Public Release:  NIMH study to guide treatment choices for schizophrenia

NIH/National Institute of Mental Health

A large study funded by NIH's National Institute of Mental Health (NIMH) provides, for the first time, detailed information comparing the effectiveness and side effects of five medications - both new and older medications - that are currently used to treat people with schizophrenia. Overall, the medications were comparably effective but were associated with high rates of discontinuation due to intolerable side effects or failure to adequately control symptoms. One new medication, olanzapine, was slightly better than the other drugs but also was associated with significant weight-gain and metabolic changes. Surprisingly, the older, less expensive medication used in the study generally performed as well as the newer medications. The study, which included more than 1,400 people, supplies important new information that will help doctors and patients choose the most appropriate medication according to the patients' individual needs. The study results are published in the September 22 issue of the New England Journal of Medicine.

"The study has vital public health implications because it provides doctors and patients with much-needed information comparing medication treatment options," said NIMH Director Thomas R. Insel, M.D. "It is the largest, longest, and most comprehensive independent trial ever done to examine existing therapies for this disease."

Schizophrenia, which affects 3.2 million Americans, is a chronic, recurrent mental illness, characterized by hallucinations, delusions, and disordered thinking. The medications used to treat the disorder are called antipsychotics. Previous studies have demonstrated that taking antipsychotic medication is far more effective than taking no medicine, and that taking it consistently is essential to the long-term treatment of this severe, disabling disorder. Although the medications alone are not sufficient to cure the disease, they are necessary to manage it.

In the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) trial, researchers directly compared an older medication (perphenazine), available since the 1950s, to four newer medications (olanzapine, quetiapine, risperidone, and ziprasidone), introduced in the 1990s. The purpose of the study was to learn whether there are differences among the newer medications and whether the newer medications hold significant advantages over the older medications; these newer medications known as atypical antipsychotics, cost roughly 10 times as much as the older medications.

The size and scope of the trial, with more than 1,400 participants at 57 sites around the country, its 18-month duration, and its inclusion of a wide range of patients in a variety of treatment settings ensure that the findings are reliable and relevant to the 3.2 million Americans suffering from schizophrenia.

At the beginning of the study, patients were randomly assigned to receive one of the five medications. Almost three quarters of patients switched from their first medication to a different medication. The patients started on olanzapine were less likely to be hospitalized for a psychotic relapse and tended to stay on the medication longer than patients taking other medications. However, patients on olanzapine also experienced substantially more weight gain and metabolic changes associated with an increased risk of diabetes than those study participants taking the other drugs.

Contrary to expectations, movement side effects (rigidity, stiff movements, tremor, and muscle restlessness) primarily associated with the older medications, were not seen more frequently with perphenazine (the drug used to represent the class of older medications) than with the newer drugs. The older medication was as well tolerated as the newer drugs and was equally effective as three of the newer medications. The advantages of olanzapine - in symptom reduction and duration of treatment - over the older medication were modest and must be weighed against the increased side effects of olanzapine.

Thus, taken as a whole, the newer medications have no substantial advantage over the older medication used in this study. An important issue still to be considered is individual differences in patient response to these drugs.

Several factors, such as adequacy of symptom relief, tolerability of side effects, and treatment cost influence a person's willingness and ability to stay on medication.

"There is considerable variation in the therapeutic and side effects of antipsychotic medications. Doctors and patients must carefully evaluate the tradeoffs between efficacy and side effects in choosing an appropriate medication. What works for one person may not work for another," said Jeffrey Lieberman, M.D., CATIE's Principal Investigator and Chair of The Department of Psychiatry, Columbia University and Director of the New York State Psychiatric Institute.

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The CATIE study was led by Lieberman, and co-Principal Investigators Scott Stroup, M.D. (University of North Carolina at Chapel Hill), and Joseph McEvoy, M.D. (Duke University). CATIE was carried out by researchers at 57 sites across the country, including private and public mental health clinics, Veteran's Health Administration Medical Centers, and University Medical Centers, where people with schizophrenia received their usual care.

This New England Journal of Medicine article is the first to report outcomes from the CATIE schizophrenia trial, and addresses many of the primary questions from the study. Future reports will address a multitude of topics (e.g., cost-effectiveness of the medications, quality of life, predictors of response) and will provide a more detailed picture of the interaction between patient characteristics, medication, and outcomes. The information from the CATIE study will inform new approaches for improving outcomes in schizophrenia.

CATIE is part of an overall NIMH effort to conduct "practical" clinical trials that address public health issues important to those persons affected by major mental illnesses in real world settings.

The NIMH mission is to reduce the burden of mental illness and behavioral disorders through research on mind, brain, and behavior. Additional information about NIMH and schizophrenia can be found at its website, www.nimh.nih.gov.

NIMH is part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.

