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Catie

Catie

Purpose

Description

Findings of the study

Purpose

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Study is a clinical trial funded by the National Institute of Mental Health and coordinated by the University of North Carolina at Chapel Hill. The purpose of the study is to evaluate the effectiveness and side effects of newer antipsychotic drugs (sometimes referred to as atypical antipsychotics) in comparison to conventional antipsychotic drugs in the treatment of schizophrenia. One of the purposes of the study was to help doctors maximize the benefits of antipsychotic drugs while minimizing their negative side effects.

Description

Atypical antipsychotic medications frequently have fewer serious adverse side effects than conventional antipsychotics. The CATIE study was an attempt to scientifically investigate the effectiveness of the newer drugs in comparison with the conventional antipsychotic drug perphenazine (Trilafon). All drugs used in the CATIE study had been previously approved by the U.S. Food and Drug Administration (FDA). The atypical antipsychotic drugs under investigation in the study were:

  • clozapine (Clozaril)
  • olanzapine (Zyprexa)
  • quetiapine (Seroquel)
  • risperidone (Risperdal)
  • ziprasidone (Geodon)

Aripiprazole (Abilify), another atypical antipsychotic drug, was not approved by the FDA in time to be included in the study. No placebos were used in the study.

All of the drugs evaluated in the CATIE study had already undergone clinical trials by the representative pharmaceutical companies in order to get FDA approval to market each drug. Although these studies were appropriately rigorous to earn FDA approval, they typically had a limited number of participants, tested only two or three drugs per study, and lasted only four to eight weeks.

As opposed to the clinical trials previously conducted by the pharmaceutical companies, the CATIE study lasted for 18 months and used over 1,400 participants. This more in-depth study allowed researchers to study drug actions and side effects in more depth as well as examine more long-term effects of their use.

Although the pharmaceutical companies donated the medications for the study and advised the researchers concerned of optimal doses, they had no other input into the design, implementation, analysis, or interpretation of the study results.

The CATIE study was open to participants from 18 to 65 years of age who had been diagnosed with schizophrenia using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), and who were able to use oral medications. Of the 1,460 patients who were enrolled in the CATIE study, 74% were male, 40% were non-white, and 12% were Hispanic. The mean (average) age of CATIE participants was 40.6 years. The average length of time participants had been schizophrenic was 14.4 years. Participants in the study came from 57 different clinical sites across the country and reflect the range of people in the United States suffering from schizophrenia.

Study participants were randomly assigned to the experimental treatments in a double-blind study. This means that the doctors administering the drugs were not able to choose which medication their patients received, and that neither the researchers, administering physicians, or patients knew which treatment the patients were receiving. This study design helped ensure that preconceived expectations about the effectiveness of any of the drugs did not affect the outcome of the study. Patients were randomly assigned to either one of the atypical antipsychotics or the control conventional antipsychotic. Patients continued on the assigned drug for 18 months or until the drug failed to continue to control their symptoms or produced intolerable side effects, or the patients decided to stop the medication or withdraw from the study.

Previous research has shown that patients taking antipsychotic medication are better off than those not taking such medication. Previous research has also found that staying on antipsychotic medication is critical to controlling the symptoms of schizophrenia and presenting a relapse . Therefore, one of the primary measures of success in the CATIE study was how long patients benefited from the medication to which they were assigned and how long before they decided it needed to be changed. When patients decided that the medication was not effective, researchers recorded the reasons the medication was stopped (e.g., the medication no longer controlled the symptoms, the side effects were intolerable). Other data collected included the effects of the medications on the symptoms of schizophrenia and level of the patient’s functioning on the medication.

Findings of the study

The study found that the conventional antipsychotic generally was equally effective and tolerated as well as the newer, more expensive, atypical antipsychotic medications. Of the atypical antipsychotics, olanzapine performed somewhat better than the other drugs in the study. Patients on this drug were less likely to be hospitalized for psychotic relapse and tended to stay on their medication longer than patients taking other antipsychotic drugs in the study. However, patients on olanzapine also tended to gain significant weight and experience other metabolic changes associated with diabetes than did patients taking the other drugs in the study.

