Schizophrenia Daily News Blog

CATIE Results - Perphenazine almost as good as newer drugs

The Wall Street Journal reported this morning that "Old Schizophrenia Drug Works As Well as Newer Treatments"

In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) results an older, less expensive antipsychotic drug known as Perphenazine (Trilafon) worked almost as well as four newer drugs, according to the results.

"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, affects approximately 3.2 million Americans today, and only about 15% of patients are able hold a job even while being treated with medications (stated Dr. Insel).

The $44 million study, known as the Clinical Antipsychotic Trials of Intervention Effectiveness, involved more than 1,400 patients who were initially put on one of five medications. Some were put on perphenazine, while others were put on one of four drugs that have been available since the 1990s; Lilly's Zyprexa; Seroquel, manufactured by AstraZeneca PLC; Risperdal, manufactured by Janssen Pharmaceuticals, a unit of Johnson & Johnson, and Geodon, manufactured by Pfizer Inc.

The first-phase results of the study will be published in the Sept. 22 edition of the New England Journal of Medicine - and the full electronic edition is available now on their web site. The full text PDF file is available here: CATIE STUDY PDF FILE (Note: after initially being free for download, the NEJM has now restricted access to this file - and you must pay for it - sorry).

"Researchers from the National Institute of Mental Health said one of the medications, olanzapine, a drug that is sold under the brand name Zyprexa by Eli Lilly & Co. worked slightly better in treating the symptoms of schizophrenia than the other drugs, but it was also associated with more serious side effects like weight gain and metabolic changes that raises risks for developing diabetes and cardiovascular disease." said the Wall Street Journal.

Also in the Wall Street Journal, Jeffrey Lieberman, of Columbia University Medical Center and the lead researcher in the Catie study, is quoted as saying that "the biggest surprise of the study was that the older drug, perphenazine, available since the 1950s, worked equally as well as the three newer drugs and almost as well as Zyprexa at controlling symptoms of schizophrenia. However, he said it was too soon to recommend that patients with schizophrenia, a mental disorder, use a particular drug. Researchers are still collecting data from the study and will be making more information available in the coming months."

In Forbes Magazine, it was stated "the data are a double-edged sword for Lilly, because they also show that Zyprexa causes more weight gain, high blood sugar and raised cholesterol than its competitors. By comparison, patients taking Pfizer's Geodon, on average, experienced no weight gain and fewer of the neurological tremors that can be a serious problem for schizophrenia patients. Lieberman, who headed up the study, agreed that Pfizer now might have grounds to say its drug has milder side effects."

Overall, three of four patients in the Catie study stopped taking the drugs before the study ended. This reinforces the knowledge that the benefit of antipsychotic drugs - for both the new and old drugs - is greatly limited by the fact that most patients don't take the medications for any significant length of time - in part because of negative side effects.

In total 74% of the 1,493 schizophrenia patients recruited for the CATIE study discontinued their assigned study medication before 18 months - a rate that was considered to be very high in a study in which the primary outcome measure was discontinuation of the study drug for any cause.

In this CATIE study where the drug adherance dropout rate was so high, Zyprexa was consered a slight favorite by posting a dropout rate that was a little lower at 64%, the lowest of any of the five study drugs.

Additionally, the period of time to discontinuation (of the drug) was significantly longer for the Zyprexa patients than in the Seroquel (quetiapine fumarate) or Risperdal (risperidone) users according to Jeffrey A. Lieberman, M.D., of the department of psychiatry at the Columbia College of Physicians and Surgeons in New York, who headed the CATIE investigators.

However, the time to discontinuation was not significantly longer in the Zyprexa part of the trial than was observed among patients using Trilafon (perphenazine) - the first generation (or "typical") antipsychotic medication - or to Geodon (ziprasidone) the newest of the second generation or atypical antipsychotics studied by the CATIE investigators. (Bristol Meyer's drug Abilify is included in the second part of the CATIE trial).

Doctors' concerns about neurological side effects in particular have sped the switch to newer schizophrenia drugs over the last decade. Studies have shown that these medications carry a lower risk than the older drugs of tardive dyskinesia, a disorder that causes tics, lip-smacking and other involuntary movements.

But the study found that at more modest doses, the older drug, perphenazine, while just as effective, was not significantly more likely to cause neurological symptoms. Dr. Lieberman said that there was no reason to believe that modest doses of other older drugs, like Haldol, would perform differently.

The patients on Zyprexa were less likely to be hospitalized because their condition worsened than those taking the other drugs, the study found. But these patients also gained the most weight, adding an average of two pounds a month while on the drug, and their lipid levels increased more than those of people on the other drugs. Weight gain and elevated lipids are risk factors for diabetes.

The complete CATIE study results, which will be fully published in the Sept. 22 issue of The New England Journal of Medicine, were also released online today after a National Institute of Mental Health press conference.

