When faced with the failure of a first-choice antipsychotic medication,
whether it be for lack of efficacy or intolerable side effects, both
clinicians and patients alike struggle to decide which drug should be tried
next. With round two results from the National Institute of Mental Health's
CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study, the
question of which antipsychotic medication to try next may now be just a bit
easier to answer.
Two reports from the massive team of CATIE clinicians and researchers
appear in the April American Journal of Psychiatry. Both reports
detailed the findings of the study's second phase, which followed patients who
discontinued taking the first medication to which they were assigned at the
outset of the study. During phase 1, patients were randomly assigned to take
one of the second-generation antipsychotics olanzapine (Zyprexa), quetiapine
(Seroquel), risperidone (Risperdal), and ziprasidone (Geodon) or the
first-generation antipsychotic perphenazine (Trilafon). Results from phase 1
of the study were reported in September 2005. Nearly three-quarters of the
patients who began taking a study medication discontinued the drug prior to
the 18-month endpoint of CATIE (Psychiatric News, October 21,
CATIE, with more than $61 million in funding from the National Institute of
Mental Health over a 10-year commitment, enrolled nearly 1,500 patients at 57
clinical sites across the country. Jeffrey Lieberman, M.D., director of the
New York State Psychiatric Institute and chair of the department of psychiatry
at Columbia University College of Physicians and Surgeons, is the study's
director and principal investigator.
The complex study protocol involved following patients in real-world
settings through three phases of study over 18 months. The CATIE protocol
specifically defined "effectiveness," the primary outcome in all
phases of the study, as the time to discontinuation of the patients' assigned
medication, for any reason. In other words, the longer a patient continued to
take his or her assigned medication, the more "effective" the drug
was considered to be. This outcome was chosen by CATIE investigators as a
proxy measure of overall patient and clinician judgment.
Of the 1,493 patients who began treatment in phase 1, 1,052 stopped taking
their assigned medication prior to the study's 18-month endpoint. All patients
who discontinued a phase 1 medication were eligible to continue on to either
arm of phase 2 (see chart on facing page) for the remainder of the 18
The first of the new reports, from first author and CATIE co-principal
investigator Joseph McEvoy, M.D., an associate professor of biological
psychiatry at Duke University School of Medicine, details outcomes on patients
who discontinued their phase 1 medication primarily due to lack of efficacy.
In phase 2E of CATIE, these patients were randomly assigned to be treated open
label with clozapine (Clozaril) or blindly assigned to receive olanzapine,
quetiapine, or risperidone. Phase 2E was designed to answer the question, If a
patient stops taking his or her medication due to lack of efficacy, what are
the benefits of clozapine relative to the other second-generation medications
as the next drug choice for that patient?
The second report, from first author and fellow CATIE co-principal
investigator Scott Stroup, M.D., M.P.H., an associate professor of psychiatry
at the University of North Carolina at Chapel Hill, details the results of the
double-blind phase 2T arm of CATIE. Phase 2T compared the effectiveness of
olanzapine, quetiapine, risperidone, and ziprasidone in patients who primarily
discontinued taking the drug to which they had been assigned in phase 1 due to
intolerability. Patients who discontinued a phase 1 medication due to lack of
efficacy but were unwilling to accept the potential risks of treatment with
clozapine could also continue in phase 2T. The 2T arm of CATIE was designed to
compare the relative tolerability profiles of the drugs.
During phase 2E, clozapine was clearly the most effective medication, using
the CATIE definition. Nearly half of the patients in open-label treatment with
clozapine continued to take the drug for the remainder of the study. For those
patients who discontinued taking clozapine, the average time before they
stopped taking their medication was also the longest, ranging from about seven
to 16 months and averaging nearly 11 months.
Olanzapine had the second-highest proportion of phase 2E patients remaining
on medication, with one-third still taking the drug at the end of the study.
However, for those who did stop taking olanzapine, time to discontinuation
varied widely (from two to 12 months), and the average of just under three
months suggests that most patients who stopped the drug did so early on.
Patients taking risperidone in phase 2E had the third highest rate of
staying on their medication through the end of the trial (14 percent);
however, the mean time to discontinuation was the shortest, at under three
Less than 10 percent of those assigned to take quetiapine continued to take
the drug through the end of the trial. The average time to discontinuation of
quetiapine was just over three months.
