A fresh look at the data from phase 1 of the CATIE (Clinical Antipsychotic
Trials of Intervention Effectiveness) study, funded by the National Institute
of Mental Health (NIMH), indicates that patients who stayed on their initially
assigned antipsychotic medication the longest may have done so, in part,
because it was the same drug they were taking prior to entering the study. In
other words, continuity appears to have helped foster longevity.
The new analysis, by Susan Essock, Ph.D., a professor and director of the
Division of Health Services Research in the Department of Psychiatry at Mt.
Sinai School of Medicine, appears in the December American Journal of
Essock was not originally part of the CATIE research team, but she
approached principal investigator Jeffrey Lieberman, M.D., director of the New
York State Psychiatric Institute, with the idea of analyzing the effects of
switching versus not switching medications at initial drug assignment. In
keeping with NIMH's vision of open access, the CATIE data were made available
Essock's main question was deceptively simple: is it more advantageous to
continue taking the medication being received at entry into a clinical trial
or to switch to a different medication at the start of the study? If staying
with the same medication was more advantageous than switching, Essock expected
that those who stayed with the same medication would have longer times to
discontinuation for any reason, the primary outcome measure in the CATIE
Each of the patients entering the trial, along with their clinicians,
presumably were at least somewhat dissatisfied with the antipsychotic being
taken; otherwise, entering a clinical trial would not likely have been a
In CATIE phase 1, 23 percent of participants randomly assigned to
olanzapine (Zyprexa) were already taking olanzapine, 18 percent of those
randomly assigned to take risperidone (Risperdal) were already taking
risperidone, and 5 percent assigned to quetiapine (Seroquel) were already
taking quetiapine prior to the study. Less than 5 percent of patients randomly
assigned by the study to take perphenazine or ziprasidone were taking those
drugs prior to entering the study. Because of the low number of patients
involved, statistical comparisons involving quetiapine, perphenazine, and
ziprasidone were not done, due to an inherent lack of statistical
To investigate the "staying versus switching" question
completely, though, Essock and her collaborators had to approach the question
from both sides of the study's baseline: the first subanalysis involved the
group of patients randomly assigned to either olanzapine or risperidone upon
entering the study and investigated how well they had done based on whether
they stayed with their pre-study medication or switched to another study drug.
The second subanalysis involved the group of patients who were taking either
olanzapine or risperidone prior to entering the study and investigated how
well they fared if they stayed versus switched.
The researchers had already hypothesized that "stayers" would
have better outcomes; that is, continuity of medications would lead to longer
times to drug discontinuation. But if the "stayers" did fare
better, Essock and her colleagues reasoned, the collective"
better" results seen with those patients could potentially
significantly bias the overall phase 1 results. Therefore, they also wanted to
determine whether the phase 1 results would be different if study participants
randomly assigned to stay with their medication were excluded from the CATIE
phase 1 analysis (therefore removing the potential bias).
Essock and her colleagues found that patients who were randomly assigned to
either olanzapine or risperidone and were "stayers" did indeed
have the lowest rates of discontinuation of their study medications overall,
compared with "switchers" who took olanzapine or risperidone
during the study after switching from a different baseline medication. In
addition, the researchers found that patients staying with olanzapine were
significantly less likely to stop taking their study drug, compared with those
staying on risperidone.
Essock and her colleagues wrote, "Although both staying with one's
baseline medication and being randomly assigned to double-blind olanzapine
treatment led to longer times to discontinuation, there was no extra
synergistic effect of staying with olanzapine."
Second, patients who were taking olanzapine prior to entering the study and
were randomly assigned to stay on olanzapine during the study fared
significantly better, with longer average times to discontinuation, compared
with patients assigned to switch drugs at study entry. In contrast, for those
who were taking risperidone prior to entering the study, there was no
significant difference between them and those who switched to any of the other
Finally, Essock looked at the outcome measures for time to discontinuation
for any cause from CATIE phase 1 treatment, with all patients who were"
stayers" excluded from the analysis. With stayers removed, the
magnitude of the differences between olanzapine and the other drugs was
smaller; however, the general pattern was the same for discontinuation of
phase 1 treatment for any reason.
In everyday clinical practice, patients with schizophrenia often change
medications in an attempt to find a drug that offers better control of
symptoms, fewer adverse effects, or both.
Yet, "the switch or stay question is harder to answer in psychiatry
than in most other medical specialties," pointed out John Davis, M.D., a
professor of psychiatry at the University of Illinois at Chicago; Stephen
Marder, M.D., a professor of psychiatry at the University of California at Los
Angeles; and Carol Tamminga, M.D., a professor of psychiatry at the University
of Texas Southwestern Medical School, in an editorial accompanying the
"Schizophrenia almost always responds incompletely to
treatment," they continued, and "a patient's optimal response is
always a matter of judgment and usually difficult to assess, quantitate, and
record in the chart." It is also important "that clinicians
monitor and record efficacy and side-effect changes, thereby providing a
picture over time of how well a patient is doing... .Careful monitoring may
preserve the clinically useful information of why a patient may do better with
a given drug."
The findings of the current report, Essock and her colleagues said,
indicate that the potential success of a switch in medications is "a
function both of the medication being switched from and the medication being
switched to, and that switches have only modest success rates," at least
among the medications used during CATIE phase 1 in the patient population
enrolled in CATIE.
"On average, it may be better to stay with olanzapine," Essock
and her colleagues said, "than to switch to one of the other
antipsychotics used in phase 1." However, those who switched to
olanzapine for phase 1 were more likely to discontinue it due to
intolerability compared with those who stayed with olanzapine at study entry.
Those who switched to olanzapine were also more likely to discontinue it due
to intolerability compared with both patients who stayed on risperidone or
switched to risperidone. As a result, Essock and her colleagues noted,"
these limitations in olanzapine's tolerability acted to offset some of
its superior efficacy as originally reported."
"These findings suggest that unless the clinical situation requires a
medication change, prescribers should take steps to optimize current
medication regimens (e.g., via dosage changes, behavioral or psychosocial
interventions, adjunctive medications) before switching medications,"
the researchers wrote.
Yet, in the accompanying editorial, the authors pointed out that the
decision to stay or switch isn't all that straightforward.
"If staying with olanzapine treatment," they wrote, "is
associated with fewer discontinuations for psychosis, but changing to another
antipsychotic is associated with a lower risk of serious side effects such as
heart disease, then what should the clinician do?"
Patients and clinicians, they confirmed, "face this very difficult
question nearly every day."
What Essock and her colleagues stress is "working diligently with
patients to maximize the effectiveness of the current antipsychotic, before
taking on the risks associated with a medication change, in hopes that the
next one will be more satisfactory."
"Effectiveness of Switching Medications" and the
editorial "Switch or Stay?" can be accessed at<www.ajp.psychiatryonline.org>
under the December issue. ▪