research reviews
CATIE: Clinical Antipsychotic Trials of Intervention Effectiveness
Introduction
The following is a summary of an article, entitled “The Significance of CATIE: An Expert Interview With Jeffrey A. Lieberman, M.D.”, that appeared in Medscape Psychiatry & Mental Health. 2006;11(1).
Dr. Liebereman is Professor and Chairmen, Department of Psychiatry, Columbia University, New York, NY and Psychiatrist in Chief, New York Presbyterian Hospital/Columbia University Medical Center, New York, NY.
CATIE
Phase 1 results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) first appeared in September of 2005.1 CATIE was a multicenter, randomized, double-blind study of antipsychotic medications funded by NIMH (the National Institute of Mental Health).
It was the first study to directly compare a typical (first-generation) antipsychotic with several atypical (second-generation) antipsychotics in a large number of patients with chronic Schizophrenia.
Purpose
This study was undertaken to investigate the assumption that atypical antipsychotic medications are both more effective and safer than older typical antipsychotics, particularly since an increase in their use has led to higher costs. Formally, the questions that were to be answered by CATIE were:
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Are the second-generation antipsychotic agents better than the first-generation medications? -
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How do the second-generation drugs compare with each other?
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Are the second-generation agents cost-effective?
Phase 1
The first report described the results of efficacy and safety. The CATIE study involved 3 novel aspects:
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it included all patients with Schizophrenia, except those experiencing their first episode and those with treatment resistant Schizophrenia
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it was a relatively long-term study (eighteen months)
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it was both a standard clinical trial and a pragmatic clinical trial. In other words it was constructed as standard research (patients were initially randomly assigned to groups where they received one of five different medications), but also approximated “real-world” treatment, since patients could be randomly reassigned one or two times to another group, if improvement did not meet the expectations of either the patient or their clinician.
1500 patients who suffered from Schizophrenia were randomly assigned to received olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ziprasidone (Geodon) or the first-generation antipsychotic perphenazine (Trilafon).
The media reported the results with simplistic conclusions. Dr. Lieberman’s interpretation was:
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While all of the medications studied were effective, they demonstrated clear-cut limitations in their ability to control symptoms or in their potential to cause side effects.
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Only a quarter of the total patients continued with their first medication for the entire 18 months; three quarters of them switched to another medication, either because the first medication did not work as well as they hoped or because it caused undesirable side effects.
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Olanzapine appeared to be the most effective in controlling symptoms, but also produced the highest rate of side effects.
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When a non-high potency first-generation drug (perphenazine) was used in a moderate dosage, it performed well compared to atypical agents.
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Even though all of the medications worked more or less the same, there were meaningful differences between them in terms of efficacy and side effects for individual patients.
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Those differences were meaningful in terms of individualizing treatment for any given patient.
Olanzapine
Olanzapine was the medication that patients stayed on the longest (even though it produced the highest rate of side effects). Dr. Lieberman concluded that this observation was related to its high degree of efficacy.
He stated, “Like clozapine, its pharmacology is such that it alleviates symptoms of the illness better than other agents. They may subjectively tolerate metabolic side effects and weight gain better than the neurologic side effects of classic (first-generation) antipsychotics.
30% of the patients taking olanzapine gained 7% or more of their baseline body weight, this did not cause either the patient or doctor to switch to another medication. Apparently, the benefit with respect to symptom control overshadowed the side effect of weight gain.
While weight gain is generally unhealthy and may cause distress in patients for cosmetic reasons, it is not necessarily physically uncomfortable like neurologic side effects (Parkinsonism, akathisia and dystonia). Patients are not aware of the other metabolic side effects (subclinical hyperglycemia or hyperlipidemia) and so they are not uncomfortable."
He concluded that delayed consequences of these effects could impact the patient’s desire to continue with olanzapine long-term.
Predictability
Dr. Lieberman indicated that, thus far, there has been no analysis of risk factors that might offer information related to whether or not patients of a certain gender or race, or those with a particular clinical history, might be more prone to develop weight gain versus EPSE. This analysis is pending.
He did indicate that treatment history and sensitivities could be used with the results of the study to make some preliminary choices regarding medications.
Examples:
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If a particular patient has been prone to gaining weight, but has symptoms that are not resistant to treatment, olanzapine would not be a good choice initially. Ziprasidone (which was associated with the least weight gain) would be a better choice; as would risperidone or even perphenazine.
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If a patient has a history of sensitivity to EPSE, perphenazine and risperidone should be avoided.
First-episode Psychosis
Dr. Lieberman reported that “olanzapine and haloperidol did not substantially differ in their effects on psychosocial functioning and health status improvement in the first year of treatment following the onset of schizophrenic psychosis”, but 50% of patients discontinued medication, more often haloperidol than olanzapine.2
Dr. Lieberman stated, “First-episode patients are more responsive to treatment than at any later stage of illness. They’re more sensitive to the therapeutic effects and to the side effects of medications. They also require doses about 50% lower, on average, than patients with chronic schizophrenia. So the considerations are markedly different for first-episode patients.”
Unlike in the CATIE study, that study2 showed that haloperidol and olanzapine did not differ substantially. Dr. Lieberman’s response was that, “What that means is that haloperidol works as well as olanzapine at controlling symptoms and facilitating recovery. Only a small proportion of people are treatment-resistant at that stage (10-15%), so most first episode patients are going to get better on just about any antipsychotic, but they’re going to be very susceptible to side effects. Haloperidol was associated with a much higher incidence of EPS, and a lot of people dropped out because of that. So the side effect profile becomes the determining factor in adherence to treatment in first-episode patients.”
