top
What is the “CATIE Study?”
The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)
Study, funded by the National Institute of Mental Health (NIMH), is a nationwide
three-phase clinical trial comparing the effectiveness of older and newer
antipsychotic medications used to treat schizophrenia. CATIE is the largest,
longest, and most comprehensive independent trial ever conducted to study
pharmacotherapies for schizophrenia.
Purpose of the Study.
The purpose of the CATIE study, which was conducted between January 2001
and December 2004, was to examine the effectiveness of antipsychotic medications
in a large and diverse population of consumers with schizophrenia, over
a relatively long period of time, in a variety of treatment settings.
Through CATIE, NIMH sought to research the effectiveness of treatments
for schizophrenia under “real world” conditions, as opposed
to the tightly controlled conditions—and limited populations—that
are usually included in clinical trials for medications. In addition,
CATIE compared antipsychotic treatments to each other, rather than to
a placebo, as is usually done in clinical trials.
Release of Study Results. The study results are being
released in three phases.
Phase 1 – Results were released in the September 22nd issue of
the New England Journal of Medicine. The findings compared all-cause discontinuation
rates, efficacy and side effects across the five study drugs, which
included
one older generation antipsychotic and four second generation (also
called atypical) antipsychotic medications.
Phase 2 – Results were released on April 1, 2006 in the American
Journal of Psychiatry. Phase 2 compared atypical antipsychotics with each
other in two different groups of participants. One group was randomized
to treatment with clozapine if they failed one of the initial study medications.
The other group took part in a medication trial which used ziprasidone
and not clozapine.
Phase 3 – Results will include descriptive data on patients treated
with aripiprazole (Abilify), which was added to the study after its
approval in 2004. The date for the release of these results is unknown.
According to CATIE researchers, subsequent releases of data will also examine
results in the following areas: cost-effectiveness (both for medication
and across all health expenditures); cognitive improvement; rates of
recovery; patient value of treatments in terms of functional performance;
and reversibility
of side effects. According to NIMH, “As additional results from CATIE
are analyzed, disseminated, and put into context, the hope is that the
cumulative findings will yield a more complete picture of the interaction
between patient
characteristics, medication, environment, and outcomes.”[1]
“Cumulative findings” is the key term here. Once all of the
CATIE findings have been released, they could provide an extremely valuable
tool to help consumers with schizophrenia and their clinicians make more
informed choices about which treatment is best for each individual. However,
as it currently stands, CATIE findings are still far from complete, and
in most cases are inadequate to guide individual treatment decisions or
inform public policy.
top
How was CATIE conducted?
Study Participants and Sites.
The CATIE clinical trials included 1,460 [2] participants
at 57 clinical sites across the country.
- Participants
in the study ranged in age from 18 to 65 years old, and all had a
diagnosis of schizophrenia (individuals experiencing first-time
episodes and treatment-refractory schizophrenia were excluded from
the study). Seventy-four percent of the participants were male.
- Many
participants had co-occurring health and mental health problems,
such as depression (28% of participants), anxiety (at least 14%), drug
dependence/abuse (29%), diabetes (11%) and hypertension (20%).
- Sixty
percent of participants identified themselves as white/Caucasian;
35% as African American/Black; 12% as Spanish, Hispanic or Latino;
2% as Asian; less than 1% as American Indian or Alaska Native;
less than 1%
as
Native Hawaiian or other Pacific Islander; and 2% as “two or
more races.” [3]
- According to researchers at an NIMH briefing on
September 26, 2005, about 30% of CATIE participants were recruited
during a hospitalization
that resulted from an individual’s previous decision to discontinue
medication. Data was not provided, however, on the reasons for
these decisions.
- CATIE was conducted at many different treatment
sites—including
private clinics, academic centers, Veterans Administration hospitals,
and public mental health centers—in an attempt to be broadly
representative of the real-life settings where consumers receive
care.
