To the Editor: Honer et al. (Feb. 2 issue)1 showed that clozapineaugmented with risperidone is unlikely to yield a moderate-to-largeeffect in patients with refractory schizophrenia. They concludethat there is no support for antipsychotic polypharmacy, a viewalso apparent in the accompanying editorial by Davis.2 However,their confidence interval for the difference in the change inscores on the Positive and Negative Syndrome Scale still includessmall-to-moderate effect sizes (0.3 to 0.5). Given the individualsuffering and economic burden due to schizophrenia,3 we thinkthat even a moderate effect of combined treatment is worth considering.Moreover, although the primary analysis was rightly performedaccording to the intention-to-treat principle, the authors didnot address the effect of patient compliance (e.g., by per-protocolanalysis). Thus, their conclusion seems to be premature. Rather,augmenting clozapine in cases of treatment-resistant schizophreniawith second-generation antipsychotic agents possessing a favorableneuropharmacologic profile requires evaluation in randomized,controlled trials with larger sample sizes. Furthermore, thestudy presented does not provide evidence against the combinationof different psychopharmacologic approaches.4
Guido Grass, M.D. Martin Hellmich, D.Med.Sc. F. Markus Leweke, M.D. University of Cologne 50924 Cologne, Germany m.leweke{at}uni.de
References
Honer WG, Thornton AE, Chen EYH, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med 2006;354:472-482. [Free Full Text]
Davis JM. The choice of drugs for schizophrenia. N Engl J Med 2006;354:518-520. [Free Full Text]
Wu EQ, Birnbaum HG, Shi L, et al. The economic burden of schizophrenia in the United States in 2002. J Clin Psychiatry 2005;66:1122-1129. [Medline]
To the Editor: The editorial by Davis concerning the lack ofbenefit from the augmentation of clozapine with risperidonein patients with schizophrenia who had a partial response incorrectlydescribes our study1 as showing results that are opposite tothose of Honer et al. In fact, we found and reported that placebowas superior to risperidone.1 Honer et al. explicitly statedthat their results were consistent with ours. Furthermore, Davisimplies that our study was biased because it was funded by industry.We reported that our study received funding from two foundationsand industry (the manufacturer of risperidone). Davis also contrastedthe results of his meta-analyses of industry-funded clinicaltrials, which found advantages of atypical over typical antipsychoticdrugs, with the results of the Clinical Antipsychotic Trialsof Intervention Effectiveness, funded by the National Instituteof Mental Health, which did not find such advantages. This furtherimplied that industry-funded studies may be unreliable. Carefulevaluation of studies is necessary before making such judgments.
Herbert Y. Meltzer, M.D. Vanderbilt University School of Medicine Nashville, TN 37212 herbert.meltzer{at}vanderbilt.edu
A. Elif Anl Yacolu, M.D. Hacettepe University 06532 Ankara, Turkey
Berna Binnur Kvrck Akdede, M.D. Dokuz Eylül University School of Medicine 35340 Izmir, Turkey
Dr. Meltzer reports having received consulting fees and grantsupport from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Pfizer,Janssen, Novartis, and Organon.
References
Anl Yacolu AE, Kvrck Akdede BB, Turgut TI, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry 2005;66:63-72. [ISI][Medline]
To the Editor: In the editorial, Davis notes that the risk ofagranulocytosis from clozapine is about 1 percent and that mortalitycan be reduced by weekly monitoring of platelet counts. Clozapinecauses a loss of neutrophils through an idiopathic marrow-suppressiveeffect on myeloid maturation (pure white-cell aplasia) thatoccurs in approximately 0.22 to 0.44 percent of exposed patients,as reported at an advisory meeting of the Food and Drug Administrationin June 2003.1 The current estimate of the rate of agranulocytosisis lower than originally reported and is based on more recentmonitoring data. The monitoring of the white-cell count as indicatedin the package insert provides a safe system for the detectionof severe neutropenia and agranulocytosis occurring with clozapine.Although thrombocytopenia associated with clozapine has beenobserved, its incidence is quite low and rarely requires intervention.Physicians prescribing clozapine should maintain monitoringof the white-cell count, not the platelet count.
Stanton L. Gerson, M.D. Case Western Reserve University Cleveland, OH 44106 slg5{at}case.edu
The authors reply: In all fairness, Grass and colleagues shouldalso note that, on the basis of the confidence interval fromour study, a small-to-moderate effect size of similar magnitudefavoring placebo augmentation is equally likely. Indeed, anadvantage of augmentation of clozapine with placebo as comparedwith augmentation with risperidone for positive symptoms wasreported elsewhere.1 We observed a moderate disadvantage withrisperidone augmentation in terms of working memory (effectsize, –0.68) and evidence of glucose dysregulation, temperingany enthusiasm for this particular strategy. The study completionrate was 96 percent, and the results were no different whenthe three patients who discontinued treatment were excluded.Risperidone has a high affinity for dopamine D2 receptors andwas chosen to complement the low affinity of clozapine —a more specific suggestion of a "favorable neuropharmacologicprofile" would be welcomed. Other classes of drugs, such asanticonvulsants or antidepressants, might augment the effectsof clozapine, but more comparisons with placebo augmentationare needed. We hope that the evidence for or against the valueof antipsychotic polypharmacy will soon catch up with the widespreadimplementation of this practice.
William G. Honer, M.D. University of British Columbia Vancouver, BC V5Z 1L8, Canada honer{at}interchange.ubc.ca
Allen E. Thornton, Ph.D. Simon Fraser University Burnaby, BC V5J 1S6, Canada
G. William MacEwan, M.D. University of British Columbia Vancouver, BC V5Z 1L8, Canada
References
Anl Yacolu AE, Kvrck Akdede BB, Turgut TI, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry 2005;66:63-72. [ISI][Medline]
The editorialist replies: I made an error in reading the numbersin the results table of the study by Yacolu et al. This randomizedtrial did not demonstrate a benefit of augmentation of clozapinewith risperidone as compared with augmentation with placebo.Thus, the studies by Honer et al. and Yacolu et al. provideconsistent evidence that risperidone augmentation does not producean additional benefit over clozapine. Since a higher dose ofrisperidone was used in the study by Yacolu et al., this studydoes not suggest that the negative findings of the Honer studyresulted from an inadequate dose of risperidone. I apologizefor my mistake. I found no evidence of bias in terms of pharmaceutical-industrysponsorship on the efficacy data from the randomized, controlledtrials comparing second-generation with first-generation antipsychoticagents. All these drugs are effective, but randomized, controlledtrials establish clozapine as the most efficacious.1,2 However,the initial European experience found clozapine associated withagranulocytosis in about 1 to 2 percent of the patients (onethird of cases were fatal). I agree with Dr. Gerson's conclusions.Mandatory monitoring of white-cell counts does indeed greatlyminimize the risk of this complication.
John M. Davis, M.D. University of Illinois at Chicago Chicago,IL 60614
References
Wahlbeck K, Cheine M, Essali A, Adams C. Evidence of clozapine's effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials. Am J Psychiatry 1999;156:990-999. [Free Full Text]
Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003;60:82-91. [Erratum, Arch Gen Psychiatry 2003;60:735.] [Free Full Text]
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