CATIE Schizophrenia Q&A's for Media

1. What is the CATIE study?
A.: The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Study, funded by the NIH's National Institute of Mental Health, is a nationwide public health focused clinical trial comparing the effectiveness of older (first available in the 1950s) and newer (available since the 1990s) antipsychotic medications used to treat schizophrenia. These newer medications, known as atypical antipsychotics, cost roughly 10 times as much as the older medications. CATIE is the largest, longest, and most comprehensive independent trial ever done to examine existing therapies for this disease. Schizophrenia is a brain disorder characterized by hallucinations, delusions, and disordered thinking. The course of schizophrenia is variable, but usually is recurrent and chronic, often causing severe disability. Previous studies have shown that taking antipsychotic medications consistently is far more effective than taking no medicine and that the drugs are necessary to manage the disease. The aim of the CATIE study was to determine which medications provide the best treatment for schizophrenia.

2. Why is CATIE important?
A: Many studies have tested new antipsychotic medications in schizophrenia. Most of these were conducted by pharmaceutical companies 1, to obtain Food and Drug Administration (FDA) approval to market a new drug. These studies were usually short-term (4 to 8 weeks), focused on limited outcomes, enrolled a narrow range of patients, and studied only one or two medications at a time. By contrast, CATIE compared four of the newer medications to one another, and to an older medication. Participants in CATIE were followed for 18 months so that investigators could evaluate longer-term patient outcomes. The more than 1400 participants in the study included those with physical or other mental health problems in addition to schizophrenia. CATIE was conducted at many different treatment sites, broadly representative of the real life settings where patients receive their care. The results from CATIE will be applicable to the wide range of people with schizophrenia in the United States.

3. How will the results of CATIE affect the care doctors provide patients?
A: For the first time, doctors and people with schizophrenia will have extensive information on antipsychotic medications from a single, large, long-term study directly comparing the drugs to each other. CATIE greatly enhances the knowledge available to guide treatment choices for people with schizophrenia. CATIE provides new information on the efficacy and side effects of antipsychotic drugs, compared head to head, helping doctors determine the appropriateness of specific medications in individual patients. The combination of maximizing the benefits while minimizing the side effects increases the likelihood that a person with schizophrenia will stay on their antipsychotic medication, a necessary ingredient for managing symptoms and reducing the risk of relapse.

4. Which medications were studied in CATIE and how was medication chosen for each patient?
A. All medications included in the study were FDA-approved antipsychotic medications used in the treatment of schizophrenia. No placebo treatments were used. Patients were randomly assigned to a medication; study participants and their doctors could not choose which medication to take, and neither the investigators nor the patients knew which antipsychotic a patient was on. This type of study, a "double-blind randomized clinical trial," produces objective results, since researchers' and participants' will have no expectations about how well a medication might work to influence the outcome. In the first phase of CATIE, patients were randomly assigned to one of four newer, "atypical" antipsychotics: olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon); or to the older, "typical" medication, perphenazine (Trilafon). Dose range for each medication was chosen based on advice from experienced clinicians, clinical practice patterns from national pharmacy databases, and discussions with the drug manufacturers. Patients continued to take this medication for the next 18 months, or until the medication could not control their symptoms adequately, or they developed an intolerable side effect, or they decided to stop the medication, or withdraw from the study for some other reason.

5. Why was perphenazine chosen as the older medication rather than haloperidol?
A: Haloperidol was one of the most widely prescribed of the older antipsychotics before the "atypical" newer antipsychotics became available in the 1990's. It remains the most frequently used comparison drug in industry-sponsored clinical trials. However, 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. This made it a good choice to use as the representative of the older medications in this study.

6. How did researchers measure how well the medications worked?
A: For patients with schizophrenia, staying on medication is critical to controlling symptoms and preventing relapse. Previous studies have shown that antipsychotic treatment is far better than no treatment. Although the medications alone are not sufficient to cure the disorder, they are necessary to manage it. Thus, it is essential for doctors to find a medication that is both effective and tolerable for a patient. This is why the primary measure of treatment success in the CATIE study was how long a patient benefited from and thus stayed on a medication before they or their doctor decided that it had to be changed. Investigators also recorded why a patient stopped a medication: if the medication did not control symptoms, or if the side effects were not tolerable, or if the patient chose to stop treatment for some other reason. In addition to this primary outcome, the study also examined medication effects on the symptoms of schizophrenia, as well as other important outcomes such as overall level of function.

7. What are the most important results of the CATIE study?
A. Overall, the medications were comparably effective but were associated with high rates of discontinuation due to intolerable side effects or failure to adequately control symptoms. One new medication, olanzapine, was slightly better than the other drugs but also was associated with significant weight-gain as a side-effect. Surprisingly, the older, less expensive medication (perphenazine) used in the study generally performed as well as the four newer medications. The study supplies important new information that will help doctors and patients choose the most appropriate medication according to the patients' individual needs.