Nearly 75% of the patients in the CATIE study switched to a different medication during the course of the study. Participants who stopped taking the medication for any reason were given the opportunity to continue in the study in one of two ways. In the “efficacy pathway,” patients who discontinued an atypical antipsychotic because it was not sufficiently effective were randomly assigned to receive another atypical antipsychotic to help determine what treatment should be chosen for such patients. In the “tolerability pathway,” patients who discontinued their medication because of side effects were allowed to receive another medication in order to help determine the next best choice for patients who experience adverse side effects with an atypical antipsychotic. The conventional antipsychotic (perphenazine) was not included in this second phase of the study because researchers had not expected the conventional medication to work as well as the newer drugs when they designed the study.

Most of the participants in the Phase II efficacy pathway study had not benefited from their first antipsychotic medication and had worse symptoms than at the beginning of the study. These participants also tended to have worse symptoms than those participants in the tolerability pathway study. Clozapine was very effective for this group and worked significantly better than the other atypical antipsychotics. Forty-four percent of participants in this part of the study were able to stay on their medication for the remainder of the study. Participants on the efficacy pathway stayed on their medication for an average of 10 months as opposed to three months for those taking the other atypical antipsychotics. In addition, most of these participants had greater symptom relief than participants taking the other medications.

As in Phase I of the study, in the tolerability pathway of the Phase II study, a high rate (74%) of patients stopped taking their medication. However, 35% of the Phase II participants in the tolerability study who took olanzapine or risperidone continued taking their medication until the end of the study. Only 23% of participants taking ziprasidone and 16% of participants taking quetiapine in the Phase I study were able to continue throughout the entire 18 months.

The results of the Phase II study show that the choice of a different medication for patients who stop taking an antipsychotic medication depends on why they stopped taking the first medication. Participants who stopped taking their antipsychotic medication in Phase I because it was not adequately controlling their symptoms were more likely to stay on their medication if they were switched to olanzapine or risperidone rather than quetiapine or ziprasidone. There was no difference between the four medications tested in Phase II, however, for participants who had stopped taking their Phase I medication because they experienced adverse side effects.

The CATIE study has several major implications. First, the results of Phase I of the study show that it is worthwhile to start patients on less expensive conventional antipsychotic medications before trying the atypicals. Specifically, physicians and patients should consider perphenazine as an alterative to atypical antipsychotics both because of its similar effectiveness and its lower price.

The CATIE study results can also be used to help select a different antipsychotic medication for those patients who were not successfully treated on another antipsychotic. The results of the Phase II study show that the reason for stopping the first medication should be considered when choosing another medication.

The study results also show that clozapine is often a good choice of medication for patients who did not respond well to other antipsychotic medications. In Phase II of the study, clozapine was more effective in controlling symptoms than the other atypical antipsychotics under evaluation. For patients whose symptoms are not well controlled on clozapine, olanzapine and risperidone tend to be more effective than ziprasidone or quetiapine. However, the side effects of these drugs must be taken into account.

The CATIE study did not reveal a clear path of next treatment for those patients who had discontinued use of an antipsychotic due to adverse side effects. In such cases, it is important to balance the degree of symptom control from the drug with the nature of its side effects. For example, olanzapine tended to result in considerable weight gain and metabolic problems, whereas ziprasidone consistently resulted in weight loss and improvement of metabolic disorders. Of the drugs tested, risperidone had the least adverse side effects.

KEY TERMS

Atypical antipsychotic —A newer antipsychotic drug that is less likely to cause significant adverse side effects than conventional antipsychotic medications. Atypical antipsychotics are also called novel antipsychotics or second-generation antipsychotics.

Clinical trial —A controlled scientific experiment designed to investigate the effectiveness of a drug or treatment in curing or lessening the symptoms of a disease or disorder.

Double-blind study —A research study in which neither the participants nor the professional administering the drug or treatment know whether they are receiving the experimental treatment or a placebo or control treatment.

