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The new england j ournal of medi ci ne
correspondence
Antipsychotic Drugs and Schizophrenia
to the editor: The report by Lieberman and
colleagues (Sept. 22 issue)
1
on the Clinical Antipsy-
chotic 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 inef-
ficacy became clear.
The study also indicates that 40 percent of all
patients discontinued as a result of their own deci-
sion. 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.
Michael Dettling, M.D.
Ion-George Anghelescu, M.D.
CharitUniversity Medicine Berlin
10961 Berlin, Germany
michael.dettling@charite.de
Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of
antipsychotic drugs in patients with chronic schizophrenia.
N Engl J Med 2005;353:1209-23.
Dossenbach M, Arango-Davila C, Silva Ibarra H, et al. Re-
sponse 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;66:1021-30.
to the editor: The CATIE study of the effective-
ness 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 re-
ceive olanzapine were already taking olanza-
pine, 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 medica-
tion longer (whether continuing to take olanza-
pine or changing medications); because the analy-
sis 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 medica-
tion at entry into the study contributed to the fa-
vorable continuation outcomes for olanzapine.
Second, a sensitivity analysis excluding data
1.
2.
this weeks letters
298 Antipsychotic Drugs and Schizophrenia
300 Vasodilators in Aortic Regurgitation
303 Childhood Growth and Coronary Events
304 Asbestos Exposure and Serum Osteopontin
305 Malignant Mesothelioma
307 Immunologic Tolerance to Intravenously
Injected Insulin
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correspondence
n engl j med 354;3 www.nejm.org january 19, 2006 299
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 exclu-
sion of patients with tardive dyskinesia from the
perphenazine group might account for the drugs
relatively good performance.
Susan 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 06269
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:
219-27.
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 fam-
ily, rather than on the health care provider. For
example, in India, drug therapy may account for
nearly 20 percent of a patients monthly income.
1

Atypical antipsychotic agents are far more expen-
sive in such countries. Olanzapine is 8.7 and 6.8
times more expensive than perphenazine in the
United States and the United Kingdom, respec-
tively, and risperidone is 4.1 and 2.1 times more
expensive.
2,3
Would patients in developing coun-
tries prefer more expensive, effective atypical drugs
that are associated with metabolic syndromes
or inexpensive but nearly equally effective typi-
cal drugs that are associated with extrapyrami-
dal 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 Kingdom
1.
Dr. Gupta reports having received honoraria and lecture fees
from AstraZeneca and education-related fees from Eli Lilly, Janssen,
and AstraZeneca.
Grover S, Avasthi A, Chakrabarti S, Bhansali A, Kulhara P.
Cost of care of schizophrenia: a study of Indian out-patient at-
tenders. Acta Psychiatr Scand 2005;112:54-63.
Charatan F. New antipsychotics offer few benefits over tra-
ditional drugs. BMJ 2005;7519:717.
British National Formulary. London: British Medical Asso-
ciation 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 analy-
ses do not solve this problem. Successful treat-
ment time appears to combine discrete time seg-
ments and thus this variable is not suitable for
KaplanMeier and proportional-hazards regres-
sion analyses. Several outcome measures are con-
founded with the duration of treatment, notably
the rates of substantial weight gain referred to in
the editorial by Freedman
2
: 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 receiv-
ing 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 meth-
odologic issues.
Naihua Duan, Ph.D.
Geffen School of Medicine at UCLA
Los Angeles, CA 90024
Helena C. Kraemer, Ph.D.
Stanford University School of Medicine
Palo Alto, CA 94305
Jim 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.
Kraemer HC, Robinson TN. Are certain multicenter ran-
domized clinical trial structures misleading clinical and policy
decisions? Contemp Clin Trials 2005;26:518-29.
1.
2.
3.
1.
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n engl j med 354;3 www.nejm.org january 19, 2006 300
Freedman R. The choice of antipsychotic drugs for schizo-
phrenia. N Engl J Med 2005;353:1286-8.
the authors reply: With regard to the com-
ments of Drs. Dettling and Anghelescu, the dose
of perphenazine was relatively low (not high) in
its therapeutic range. The dose was chosen inten-
tionally to reduce the risk of extrapyramidal symp-
toms. There was evidence that doses of quetia-
pine and ziprasidone were increased relative to
those of the other drugs. Relatively high doses of
olanzapine presumably would affect its tolerabil-
ity as well as its efficacy. Suggestions that the med-
ications used would have performed differently
at other doses are conjectures.
Dr. Duan and colleagues raise issues worth
clarification. We found no site-by-treatment in-
teractions that indicated that treatment should
be discontinued for any cause. The study design
a hybrid of paradigms of double-blinded ef-
ficacy 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 assign-
ments more often than would be expected by
chance. We thought that mixed-effects models
were the most appropriate option to use to exam-
ine efficacy measures. As expected, last-observa-
tion-carried-forward analyses favored the drug
with the longest treatment duration, whereas ob-
served-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 combi-
nation 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.
2.
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 risperi-
done 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 as-
signed 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 fol-
lows: olanzapine, 68 percent; quetiapine, 82 per-
cent; risperidone, 76 percent; perphenazine, 75
percent; and ziprasidone, 80 percent. All compari-
sons of treatment discontinuation and efficacy
that involved perphenazine excluded patients with
tardive dyskinesia at baseline, so that the patients
taking perphenazine were compared with simi-
lar patients without tardive dyskinesia who were
assigned to the atypical comparator drugs.
We agree with Drs. Gupta and Basu that policy-
makers will need data on cost-effectiveness and
additional measures of clinical outcome to de-
termine the policy implications and relevance to
other countries.
Jeffrey 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 27599
Sonia M. Davis, Dr.P.H.
Quintiles
Research Triangle Park, NC 27709
for the CATIE Investigator Group
Bang H, Ni L, Davis CE. Assessment of blinding in clinical
trials. Control Clin Trials 2004;25:143-56.
1.
Vasodilators in Aortic Regurgitation
to the editor: In the study by Evangelista et al.
regarding long-term vasodilator therapy in pa-
tients with severe aortic regurgitation (Sept. 29 is-
sue),
1
both nifedipine and enalapril failed to in-
duce adequate vasodilation, because systolic blood
pressure and diastolic blood pressure did not
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Copyright 2006 Massachusetts Medical Society. All rights reserved.