Correspondence
Antipsychotic Drugs and Schizophrenia
N Engl J Med 2006; 354:298-300January 19, 2006
- Article
To the Editor:
The report by Lieberman and colleagues (Sept. 22 issue)1 on the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), funded by the National Institute of Mental Health, raises some questions that require clarification. One can see from the results that olanzapine and perphenazine, which were superior with respect to the rate of discontinuation of treatment, were given in rather high doses, as compared with the doses used in an observational study.2 In contrast, the antipsychotic drugs that were discontinued mainly because of a lack of efficacy, quetiapine and ziprasidone, were given in doses that were rather low (for people with schizophrenia). One has to wonder why the doses of quetiapine or ziprasidone were not increased when their inefficacy became clear.
The study also indicates that 40 percent of all patients discontinued as a result of their own decision. The study does not explicitly mention the reasons for their decisions, but one can assume that a lack of objective insight into the disorder, subjective social attitudes toward schizophrenia, and the social and financial backgrounds of the patients contributed. If this was the case, further studies that assess the power of education about psychotic disease and social psychiatric options are certainly indicated.
2 ReferencesMichael Dettling, M.D.
Ion-George Anghelescu, M.D.
Charité–University Medicine Berlin, 10961 Berlin, Germany
michael.dettling@charite. de 1
Lieberman JA ,Stroup TS ,McEvoy JP , et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-1223
Full Text | Web of Science | Medline2
Dossenbach M ,Arango-Davila C ,Silva Ibarra H , et al. Response and relapse in patients with schizophrenia treated with olanzapine, risperidone, quetiapine, or haloperidol: 12-month follow-up of the International Schizophrenia Outpatient Health Outcome (IC-SOHO) study. J Clin Psychiatry 2005;66:1021-1030
CrossRef | Web of Science | Medline
To the Editor:
The CATIE study of the effectiveness of antipsychotic drugs should be subjected to two additional analyses. First, the proportions of patients randomly assigned to continue taking the antipsychotic agents that they were taking at baseline varied markedly among the treatment groups (e.g., 23 percent of those assigned to receive olanzapine were already taking olanzapine, whereas only 5 percent of those assigned to quetiapine were already taking quetiapine). The authors should report the extent to which such patients fared worse (or better) with respect to particular outcomes. Patients taking olanzapine before enrollment continued the study medication longer (whether continuing to take olanzapine or changing medications); because the analysis combined patients staying on the medication they were receiving at baseline with those who changed medications, it remains unclear to what extent the larger proportion of patients in the olanzapine group who did not change medication at entry into the study contributed to the favorable continuation outcomes for olanzapine.
Second, a sensitivity analysis excluding data on any patient with tardive dyskinesia would help in an examination of whether, as previously shown,1 those with this condition did less well than those without the condition. If so, the exclusion of patients with tardive dyskinesia from the perphenazine group might account for the drug's relatively good performance.
1 ReferencesSusan M. Essock, Ph.D.
Mount Sinai School of Medicine, New York, NY 10029
susan.essock@mssm. edu Nancy H. Covell, Ph.D.
Carlos T. Jackson, Ph.D.
University of Connecticut, Storrs, CT 062691
Jackson CT ,Covell NH ,Essock SM . Differential effectiveness of clozapine for patients nonresponsive to or intolerant of first generation antipsychotic medications. Schizophr Bull 2004;30:219-227
Web of Science | Medline
To the Editor:
The implications of CATIE for cost-effectiveness, although not a direct focus of the study, are important for countries other than the United States, especially developing countries, where the financial burden of taking medications rests predominantly on the patient and the family, rather than on the health care provider. For example, in India, drug therapy may account for nearly 20 percent of a patient's monthly income.1 Atypical antipsychotic agents are far more expensive in such countries. Olanzapine is 8.7 and 6.8 times more expensive than perphenazine in the United States and the United Kingdom, respectively, and risperidone is 4.1 and 2.1 times more expensive.2,3 Would patients in developing countries prefer more expensive, effective atypical drugs that are associated with metabolic syndromes or inexpensive but nearly equally effective typical drugs that are associated with extrapyramidal symptoms? Would health care policymakers advocate more frequent use of clinically effective atypical agents or cost-effective typical agents? Is the evidence from the CATIE study solid enough to translate the results to developing countries or even to other developed countries? Clinicians and policymakers still need more data.
Nitin Gupta, M.D.
South Staffordshire Healthcare NHS Trust, Burton upon Trent DE13 0RB, United Kingdom
nitingupta659@yahoo.co. in Debasish Basu, M.D.
Mersey Care NHS Trust, Southport PR9 0LT, United KingdomDr. Gupta reports having received honoraria and lecture fees from AstraZeneca and education-related fees from Eli Lilly, Janssen, and AstraZeneca.
3 References1
Grover S ,Avasthi A ,Chakrabarti S ,Bhansali A ,Kulhara P . Cost of care of schizophrenia: a study of Indian out-patient attenders. Acta Psychiatr Scand 2005;112:54-63
CrossRef | Web of Science | Medline2
Charatan F . New antipsychotics offer few benefits over traditional drugs. BMJ 2005;7519:717-717
CrossRef | Web of Science3
British National Formulary. London: British Medical Association and The Royal Pharmaceutical Society of Great Britain, 2005.