Placebo —A preparation without pharmacological effect that is given in place of a drug in clinical trials to determine the effectiveness of the drug under study; a “sugar pill.”

Resources

BOOKS

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed., Text rev. Washington, D.C.: American Psychiatric Association, 2000.

VandenBos, Gary R., ed. APA Dictionary of Psychology. Washington, D.C.: American Psychological Association, 2007.

PERIODICALS

Davis, S. M., G. G. Koch, C. E. Davis, and L. M. LaVange. “Statistical Approaches to Effectiveness Measurement and Outcome-Driven Re-Randomizations in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Studies.” Schizophrenia Bulletin 29.1 (2003): 73–80.

Essock, S. M., and others. “Effectiveness of Switching Antipsychotic Medications.” American Journal of Psychiatry 163.12 (Dec. 2006): 2090–95.

Keefe, R. S., and others. “Neurocognitive Assessment in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Project Schizophrenia Trial: Development, Methodology, and Rationale.” Schizophrenia Bulletin 291 (2003): 45–55.

Lieberman, J. A., and others. “Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia.” New England Journal of Medicine 353.12 (Sep. 22, 2005): 1209–23.

Lieberman, J. A., and T. S. Stroup. “Guest Editors’ Introduction: What Can Large Pragmatic Clinical Trials Do for Public Mental Health Care?” Schizophrenia Bulletin 29.1 (2003): 1–6.

McEvoy, J. P., and others. “Effectiveness of Clozapine Versus Olanzapine, Quetiapine, and Risperidone in Patients with Chronic Schizophrenia Who Did Not Respond to Prior Atypical Antipsychotic Treatment.” American Journal of Psychiatry 163.4 (Apr. 2006): 600–610.

Rosenheck, R., J. Doyle, D. Leslie, and A. Fontana. “Changing Environments and Alternative Perspectives in Evaluating the Cost-Effectiveness of New Antipsychotic Drugs.” Schizophrenia Bulletin 29.1 (2003): 81–93.

Rosenheck, R. A., and others. “Cost-Effectiveness of Second-Generation Antipsychotics and Perphenazine in a Randomized Trial of Treatment for Chronic Schizophrenia.” American Journal of Psychiatry 163.12 (Dec. 2006): 2080–89.

Schneider, L. S., and others. “Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer’s Disease Trial.” Schizophrenia Bulletin 29.1 (2003): 57–72.

Schneider, L. S., and others. “Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer’s Disease.” New England Journal of Medicine 355.125 (Oct. 2006): 1525–38.

Sernyak, M. J., D. Leslie, and R. Rosenheck. “Use of System-Wide Outcomes Monitoring Data to Compare the Effectiveness of Atypical Neuroleptic Medications.” American Journal of Psychiatry 160.2 (Feb. 2003): 310–15.

Stroup, T. S., and P. S. Appelbaum. “Evaluation of ’Subject Advocate’ Procedures in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Study.” Schizophrenia Bulletin 32.1 (Jan. 2006): 147–52.

Stroup, T. S., and others. “Effectiveness of Olanzapine, Quetiapine, Risperidone, and Ziprasidone in Patients With Chronic Schizophrenia Following Discontinuation of a Previous Atypical Antipsychotic.” American Journal of Psychiatry 163.4 (Apr. 2006): 611–22.

Stroup, T. S., and others. “The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Project: Schizophrenia Trial Design and Protocol Development.” Schizophrenia Bulletin 29.1 (2003): 15–31.

Swartz, M. S., and others. “Assessing Clinical and Functional Outcomes in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial.” Schizophrenia Bulletin 29.1 (2003): 33–43.

OTHER

CATIE. CATIE: Clinical Antipsychotic Trials of Intervention Effectiveness Schizophrenia Study, 2003. <http://www.catie.unc.edu/schizophrenia>.

National Institutes of Health. CATIE Schizophrenia Trial, 2006. <http://www.clinicaltrials.gov/ct/show/NCT00014001?order=1>.

Ruth A. Wienclaw, PhD

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