Correspondence
Prevention of Relapse in Schizophrenia
N Engl J Med 2002; 346:1412-1413May 2, 2002
- Article
To the Editor:
Csernansky et al. (Jan. 3 issue)1 found that adult outpatients with clinically stable schizophrenia or schizoaffective disorder had a lower risk of relapse if they were treated with risperidone than if they were treated with haloperidol. The rate of dropout because of adverse events or poor compliance, or for other reasons, was 50 percent higher in the haloperidol group. Risperidone was better tolerated than haloperidol, which is a known advantage of atypical antipsychotic drugs. The haloperidol group received a relatively high mean modal dose (11.7 mg per day). The greater frequency of side effects may have led to lower compliance in this group. This would explain the poor performance of haloperidol with regard to the efficacy end points.
1 ReferencesFrançois Curtin, M.D.
Swiss Agency for Therapeutic Products, CH-3000 Bern 9, Switzerland
francois.curtin@swissmedic. ch 1
Csernansky JG ,Mahmoud R ,Brenner R . A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med 2002;346:16-22
Full Text | Web of Science | Medline
To the Editor:
Numerous studies1-3 have demonstrated that doses of antipsychotic medication higher than 3.75 to 7.5 mg of haloperidol per day (the equivalent of 375 mg of chlorpromazine per day, given a 1:100 or 1:50 ratio for conversion) have no increased clinical efficacy but are associated with a significantly increased risk of extrapyramidal effects. In the study by Csernansky et al., 80.8 percent of the patients taking haloperidol took a daily dose of 7.5 to 20 mg. The mean (±SD) of the modal daily doses of haloperidol was more than twice that of risperidone; this discrepancy is reflected in the percentages of patients in each group who reported somnolence, agitation, or both. The extrapyramidal symptom of akathisia (internal restlessness) is the most difficult for patients to tolerate. Akathisia causes patients to stop their medication4 and can clinically mimic psychosis.5
Akathisia is, by definition, subjective, but its effects are often observable as restless moving about. The authors do not report on the incidence of akathisia but do report that there was hyperkinesia in 20 percent of the patients who took haloperidol, as compared with 5 percent of those who took risperidone. Janssen Pharmaceutical first introduced haloperidol to the market. Janssen never revised its dosage recommendations in response to studies demonstrating the clinical efficacy of low-dose antipsychotic medication but, rather, introduced risperidone as an “atypical” antipsychotic to be used at low doses. Unlike clozapine, which causes no extrapyramidal side effects, risperidone has substantial dopaminergic activity and is, in fact, a “conventional,” haloperidol-like antipsychotic. A study comparing low-dose haloperidol with low-dose risperidone is needed.
5 ReferencesSara Leland Peters Stalman, M.D.
RFD 1, Box 1095, Penobscot, ME 04476
sarastalman@yahoo.com 1
Baldessarini RJ ,Cohen BM ,Teicher MH . Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch Gen Psychiatry 1988;45:79-91
Web of Science | Medline2
Van Putten T ,Marshall BD ,Liberman R , et al. Systematic dosage reduction in treatment-resistant schizophrenic patients. Psychopharmacol Bull 1993;29:315-320
Medline3
Bollini P ,Pampallona S ,Orza MJ ,Adams ME ,Chalmers TC . Antipsychotic drugs: is more worse? A meta-analysis of the published randomized controlled trials. Psychol Med 1994;24:307-316
CrossRef | Web of Science | Medline4
Van Putten T . Why do schizophrenic patients refuse to take their drugs? Arch Gen Psychiatry 1974;31:67-72
Web of Science | Medline5
Van Putten T ,Marder SR . Behavioral toxicity of antipsychotic drugs. J Clin Psychiatry 1987;48:Suppl:13-19
Web of Science | Medline
To the Editor:
Csernansky et al. studied patients in stable condition who had no coexisting medical conditions or substance use or need for adjunctive psychotropic drugs. The patients also were extraordinarily compliant with their medication regimens, as indicated by pill counts, which raises questions about the generalizability of the results to the real-world clinical circumstances of patients with schizophrenia. In addition, certain groups of patients that may have different responses (e.g., patients with a first episode of schizophrenia or those with childhood-onset schizophrenia) will require separate evaluation.
