While the recent publication of Phase I results of the landmark Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study enabled pharmaceutical companies and stock pundits to declare winners and losers among the marketed antipsychotics, the big winners may be clinicians who treat the 3.2 million Americans suffering from schizophrenia.
"The results of the CATIE study provide the most comprehensive set of data on the pharmacologic treatment of schizophrenia ever assembled," Jeffrey A. Lieberman, M.D., a Columbia University psychiatrist and lead author of the study, said at a press conference. "These [results] will guide doctors in their selection of treatments and clinical management of individual patients. This is because no study has ever examined all marketed drugs in a controlled fashion for such a long time period using such extensive measures of safety and efficacy, much less the cost data."
Thomas Insel, M.D., director of the National Institute of Mental Health, which sponsored the $44 million study, described it as the largest, longest and most comprehensive independent trial ever done to examine existing therapies for this disease. The 18-month study involved 1,460 participants at 57 different clinical sites in 24 states. The effectiveness or "practical trial" sought to be broadly representative of real-life settings and included patients with physical or other mental health problems in addition to schizophrenia, as well as patients from diverse ethnic and racial backgrounds.
By and large, the patients in the study were not refractory or acutely ill, Lieberman told Psychiatric Times in an exclusive interview. "They were people who were receiving medicines as outpatients and were relatively stable. They went into the study seeking a better treatment," he said.
Phase I of the study compared four of the second-generation or atypical antipsychotics (olanzapine [Zyprexa], quetiapine(Drug information on quetiapine) [Seroquel], risperidone(Drug information on risperidone) [Risperdal] and ziprasidone [Geodon]) and one first-generation antipsychotic, perphenazine(Drug information on perphenazine) (Trilafon). Aripiprazole(Drug information on aripiprazole) (Abilify), Lieberman noted, was not approved until November 2002, so it could not be in Phase I. It was, however, added to Phase III of the study, so there will be descriptive data on how it does compare with the other medicines. The dose range for each medication was chosen based on the advice of experienced clinicians, clinical practice patterns from national pharmacy databases and discussions with the drugs' manufacturers. As described in the New England Journal of Medicine, the primary outcome measure for Phase I of the CATIE trial was all-cause treatment discontinuation, which reflects both clinicians' and patients' judgments about efficacy and tolerability (Lieberman et al., 2005). Secondary outcomes were the specific reasons for treatment discontinuation (e.g., inefficacy or intolerability owing to such side effects as weight gain, extrapyramidal signs or sedation as judged by the patient's clinician) and scores on the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression (CGI) scale.
Robert Baker, M.D., medical director at Eli Lilly and Company, explained that CATIE showed olanzapine(Drug information on olanzapine) "to be more effective on the [all-cause] discontinuation rate than other medications studied," and it had favorable findings for olanzapine "in terms of duration of successful treatment and risks of rehospitalization." The average time to discontinuation, according to Lilly's press statement, was 9.2 months for olanzapine, 4.6 months for quetiapine, 4.8 months for risperidone, 3.5 months for ziprasidone(Drug information on ziprasidone) and 5.6 months for perphenazine. The differences were statistically significant for olanzapine compared with risperidone and quetiapine, but not for perphenazine or ziprasidone. Total PANSS scores improved over time in all groups, according to Lilly, but patients taking olanzapine had greater initial improvement.
In Pfizer Inc.'s comment on the study results, Joseph Feczko, M.D., chief medical officer, said there were small differences in efficacy among the agents but important differences in potentially dangerous long-term health risks. The company's press statement said its drug ziprasidone "was the only medicine to reduce weight, cholesterol, lipids and measures of glucose, while effectively improving patients' psychiatric symptoms." Patients treated with the drug experienced an average weight loss of 2 lb, as well as cholesterol and triglyceride reductions of 9.2 mg/dL and 18.1 mg/dL, respectively.
Meanwhile, Janssen Pharmaceutica Products, L.P., questioned the results of the trial, stating that the efficacy results for risperidone "did not demonstrate the full efficacy of Risperdal because many patients in the CATIE trial received doses that were too low."
Glenn Gormley, M.D., Ph.D., chief medical officer of AstraZeneca, noted that the "study points to the importance of balancing the risks and benefits to patients when choosing an antipsychotic. The balance of efficacy and tolerability that Seroquel provides makes it an ideal choice in the treatment of schizophrenia."
Schering-Plough, which provided perphenazine for the study, discontinued production of the drug in May of 2002, but a company representative noted the drug is available as a generic.
"The biggest surprise of the study was that the older medication, perphenazine, was comparably effective to at least three of the new medications and not much worse than the new drug that did the best--olanzapine," said Lieberman, chair of the department of psychiatry at the College of Physicians and Surgeons at Columbia University and director of the New York State Psychiatric Institute. (He conducted most of the study while still a professor of psychiatry at the University of North Carolina.)
