CATIE Phase I Helps Clinicians Tailor Schizophrenia Treatment

While the recent publication of Phase I results of the landmark ClinicalAntipsychotic Trials of Intervention Effectiveness (CATIE) study enabledpharmaceutical companies and stock pundits to declare winners and losers amongthe marketed antipsychotics, the big winners may beclinicians who treat the 3.2 million Americans suffering from schizophrenia.

"The results of the CATIE study provide the most comprehensive set of dataon the pharmacologic treatment of schizophrenia ever assembled," Jeffrey A.Lieberman, M.D., a Columbia University psychiatristand lead author of the study, said at a press conference. "These [results] willguide doctors in their selection of treatments and clinical management ofindividual patients. This is because no study has ever examined all marketeddrugs in a controlled fashion for such a long time period using such extensivemeasures of safety and efficacy, much less the cost data."

Thomas Insel, M.D., director of the NationalInstitute of Mental Health, which sponsored the $44 million study, described itas the largest, longest and most comprehensive independent trial ever done toexamine existing therapies for this disease. The 18-month study involved 1,460participants at 57 different clinical sites in 24 states. The effectiveness or "practicaltrial" sought to be broadly representative of real-life settings and includedpatients with physical or other mental health problems in addition toschizophrenia, 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 inan exclusive interview. "They were people who were receiving medicines asoutpatients and were relatively stable. They went into the study seeking abetter treatment," he said.

Phase I of the study compared four of the second-generation or atypical antipsychotics (olanzapine [Zyprexa], quetiapine [Seroquel], risperidone [Risperdal] and ziprasidone[Geodon]) and one first-generation antipsychotic, perphenazine (Trilafon). Aripiprazole (Abilify), Liebermannoted, was not approved until November 2002, so it could not be in Phase I. Itwas, however, added to Phase III of the study, so there will be descriptivedata on how it does compare with the other medicines. The dose range for eachmedication was chosen based on the advice of experienced clinicians, clinicalpractice patterns from national pharmacy databases and discussions with thedrugs' manufacturers. As described in the NewEngland Journal of Medicine, the primary outcome measure for Phase I of theCATIE trial was all-cause treatment discontinuation, which reflects bothclinicians' and patients' judgments about efficacy and tolerability (Liebermanet al., 2005). Secondary outcomes were the specific reasons for treatmentdiscontinuation (e.g., inefficacy or intolerability owing to such side effectsas weight gain, extrapyramidal signs or sedation asjudged by the patient's clinician) and scores on the Positive and NegativeSyndrome Scale (PANSS) and the Clinical Global Impression(CGI) scale.

Robert Baker, M.D., medical director at Eli Lilly and Company, explainedthat CATIE showed olanzapine "to be more effective onthe [all-cause] discontinuation rate than other medications studied," and ithad favorable findings for olanzapine "in terms ofduration of successful treatment and risks of rehospitalization."The average time to discontinuation, according to Lilly's press statement, was9.2 months for olanzapine, 4.6 months for quetiapine, 4.8 months for risperidone,3.5 months for ziprasidone and 5.6 months for perphenazine. The differences were statisticallysignificant for olanzapine compared with risperidone and quetiapine, butnot for perphenazine or ziprasidone.Total PANSS scores improved over time in all groups, according to Lilly, butpatients taking olanzapine had greater initialimprovement.

In Pfizer Inc.'s comment on the study results, Joseph Feczko,M.D., chief medical officer, said there were small differences in efficacyamong the agents but important differences in potentially dangerous long-termhealth risks. The company's press statement said its drug ziprasidone"was the only medicine to reduce weight, cholesterol, lipids and measures ofglucose, while effectively improving patients' psychiatric symptoms." Patientstreated with the drug experienced an average weight loss of 2 lb, as well ascholesterol and triglyceride reductions of 9.2 mg/dLand 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 receiveddoses that were too low."

Glenn Gormley, M.D., Ph.D., chief medical officerof AstraZeneca, noted that the "study points to theimportance of balancing the risks and benefits to patients when choosing anantipsychotic. The balance of efficacy and tolerability that Seroquel provides makes it an ideal choice in the treatmentof schizophrenia."