To the Editor:
The report by Lieberman et al. raises certain methodologic and statistical issues. It appears that no consideration is given to site-by-treatment interactions, an important issue for multicenter trials.1 Fully successful blinding seems unlikely to be achieved, given the multiple dosing regimens used in CATIE. The efficacy analyses (Fig. 2E and 2F of the article by Lieberman et al.) are compromised by the huge discontinuation rates; the mixed-effects models used in the analyses do not solve this problem. Successful treatment time appears to combine discrete time segments and thus this variable is not suitable for Kaplan–Meier and proportional-hazards regression analyses. Several outcome measures are confounded with the duration of treatment, notably the rates of substantial weight gain referred to in the editorial by Freedman2: “Thirty percent of the patients receiving olanzapine gained more than 7 percent of their body weight during the trials, as compared with 7 to 16 percent of those receiving the other drugs.” Patients taking olanzapine had more time in phase 1 of the study to show weight gain. Given the major clinical and public health implications of CATIE, we believe that the authors should comment on these and other methodologic issues.
Naihua Duan, Ph.D.
Geffen School of Medicine at UCLA, Los Angeles, CA 90024Helena C. Kraemer, Ph.D.
Stanford University School of Medicine, Palo Alto, CA 94305Jim Mintz, Ph.D.
Geffen School of Medicine at UCLA, Los Angeles, CA 90024
jmintz@ucla.edu Dr. Duan reports having received research funding from Pfizer; Dr. Mintz, research funding from Eli Lilly and consulting fees from Janssen and Otsuka America; and Dr. Kraemer, consulting fees from Eli Lilly.
2 References1
Kraemer HC ,Robinson TN . Are certain multicenter randomized clinical trial structures misleading clinical and policy decisions? Contemp Clin Trials 2005;26:518-529
CrossRef | Web of Science | Medline2
Freedman R . The choice of antipsychotic drugs for schizophrenia. N Engl J Med 2005;353:1286-1288
Full Text | Web of Science | Medline
Author/Editor Response
With regard to the comments of Drs. Dettling and Anghelescu, the dose of perphenazine was relatively low (not high) in its therapeutic range. The dose was chosen intentionally to reduce the risk of extrapyramidal symptoms. There was evidence that doses of quetiapine and ziprasidone were increased relative to those of the other drugs. Relatively high doses of olanzapine presumably would affect its tolerability as well as its efficacy. Suggestions that the medications used would have performed differently at other doses are conjectures.
Dr. Duan and colleagues raise issues worth clarification. We found no site-by-treatment interactions that indicated that treatment should be discontinued for any cause. The study design — a hybrid of paradigms of double-blinded efficacy and effectiveness — did make maintenance of blinding challenging. However, an evaluation with the use of the blinding index described by Bang et al.1 showed that neither clinicians nor patients correctly guessed the treatment assignments more often than would be expected by chance. We thought that mixed-effects models were the most appropriate option to use to examine efficacy measures. As expected, last-observation-carried-forward analyses favored the drug with the longest treatment duration, whereas observed-cases analyses diminished the differences among patients who stayed on the assigned drugs for long durations. The duration of successful treatment is an outcome intended to integrate our primary outcome, the time spent taking a drug, with data on efficacy. We agree that the combination of disjoint time segments in this measure can complicate the interpretation of the results, but survival methods are suitable, in that the amount of time is a component of the total time to the discontinuation of treatment. Statistical testing of safety outcomes, including weight gain, were adjusted for time receiving treatment.
Dr. Essock and colleagues raise an important question with regard to the effects of staying on a medicine taken previously or starting a new one. Patients assigned to olanzapine or risperidone who stayed on their baseline medication remained in phase 1 longer than other patients in the treatment groups (hazard ratio, 0.69; P=0.007). However, this does not account for the study results, since the results of a sensitivity analysis excluding all the patients included in the intention-to-treat analysis who were assigned to their baseline medication (15 percent of the total) were similar to those of the primary analysis; the overall test of the comparison of the treatments, however, was not significant (P=0.086). Discontinuation rates for the drugs were as follows: olanzapine, 68 percent; quetiapine, 82 percent; risperidone, 76 percent; perphenazine, 75 percent; and ziprasidone, 80 percent. All comparisons of treatment discontinuation and efficacy that involved perphenazine excluded patients with tardive dyskinesia at baseline, so that the patients taking perphenazine were compared with similar patients without tardive dyskinesia who were assigned to the atypical comparator drugs.
We agree with Drs. Gupta and Basu that policymakers will need data on cost-effectiveness and additional measures of clinical outcome to determine the policy implications and relevance to other countries.
1 ReferencesJeffrey A. Lieberman, M.D.
Columbia University College of Physicians and Surgeons, New York, NY 10032
jlieberman@columbia.edu T. Scott Stroup, M.D., M.P.H.
University of North Carolina School of Medicine, Chapel Hill, NC 27599Sonia M. Davis, Dr.P.H.
Quintiles, Research Triangle Park, NC 27709for the CATIE Investigator Group
- Citing Articles (1)
Citing Articles
1
J. Rabinowitz, O. Davidov. (2008) A Composite Approach That Includes Dropout Rates When Analyzing Efficacy Data in Clinical Trials of Antipsychotic Medications. Schizophrenia Bulletin 34:6, 1145-1150
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