- In typical clinical trials for FDA approval of antipsychotics,
participants are followed for four to eight weeks. Participants
in CATIE were followed
for 18 months so that investigators could evaluate longer-term
consumer outcomes.
Study Phases.
The CATIE trial includes three phases. In Phase 1, participants
were randomly assigned to one of four newer, "atypical" antipsychotic
medications: olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal),
and ziprasidone (Geodon); or to one older-generation antipsychotic, perphenazine
(Trilafon). No participants received placebos. Participants continued to
take this medication for the next 18 months, or until one of the following
occurred:
• the medication could not control their symptoms adequately;
• they developed an intolerable side effect; or
• they decided to stop the medication, or withdraw from the study for
some other reason.
In Phase 2, Of the 1,052 participants with DSM-IV diagnosis of schizophrenia
who discontinued phase 1 treatment before 18 months, 509 left the study
entirely, 99 participants entered the efficacy pathway, and 444 entered
the tolerability pathway.
- The efficacy pathway compared clozapine to the other newer atypical
antipsychotic medications. Participants who chose this pathway either
agreed to be assigned
to clozapine, which they received open label (with knowledge of what
they were receiving) or were randomly assigned to receive one of the
other study
medications (olanzapine, risperidone, or quetiapine) different from
the one they took in phase 1.
- The tolerability pathway compared ziprasidone to the other study medications.
Participants who chose this pathway were randomly assigned to receive
either ziprasidone or an atypical medication different from their phase
1 medication.
Outcomes Measured.
During Phase 1, the primary outcome measure studied was the rate of treatment
discontinuation, for any reason (e.g., lack of efficacy, troublesome side
effects, or other reasons). Secondary outcome measures studied included
measures for clinical and functional outcomes, safety and neurocognition.
These are the findings that were reported in the New England Journal
of Medicine on September 22, 2005.
During Phase 2, in the efficacy pathway, the primary outcome measure was
the time until discontinuation for any reason. Secondary outcomes include
time to discontinuation for inadequate therapeutic benefit, intolerable
side effects, or patient decision. In the tolerability pathway, the primary
outcome measure was the same as the efficacy pathway. A key secondary
outcome was the reason for treatment discontinuation as judged by the study
doctor
and secondary safety and tolerability outcomes. Results from phase 2
of the study analyzed effectiveness, efficacy and tolerability of many of
the
atypical antipsychotics available as well as an older medication, clozapine.
These findings were reported in two articles in the April 1, 2006 issue
of the American Journal of Psychiatry.
During Phases 2 and 3 of CATIE,
participants whose assigned treatment was discontinued during Phase
1 could receive other treatments, and investigators
followed their progress.
In addition, the investigators will continue to study other outcomes, including
cost-effectiveness, quality of life, and predictors of response to given
medications. The Phase 3 findings have not yet been released.
Findings to Date.
The CATIE Phase 1 trials found that in each of the five medication treatment
groups, a majority of participants discontinued their assigned treatment
due to inefficacy, intolerable side effects, and/or other reasons. Olanzapine
(Zyprexa) had the lowest rates of discontinuation, but was also associated
with higher rates of side effect such as greater weight gain and increases
in measures of glucose and lipid metabolism. Specifically, 64% of those
assigned to olanzapine discontinued the treatment before 18 months, followed
by risperidone (74%), perphenazine (75%), ziprasidone (79%) and quetiapine
(82%).
In short, each of the medications worked well for some individuals, but
not others. The high treatment discontinuation rates are disappointing,
but echo what many consumers and families have experienced—that it
often requires trying more than one medication before finding the treatment
that is effective for each individual. CATIE findings are consistent with
previous research and clinical experience that has shown that complex factors—such
as ethnicity, co-occurring illnesses and tolerance of side effects—all
impact an individual’s response to a medication.