Based on time to discontinuation, clozapine was statistically significantly
better than both quetiapine and risperidone. Although the average time to
discontinuation appears much better with clozapine compared with olanzapine,
the difference was not statistically significant because the range of times to
discontinuation were quite wide for both drugs. Fewer patients stopped taking
clozapine due to lack of efficacy than any of the other three drugs, a
difference that was statistically significant.
In addition, three months after entering phase 2E, patients taking
clozapine had statistically significantly greater reductions in
psychopathology, measured as greater reductions in scores on the Positive and
Negative Syndrome Scale total score, compared with those taking quetiapine and
risperidone, but not olanzapine.
In terms of side effects during phase 2E, insomnia was most common in those
taking risperidone (31 percent) and least common in those taking clozapine (4
percent). Anticholinergic symptoms were most common in those taking quetiapine
(47 percent) and less common in those taking clozapine (20 percent). No
significant between-drug differences were seen for metabolic measures or rate
of use of hypoglycemic or lipid-controlling medications. Prolactin levels rose
in patients taking risperidone and fell in those on the other three
In the group of patients taking clozapine, one of the 45 patients developed
eosinophilia, and one patient developed agranulocytosis. In both cases,
medication was stopped, and the patients improved.
Overall, clozapine was a significantly more effective choice, by CATIE's
definition, for those patients needing to stop their assigned phase 1
medication. Surprisingly, the statistical advantages for clozapine were
significant, despite the small numbers of patients in each of the comparison
In phase 2T, directly comparing the four second-generation drugs without
including clozapine, the treatment groups were significantly larger. Overall
olanzapine and risperidone were not significantly different in terms of
patients' remaining on medication through the remainder of the 18-month trial.
Risperidone slightly edged out olanzapine, with ziprasidone third and
In terms of time to discontinuation for any reason during phase 2T,
between-drug differences were significant. Patients taking either olanzapine
or risperidone continued to take their medication for nearly twice as long as
patients taking either quetiapine or ziprasidone.
Overall, differences in time to discontinuation for lack of efficacy during
phase 2T were statistically significant; however, differences in
discontinuation due to intolerability during phase 2T were not. Yet some
differences in tolerability were apparent. Patients taking olanzapine gained
more weight than patients on any other drug, with those taking ziprasidone, on
average, loosing weight. Olanzapine was also associated with significant
increases in total cholesterol and triglycerides, while risperidone and
ziprasidone were both associated with decreases in these measures.
According to the CATIE definition then, olanzapine and risperidone were
more "effective" than quetiapine and ziprasidone, yet neither was
as effective as clozapine.
Robert Freedman, M.D., editor in chief of the American Journal of
Psychiatry, noted in a statement, "These studies are the largest,
most comprehensive set of data available on the pharmacological treatment of
schizophrenia. As intended, their results provide guidance to doctors,
patients, and families on a logical sequence of treatments with significant
information on the probability of therapeutic response and the severity of
side effects at each phase."
Darrel Regier, M.D., M.P.H., is executive director of the American
Psychiatric Institute for Education and Research and director of APA's
Division of Research. He added, "CATIE shows that there's no
one-size-fits-all treatment. All of these medications have substantial
benefits and, as with any medication, have side effects as well. It is vital
that we preserve access to a full range of medications and respect physicians'
clinical judgments about which medication to use and when to
Regier also noted an urgent need for further research into the biological
processes underlying schizophrenia and potential molecular targets for new
"Effectiveness of Clozapine Versus Olanzapine, Quetiapine, and
Risperidone in Patients With Chronic Schizophrenia Who Did Not Respond to
Prior Atypical Antipsychotic Treatment" is posted at<http://ajp.psychiatryonline.org/cgi/content/full/163/4/600>."
Effectiveness of Olanzapine, Quetiapine, Risperidone, and Ziprasidone
in Patients With Chronic Schizophrenia Following Discontinuation of a Previous
Atypical Antipsychotic" is posted at<http://ajp.psychiatryonline.org/cgi/content/full/163/4/611>.
An accompanying editorial, "Practical Treatment Information for
Schizophrenia," is posted at<http://ajp.psychiatryonline.org/cgi/content/full/163/4/563>.▪
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