Contrary to expectations, Lieberman said, the older, less expensive medication did not cause substantially more Parkinsonian-type side effects than the new drugs. He attributed this to the fact that perphenazine has a lower potency than the usual comparator, haloperidol(Drug information on haloperidol) (Haldol), and that it was given at moderate doses. Perphenazine, he said, "clearly is an effective treatment and should not be disregarded just because it is older." He added that clinicians might extrapolate from the study results that if they used first-generation antipsychotics in moderate doses, particularly those not of the highest potency, they could diminish the substantial side-effect burden.
Robert Rosenheck, M.D., professor of psychiatry and epidemiology at Yale University and one of the study authors, noted in the press conference that when the CATIE study was being designed in 1998 and 1999, some researchers questioned the idea of comparing second-generation antipsychotics to a first-generation one. "The field had concluded that the new drugs were superior. Because we were willing to ask a question that most people thought they had the answer to, we were open to getting the surprising answer that there wasn't that much difference," he said.
Adverse EffectsDuring the press conference, Lieberman noted that, although the treatments used in the study are effective and are "far better than no treatment at all," patients and their physicians are looking for more in the way of symptom relief and recovery, and "they want this with fewer side effects than current treatments impose."
This desire for something better was reflected in the overall discontinuation rates. Nearly three-quarters (74%) of the patients discontinued the study medication before 18 months: 64% of those assigned to olanzapine; 75%, perphenazine; 82%, quetiapine; 74%, risperidone; and 79%, ziprasidone. The rates of treatment discontinuation due to intolerable side effects also differed between treatments (p=0.04). Risperidone had the lowest percentage of patients discontinuing due to intolerability (10%), followed by 15% each for patients taking perphenazine, quetiapine or ziprasidone, and 18% for those taking olanzapine. Olanzapine, more than the other antipsychotics, was associated with weight gain and increases in glycosylated hemoglobin, total cholesterol and triglycerides--changes linked to the development of metabolic syndrome (Lieberman et al., 2005).
"What we are seeing … is the fact that there is a spectrum of propensity for the newer medications to produce [weight gain] and a change in these metabolic measures, but olanzapine does this the most. So we see that quetiapine and risperidone also, but to a lesser degree, produce changes in these measures," Lieberman said. Thirty percent of patients in the olanzapine group gained 7% or more of their baseline body weight during the trial compared to 7% taking ziprasidone, 12% taking perphenazine, 14% taking risperidone and 16% taking quetiapine (Lieberman et al., 2005).
In an editorial accompanying the NEJM article, Robert Freedman, M.D., (2005) warned, "Even the most feared side effect of first-generation drugs, tardive dyskinesia, seems less troubling than potentially fatal metabolic problems." Responding to Freedman's comment, Rosenheck said, "This study showed that there [were] increased weight and increased triglycerides that put someone at risk, but you can't leap from increased risk to increased mortality. That will take much larger and much longer studies to answer whether there is actually increased mortality."
With regard to other side effects, patients in the olanzapine and quetiapine groups had lower rates of insomnia than patients in the other groups: olanzapine, 16%; quetiapine, 18%; risperidone, 24%; perphenazine, 25%; and ziprasidone, 30%. Quetiapine was associated with a higher rate of anticholinergic effects than other drugs (31% versus 20% to 25%), and risperidone was associated with hyperprolactinemia (Lieberman et al., 2005). "Concerns about potential prolongation of the corrected QT interval with ziprasidone and of cataracts with quetiapine were not realized in this study," the study authors said in the NEJM article. There were no significant differences among the groups in the incidence of extrapyramidal side effects, akathisia or movement disorders as reflected by rating scale measures of severity.
Given the variations in efficacy and side effects, Liebermann said a "cut-and-dried algorithm" would not work. Rather, the choice of the antipsychotic should be governed by physicians' assessments of a patient's clinical status and past history of response. As an example, he said, if a clinician is treating a patient who has particularly severe symptoms and who has had an unresponsive or less responsive history with other medications, the clinician might be more inclined to go with a drug like olanzapine, if the patient is not ready to move to clozapine(Drug information on clozapine) (Clozaril), which is generally reserved for patients whose symptoms are resistant to other medicines.
"You might want to use it because it looks like it is most effective, and your priority is to control the psychiatric illness, even if there is a potential for the patient getting more side effects," he said. "Then again, if you have a patient who is a new patient or is a patient who has done well in the past on other medications but has shown a particular sensitivity to side effects, then drugs like ziprasidone or risperidone, as well as perphenazine, are really good choices, because risperidone had the lowest rate of discontinuation due to side effects and ziprasidone had the least amount of weight and metabolic effects along with perphenazine."
In the PT interview, Lieberman warned against using the Phase I results of CATIE "to restrict options or to restrict formularies. If anything, they suggest that doctors and patients need to have a range of choices, because of the variability among the antipsychotic drugs with regard to efficacy and side effects, and among patients in terms of their response characteristics and side effect sensitivities." Additionally, he said, "it is premature to come to any kind of decision about possible policy implications until the results of the rest of the study come out, particularly the cost-effectiveness data."