Across the treatment groups, an average of 39% discontinued their treatment
due to inefficacy or intolerability, 30% due to decisions by study participants
and/or their advocates, and 5% for other reasons. We do not yet know why
some people responded well to each medication while others did not, or the
reasons why some participants (or their patient advocates) chose to discontinue
the medications.
In CATIE Phase 2, the main results of the efficacy (clozapine) pathway
indicated that clozapine was remarkably effective in this group of study
participants and was substantially better than all the other atypical medications:
20 out of 45 patients (44%) who received clozapine were able to stay on
clozapine for the rest of the study, whereas only eight out of 45 patients
(18%) who received another atypical antipsychotic medication were able to
stay on that medication to complete the study. The participants taking clozapine
remained on it for an average of 10 months compared to an average of three
months for those taking any of the three other medications. Those taking
clozapine also had greater symptom reduction than those who took any of
the other medications. Only one patient developed one of the most severe
adverse side-effects, agranulocytosis (and was taken off clozapine).
The main results of the tolerability (ziprasidone) pathway indicated that
about 35% of the participants who took olanzapine or risperidone were able
to continue on their medication until the end of the 18 months of the study.
This compares to only 23% of those who took ziprasidone and 16% of those
who took quetiapine that were able to continue.
It was important to examine the results in phase 2 separately for those
participants who had stopped their phase 1 medication for different reasons.
For those who had stopped phase 1 medication due to inadequate management
of psychotic symptoms, those taking olanzapine or risperidone in phase 2
stayed on their medication for a significantly longer duration than those
taking quetiapine or ziprasidone, results that are similar to the overall
results above. However, for the participants who had stopped phase 1 medication
due to side effects, there were no significant differences among the four
phase 2 medications. Thus, which medication works best depends in large
part on why a patient was switched to it.
Both phase 1 and 2 of the study confirm that a complete range of medications
is necessary to help consumers and their caregivers find the treatment that
works best for them.
top
Does the CATIE study prove that older antipsychotics are interchangeable
with atypical antipsychotics?
Absolutely not. Unfortunately, this misinterpretation was widely disseminated
through the media when the Phase 1 results were published in 2005. In fact,
the study strongly reinforces what consumers and families have known for
years—that there is no “one size fits all” treatment for
schizophrenia. Moreover, the study demonstrates that significant further
research is needed into better treatment options for individuals and the
impact that factors that are not measured in randomized controlled-trials
have in successful clinical and functional outcomes.
-
In the CATIE trials, no one drug was found to be effective for the
majority of consumers. This reinforces the position that “fail-first” policies
are clinically unsound.
-
While study participants across the medications
experienced a range of side effects, there were differences between
drugs in the types
of side effects that caused treatment discontinuation. For example,
perphenazine
(the older antipsychotic) was associated with more discontinuation
for extrapyramidal side effects than the other drugs, whereas olanzapine
was associated with more discontinuation for weight gain or metabolic
effects. In Phase 2, in the efficacy pathway, insomnia was most
common side effect with risperidone, anticholingergic[4] symptoms
were associated with quetiapine and sialorrhea[5] was
most common with clozapine. In the clozapine group, one patient
had a serious adverse event of eosinophilia[6] and
one patient developed agranulocytosis[7] ,
these patients discontinued use of clozapine. In the tolerability
pathway, patients receiving risperidone
experienced higher rates of adverse effects involving sexual functioning
and galactorrhea[8] . Patients
on olanzapine experienced more weight gain.
- Only one older antipsychotic
medication—perphenazine—was
included in the CATIE trial. According to NIMH, one commonly-prescribed
older antipsychotic, haloperidol (Haldol), was not included in
the study because:
“patients who take haloperidol experience high rates of movement side effects,
called extrapyramidal side effects (EPS), such as rigidity and stiff movements,
persistent muscle spasms, tremors, and uncontrollable restlessness. Because many
individuals find EPS particularly difficult to tolerate, haloperidol is an unpopular
treatment choice for many people with schizophrenia. Although EPS is associated
to some degree with all the older ‘typical’ antipsychotic
medications, perphenazine is an effective older antipsychotic
that is less likely to produce
EPS.” [9]
- Yet, in common clinical practice, Haldol is the more-frequently used
older antipsychotic medication. Moreover, many Medicaid preferred drug
list debates have focused on Haldol as a first-line or preferred treatment
over the atypical medications.