VA (Veterans Administration) Cooperative Study
This study3 compared the cost effectiveness of olanzapine vs haloperidol. The study indicated that the outcomes (improvement) and treatment retention (patients who continued a specific medication) did not differ significantly, but the cost for olanzapine was greater. This was because the VA study did not count the reduction in costs for inpatient treatment and those related to additional changes in medication that patients who were taking olanzapine avoided.
Related findings from the CATIE study are not yet available. Dr. Lieberman did indicate that patients taking olanzapine may have required more healthcare services and did require less hospitalization, but it is not yet known whether reduced costs for hospitalization would offset the greater cost for the medication and those for any added healthcare services.
He also pointed out that the population of patients studied by the VA may not be representative of patients with Schizophrenia in general.
Psychosocial Interventions
Dr. Lieberman indicated that there is good evidence that a number of psychosocial interventions would have a positive effect on treatment adherence and outcome.4
He went on to say that:
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any type of compliance enhancement therapy by case management, assertive community treatment, and psychoeducation would be useful
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having some type of supportive employment would be highly desirable
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these entities were not tested in the CATIE study
Summary
Based upon information provided by this article and the references cited:
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the CATIE study, a multicenter, randomized double-blind study involving 1500 patients with chronic Schizophrenia, was the first study to directly compare a typical antipsychotic agent with several atypical agents
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it was designed to determine if atypical antipsychotics were better than typical antipsychotics, how atypical antipsychotics compared with one another, and whether atypical antipsychotics were cost-effective
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while all medications studied were effective, they demonstrated clear-cut differences in their ability to control symptoms or in their potential to cause side effects
-
-
olanzapine appeared to be the most effective in controlling symptoms, but also produced the highest rate of side effects
-
-
when perphenazine was used in a moderate dosage, it performed well compared to atypical agents
-
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there were meaningful differences between medications in terms of efficacy and side effects for individual patients
-
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those differences were meaningful in terms of individualizing treatment for any given patient
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patients stayed on olanzapine the longest, even though it produced the highest rate of side effects
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this may be due to the type of side effects produced (less uncomfortable side effects) and its greater efficacy
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currently available data can help us choose a medication to avoid certain side effects if we have knowledge related to how well patients respond to medications and what side effects they are most sensitive to
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first-episode patients are more responsive to treatment than at any latter stage in their illness, are more sensitive to side effects, and require doses of medications that are 50% lower than patients with chronic Schizophrenia
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therefore, the considerations related to the choice of medications are different for this population (the side effect profile becomes the determining factor in adherence to treatment for first-episode patients)
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patients taking olanzapine may require more healthcare services, but do require less hospitalization
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t is not known whether a reduction in days in the hospital will offset the costs of other healthcare services and the additional cost of the medication
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there is good evidence that a number of psychosocial interventions (case management, assertive community treatment, psychoeducation and supportive employment) would have a positive effect on treatment adherence and outcome
The Author’s Criticisms and Conclusions
Clozapine, the most effective antipsychotic agent for refractory schizophrenia, was excluded from the list of atypical antipsychotics in this study.
Perphenazine, a typical antipsychotic known to be relatively free from either anticholinergic side effects and EPSE (extrapyramidal side effects) was chosen to represent typical antipsychotics.
Atypical antipsychotic agents clearly offer advantages over typical agents in terms of some side effects, particularly neurologic side effects (Parkinsonism, akathisia and dystonias).
Some atypical agents, notably quetiapine and aripiprazole, have side effect profiles that are much more benign that any of the typical agents.
Patients treated with typical antipsychotics are approximately twice as likely to develop definitive tardive dyskinesia compared with those treated with atypical agents.5 6 Rates for atypical antipsychotics in general is are about 1/10 that of haloperidol. Rates for clozapine and quetiapine are probably much lower.
At least two atypical agents, clozapine and olanzapine, have been shown to be more effective than typicals in reducing symptoms.
An analysis of potential differences between typical and atypical agents with respect to improving mood, effects on cognition, and cost-effectiveness is pending.
1Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223. Abstract
2Lieberman J, Tohen M, Green AI, et al. Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized double-blind trial of olanzapine vs. haloperidol. Am J Psychiatry. 2003;160:1396-1404. Abstract
3Rosenheck R, Perlick D, Bingham D, et al. Effectiveness and cost of olanzapine and haloperidol in the treatment of schizophrenia: a randomized controlled trial. JAMA. 2003;290:2693-2702. Abstract
4Lehman AF, Buchanan RW, Dickerson FB, et al. Evidence-based treatment for schizophrenia. Psychiatr Clin North Am. 2003;26:939-954. Abstract
5Dolder, CR, Jeste, DV Incidence of tardive dyskinesia with typical versus atypical antipsychotics in very high risk patients. Biological Psychiatry Volume 53, Issue 12, 15 June 2003, 1142-1145
6Kane, JM Tardive dyskinesia rates with atypical antipsychotics in adults: prevalence and incidence. J Clin Psychiatry. 2004;65 Suppl 9:16-20
(Sources: The author’s knowledge base, unless otherwise noted.)
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