The study was conducted at 57 sites across the USA, included 336 patients on Zyprexa (7.5 to 30 mg per day); 261 patients on Trilafon (8 to 32 mg/day); 337 on Seroquel (200 to 800 mg/day) and 341 patients on Risperdal (1.5 to 6.0 mg/day). A fifth part of the trial, in which patients used Geodon (185 patients 40 to 160 mg) was added after January 2002 when that drug was approved by the FDA.

The average age of the patients was 40 and 74% were men.

Some of the Top Findings of the CATIE Study were:

Discontinuation of the drug for lack of efficacy was highest among patients in on Seroquel (28%) and lowest for those on Zyprexa (15%).

Nineteen percent of patients on Zyprexa cited intolerability as the reason for stopping the drug, while intolerability caused just 10% Risperdal patients to stop the drug.

Seroquel had the highest rate of discontinuation for any cause (82%) versus 79% for those on Geodon, 75% for those on Trilafon, 74% for Risperdal and 64% for Zyprexa.

It was reported that 30% of Zyprexa-treated patients gained more than 7% of their body weight during the study, which was significantly greater than weight gain with other study drugs (P<0.001).

Predictors of an earlier time to drug discontinuation included
1. higher baseline Positive and Negative Syndrome Scale (PANSS) score at baseline (P=0.001);
2. younger age (P<0.001);
3. longer duration since first use of an antipsychotic drug (P=0.057) 4. antipsychotic drug taken before study entry (P=0.001).

Patients taking either Zyprexa or Risperdal before entering the study were likely to continue the study drug for a longer time.

In a NEJM editorial that accompanies the study, Robert Freedman, M.D., of the department of psychiatry at the University of Colorado Health Sciences Center wrote that the CATIE results "could be viewed as discouraging."

The trial, he wrote, identifies Zyprexa as one of two drugs that appear to be more effective than other agents. The other drug, Clozaril (clozapine) was not included in the CATIE trial and Dr. Freedman noted that Clozaril is known to cause toxic side-effects including agranulocytosis, which has limited its use to only about 10% of persons with schizophrenia.

So, Dr. Freedman wrote, Zyprexa and Clozaril although effective have side-effects that that make "even the most feared side effect of first generation drugs, tardive dyskinsia, seem less troubling than potentially fatal metabolic problems."

Nonetheless, Dr. Freedman concluded that CATIE does provide "solid evidence to help clinicians and patients make the difficult decisions needed to optimize management of schizophrenia with the compounds currently available."

Currently doctors tend to shy away from older antipsychotic medications like perphenazine because they are associated with movement disorders like rigidity, stiff movements, tremor and muscle restlessness. In the study, however, such movement side effects weren't widely seen with perphenazine.

Thomas Insel, the director of the National Institute of Mental Health stated at the press conference that the newer drugs account for 90% of drugs used to treat schizophrenia at a cost of about $10 billion annually.

Researchers followed the 1,400 patients for 18 months. One of the measures was whether patients stayed on the medication to which they were assigned. Overall, 74% of patients stopped taking their initial medication and were switched to another drug, a measure called the switch rate. Researchers said patients started on Zyprexa were less likely to be hospitalized for a psychotic relapse and tended to stay on the medication longer than patients taking other medications.

Dr. Lieberman said cost-effectiveness of the medication will be published in a later study. While it might appear putting patients on the older drug would be cheaper than Zyprexa, for example, he said the fact that hospitalizations were reduced could mean Zyprexa is less expensive overall.

One thing that all agreed on was that the current state of schizophrenia treatment leaves a lot to be desired, and that the field longs for new and different drugs.

"The message is the glass is half full," Dr. Lieberman said. "The drugs work but they are not satisfactory to many patients, and three-quarters of the people in our study voted with their feet and discontinued the drugs."

Today's Press Release from the National Institute of Mental Health on the CATIE trial:

NIMH Study To Guide Treatment Choices for Schizophrenia
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.

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.

MORE CATIE INFORMATION:

CATIE Schizophrenia Q&As.

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?

CATIE Study Medications

Older Medication:
Perphenazine (Trilafon)

Newer Medication:
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Risperidone (Risperdal)
Ziprasidone (Geodon)

(Aripiprazole [Abilify] was not approved by the FDA in time to be included in this phase of the study)

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 1990s. 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?

CATIE Participants

Patients Enrolled: 1,460
Mean Age: 40.6
Gender: 74% male
Race: 40% non-white;
12% Hispanic

Average Length of Illness: 14.4 years

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

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.

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.

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.

More information on CATIE:

CATIE WEB SITE

NIMH WEB SITE

Source reference:
Lieberman JA "Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia" New England Journal of Medicine 2005; 353:1209-23

Source reference:
Freedman R "The Choice of Antipsychotic Drugs for Schizophrenia" N Engl J Med 2005; 353:1286-89.

Wall Street Journal: Old Schizophrenia Drug Works
As Well as Newer Treatments, September 19th, 2005.

A Victory For Lilly--With Reservations - Forbes Magazine