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

Comments on Paper and Primary News
Primary News: Trial Fails to Support Polypharmacy in Refractory Schizophrenia

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 15 February 2006 Posted 15 February 2006
  I recommend this paper

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

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Primary News: Trial Fails to Support Polypharmacy in Refractory Schizophrenia

Comment by:  Herbert Meltzer (Disclosure)
Submitted 16 February 2006 Posted 17 February 2006
  I recommend this paper

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

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Primary News: Trial Fails to Support Polypharmacy in Refractory Schizophrenia

Comment by:  William Honer
Submitted 15 May 2006 Posted 16 May 2006
  I recommend this paper

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

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