Among the study participants who took perphenazine, only 25%
found it effective and tolerable enough to continue treatment.
Given that
the success rate was no better than that of the other study
drugs, it would clearly be inappropriate to use perphenazine
as a “fail-first” drug.
In Phase 2, clozapine was remarkably effective and was substantially
better than all the other atypical medications: 44% who received
clozapine were able to stay on clozapine for the rest of the
study. Unfortunately,
clozapine is associated with serious side effects, including
life-threatening blood and heart complications such as agranulocytosis
(decreased white
blood cell count) and myocarditis (inflammation of the heart);
as a result, people who take clozapine must be monitored closely,
which includes
blood tests.
top
What questions does CATIE leave unanswered?
The preliminary results of the CATIE study looked solely at comparability
among the medications regarding discontinuation, efficacy and side effects.
There are many questions that analysis of the first two phases did not explore,
including the following:
- Are certain subgroups of the participant population studied more prone
to the side effects of these medications?
- To what extent is efficacy
of any given medication affected by gender? By race/ethnicity?
- Were
higher levels of clinical contact a factor in some participants’ response
to treatment?
- Was the provision (or absence) of support services
a factor in some participants ’ response to treatment?
- Were there
differences in the patient cadres at respective study sites that
may have accounted for some of the results or that may
inform clinical practices?
- According to the study authors, “Dose
could have been a factor in the performance of the various agents
studied,” noting that the
FDA-approved and commonly-prescribed dose ranges used in CATIE “may
be below their optimal therapeutic doses.”[10] Would the findings
have been different if doctors and participants had explored higher
dose ranges
rather than choosing to switch medications?
- What is the effect
on consumer outcomes of switching a medication?
- How will CATIE
findings address newer atypical antipsychotic medications that were
not part of the complete trial period?
- What are the implications for
public policy affecting reimbursement and service access?
- How should
policymakers interpret CATIE results?
- What decisions does CATIE
support? What decisions cannot be made based on CATIE results?
“ [CATIE] will provide valuable information to help physicians
and patients choose the most appropriate medication for them. There is considerable
variation
among individuals; what works for one does not necessarily work for another.
It is important to have a variety of treatment options. The CATIE study
provides specific information, on therapeutic effects as well as side
effects, about those options. ”
National Institute of Mental Health
September 2005 8
top
For additional information or to speak with an expert or individual
with mental illness, please call (703) 797-2588 or email mediainfo@nmha.org.
- National Institute of Mental
Health. September 2005. Questions and Answers About the NIMH Clinical
Antipsychotic Trials of Intervention
Effectiveness Study (CATIE). Available at: http://www.nimh.nih.gov/healthinformation/catie_qa.cfm..
- Initially,
1493 participants were enrolled in the study, but all data from
one site (33 participants) was excluded due to concern about the
integrity
of data
from that site.
- Because of rounding, percentages may not add up to 100%.
- Dry mouth,
urinary retention, blurred vision, and constipation
- Excessive drooling
- Abnormally high amounts of white blood cells found
in either the blood or in body tissues
- An insufficient number of
white blood cells
- Inappropriate lactation
- National Institute of Mental Health. September
2005. Questions and Answers About the NIMH Clinical Antipsychotic
Trials of Intervention Effectiveness
Study (CATIE).
- Lieberman, J.A. et al. 2005. Effectiveness of Antipsychotic
Drugs in Patients with Chronic Schizophrenia. New England Journal
of Medicine, Vol. 353,
No. 12, p. 1218.
|