At the beginning of the study, patients were randomly assigned to receive one of the five medications. Almost three quarters of patients switched from their first medication to a different medication. The patients started on olanzapine were less likely to be hospitalized for a psychotic relapse and tended to stay on the medication longer than patients taking other medications. However, patients on olanzapine also experienced substantially more weight gain and metabolic changes associated with an increased risk of diabetes than those participants taking the other drugs.

Perphenazine (the older medication) equally as effective as the other three newer medications (risperidone, quetiapine, and ziprasidone) and was as well tolerated as the newer drugs. The three newer medications performed similarly to one another.

Contrary to expectations, movement side effects (rigidity, stiff movements, tremor, and muscle restlessness) primarily associated with the older medications were not seen more frequently with perphenazine than with the newer drugs. The advantages of olanzapine - in symptom reduction and duration of treatment - over perphenazine were modest and must be weighed against the increased side effects of olanzapine.

Thus, taken as a whole, the newer medications have no substantial advantage over the older medication used in this study. An important issue still to be considered is individual differences in patient response to these drugs.

Several factors, such as adequacy of symptom relief, tolerability of side effects, and treatment cost, influence a person's willingness and ability to stay on medication. Patients and doctors must carefully evaluate the trade off between effectiveness, side effects, and cost in choosing an appropriate medication. Doctors must carefully monitor the physical health of their patients as well as the symptoms of psychosis.

8. Q: Do these results indicate that physicians should alter their treatment plans for patients with schizophrenia?
A: This study provides the largest, longest, and most comprehensive independent trial ever conducted to study existing therapies for this disease. It 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.

9. Who participated in CATIE?
A: CATIE participants included people with schizophrenia from across the country -- 57 different clinical sites in 24 states -- being treated in a variety of settings (e.g. private clinics, academic centers, Veterans Administration hospitals, and public mental health centers). The patients enrolled in CATIE broadly reflect the 3 million people with schizophrenia in the U.S. today. CATIE participants had chronic schizophrenia and were in need of antipsychotic treatment. The only patients excluded were those who were in a first episode of psychosis, those with treatment-resistant schizophrenia, and those with serious and unstable medical conditions.

10. Who conducted CATIE?
A: After a competitive, peer-reviewed process, NIMH selected the University of North Carolina (UNC) to implement CATIE. The trial is led by Dr. Jeffrey Lieberman, Principal Investigator (now at Columbia University), and co-investigators including Scott Stroup, M.D., M.P.H., Diana Perkins M.D., M.P.H., Ed Davis, Ph.D. (UNC), Joseph McEvoy, M.D., Marvin Swartz, M.D., Richard Keefe, Ph.D. (Duke University), Robert Rosenheck, M.D. (Yale University), and NIMH staff. Quintiles, a private contract research organization (CRO), assisted with study implementation and data analysis of the trial. The $42.6 million study was conducted over a five-year period at 57 clinical sites across the country.

11. What role did the pharmaceutical companies have in CATIE?
A: The pharmaceutical companies donated the study medications and provided advice about the optimal dose for that company's medication. The pharmaceutical companies had no other input into the design or implementation of the study, no involvement in planning or conducting the data analysis, and did not participate in preparing manuscripts for publication. The medications used in the study and their manufacturers included:

  • olanzapine (Zyprexa), manufactured by Eli Lilly and Company
  • perphenazine (Trilafon), Schering-Plough and Novartis
  • quetiapine (Seroquel), manufactured by Astra Zeneca Corporation
  • risperidone (Risperdal), manufactured by Janssen Pharmaceuticals
  • ziprasidone (Geodon), manufactured by Pfizer, Inc.

    12. What other information will doctors and patients be able to learn from CATIE in the future?
    A: The investigators will continue to study other important outcomes, including cost-effectiveness, quality of life, and predictors of response. 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.

    References
    1. Lieberman, J.A. and Stroup, T.S. (2003). Guest editor's introduction: what can large pragmatic clinical trials do for public mental health care. Schizophrenia Bulletin, (29) 1, p. 1-6.

    2. Stroup, T. S., McEvoy, J.P., Swartz, M.S., Byerly, M.J., Glick, I.D., Canive, J.M., McGee, M.F., Simpson, G.M., Stevens, M.C., Lieberman, J.A. (2003). The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Project: schizophrenia trial design and protocol development. Schizophrenia Bulletin, (29) 1, p. 15-31.

    3. Lieberman, J.A., Stroup, T.S., McEvoy, J.P., Swartz, M.S., Rosenheck, R.A., Perkins, D.O., Keefe, R.S.E., Davis, S.M., Davis, C.E., Lebowitz, B.D., Severe, J., Hsiao, J.K. (2005). Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. New England Journal of Medicine, (353), p.1209 -1223.

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