The National Institute of Mental Health has initiated a research program to complement studies such as that of Csernansky et al. and to address the comparative effectiveness of the atypical and conventional antipsychotic drugs. This program (Clinical Antipsychotic Trials of Intervention Effectiveness) includes an 18-month trial comparing all the atypical antipsychotic drugs that are currently marketed in the United States (olanzapine, quetiapine, risperidone, ziprasidone, and clozapine) with the conventional antipsychotic drug perphenazine. Patients with coexisting medical conditions and substance use can participate unless there is a specific contraindication. Patients are followed for the duration of the study regardless of their outcomes.
Jeffrey Lieberman, M.D.
Scott Stroup, M.D., M.P.H.
University of North Carolina School of Medicine, Chapel Hill, NC 27599-7160
jeffrey_lieberman@med.unc. edu Lon Schneider, M.D.
University of Southern California Keck School of Medicine, Los Angeles, CA 90033Author/Editor Response
The authors reply:
To the Editor: In our study, extrapyramidal side effects, including akathisia, were measured by trained raters,1 and this information was included when the reasons for dropout were assigned. Differences between groups in the rate of dropout for reasons other than the primary outcome variable may introduce bias. However, the distribution of reasons for dropout unrelated to relapse was similar in both treatment groups. Thus, the differences in the dropout rate appeared to be due primarily to differences in the rate of relapse, rather than to differences in the rate of adverse events. Furthermore, the Kaplan–Meier analysis adjusted for differences in the duration of follow-up.2
With respect to dosage, we agree that trials testing excessively large doses may report biased results for both efficacy and safety.3 However, the daily doses in our trial — 4.9 mg of risperidone and 11.7 mg of haloperidol — were quite similar to those used in ordinary practice (4.2 mg and 11.1 mg, respectively).4 Moreover, patients taking 7.5 mg of haloperidol per day or less had a higher rate of dropout related to adverse events than patients taking more than 7.5 mg per day (23.7 percent vs. 13.3 percent).
Compliance was high and equal in the two treatment groups, and therefore a difference in compliance is an unlikely explanation for the difference in the rate of relapse. As Curtin observes, atypical antipsychotic drugs are better tolerated than conventional drugs, and many hope that better tolerability translates into better compliance and outcomes. Our data support the hypothesis that any first-line atypical antipsychotic drug is more efficacious than a conventional drug over the long term. We found that even when the putative advantage of improved compliance was removed, treatment with risperidone and haloperidol led to different outcomes.
Because we used a controlled design, we may have been better able to separate the “true” benefits of these different molecules from the numerous influences on outcome that are common in everyday practice. However, Lieberman and colleagues are correct to emphasize the value of effectiveness trials in schizophrenia,5 and we look forward to the results of their study. An understanding of both the absolute efficacy and safety of a particular drug and the clinical effectiveness of a treatment program using that drug can best lead to interventions that improve long-term patient outcomes.
5 ReferencesJohn G. Csernansky, M.D.
Washington University School of Medicine, St. Louis, MO 63110
csernanj@medicine.wustl. edu Ramy Mahmoud, M.D., M.P.H.
Janssen Research Foundation, Titusville, NJ 08560-02001
Chouinard G ,Ross-Chouinard A ,Annable L ,Jones BD . Extrapyramidal Symptom Rating Scale. Can J Neurol Sci 1980;7:233-233 abstract.
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Lang TA, Secic M. How to report statistics in medicine: annotated guidelines for authors, editors, and reviewers. Philadelphia: American College of Physicians, 1997:249, 252.
3
Volavka J ,Czobor P ,Sheitman B , et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry 2002;159:255-262
CrossRef | Web of Science | Medline4
IMS Health. National Disease and Therapeutic Index: based on prescriptions for the diagnosis of schizophrenia for calendar year ending December 2000. (Accessed April 1, 2002, at http://www.IMShealth.com.)
5
Mahmoud R ,Engelhart L ,Ollendorf D ,Oster G . The Risperidone Outcomes Study of Effectiveness (ROSE): a model for evaluating treatment strategies in typical psychiatric practice. J Clin Psychiatry 1999;60:Suppl 3:42-47
Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
2006. Neuroleptic drugs. , 2438-2489.
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