drugs. Basically, our conclusion in the paper is that the difference between risperidone and placebo augmentation of clozapine is unlikely to be...  Read more

View all comments by William Honer
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