Schering-Plough, which provided perphenazine forthe study, discontinued production of the drug in May of 2002, but a companyrepresentative 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 ofthe new medications and not much worse than the new drug that did the best--olanzapine," said Lieberman, chair of the department ofpsychiatry at the College of Physicians and Surgeons at Columbia University anddirector of the New York State Psychiatric Institute. (He conducted most of thestudy while still a professor of psychiatry at the University of North Carolina.)

Contrary to expectations, Lieberman said, the older, less expensivemedication did not cause substantially more Parkinsonian-typeside effects than the new drugs. He attributed this to the fact that perphenazine has a lower potency than the usual comparator,haloperidol (Haldol), and that it was given atmoderate doses. Perphenazine, he said, "clearly is aneffective treatment and should not be disregarded just because it is older." Headded that clinicians might extrapolate from the study results that if theyused first-generation antipsychotics in moderatedoses, particularly those not of the highest potency, they could diminish thesubstantial side-effect burden.

Robert Rosenheck, M.D., professor of psychiatryand epidemiology at Yale University and one of thestudy authors, noted in the press conference that when the CATIE study wasbeing designed in 1998 and 1999, some researchers questioned the idea ofcomparing second-generation antipsychotics to afirst-generation one. "The field had concluded that the new drugs weresuperior. Because we were willing to ask a question that most people thoughtthey had the answer to, we were open to getting the surprising answer thatthere wasn't that much difference," he said.

Adverse Effects

During the press conference, Lieberman noted that, although the treatmentsused 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 reliefand recovery, and "they want this with fewer side effects than currenttreatments impose."

This desire for something better was reflected in the overalldiscontinuation rates. Nearly three-quarters (74%) of the patients discontinuedthe study medication before 18 months: 64% of those assigned to olanzapine; 75%, perphenazine;82%, quetiapine; 74%, risperidone;and 79%, ziprasidone. The rates of treatmentdiscontinuation due to intolerable side effects also differed betweentreatments (p=0.04). Risperidone had the lowest percentage of patients discontinuingdue 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 glycosylatedhemoglobin, total cholesterol and triglycerides--changes linked to thedevelopment of metabolic syndrome (Lieberman et al., 2005).

"What we are seeing ... is the fact that there is a spectrum of propensity forthe newer medications to produce [weight gain] and a change in these metabolicmeasures, but olanzapine does this the most. So wesee that quetiapine and risperidonealso, but to a lesser degree, produce changes in these measures," Liebermansaid. Thirty percent of patients in the olanzapinegroup gained 7% or more of their baseline body weight during the trial comparedto 7% taking ziprasidone, 12% taking perphenazine, 14% taking risperidoneand 16% taking quetiapine (Lieberman et al., 2005).

In an editorial accompanying the NEJMarticle, Robert Freedman, M.D., (2005) warned, "Even the most feared sideeffect of first-generation drugs, tardive dyskinesia, seems less troubling than potentially fatalmetabolic problems." Responding to Freedman's comment, Rosenhecksaid, "This study showed that there [were] increased weight and increasedtriglycerides that put someone at risk, but you can't leap from increased riskto increased mortality. That will take much larger and much longer studies toanswer whether there is actually increased mortality."

With regard to other side effects, patients in the olanzapineand quetiapine groups had lower rates of insomniathan 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% to25%), and risperidone was associated with hyperprolactinemia (Lieberman et al., 2005). "Concernsabout potential prolongation of the corrected QT interval with ziprasidone and of cataracts with quetiapinewere not realized in this study," the study authors said in the NEJM article. There were no significantdifferences among the groups in the incidence of extrapyramidalside effects, akathisia or movement disorders asreflected by rating scale measures of severity.

Given the variations in efficacy and side effects, Liebermann said a "cut-and-driedalgorithm" would not work. Rather, the choice of the antipsychotic should begoverned by physicians' assessments of a patient's clinical status and pasthistory of response. As an example, he said, if a clinician is treating apatient who has particularly severe symptoms and who has had an unresponsive orless responsive history with other medications, the clinician might be moreinclined to go with a drug like olanzapine, if thepatient is not ready to move to clozapine (Clozaril), which is generally reserved for patients whosesymptoms are resistant to other medicines.

"You might want to use it because it looks like it is most effective, andyour priority is to control the psychiatric illness, even if there is apotential for the patient getting more side effects," he said. "Then again, ifyou have a patient who is a new patient or is a patient who has done well inthe past on other medications but has shown a particular sensitivity to sideeffects, then drugs like ziprasidone or risperidone, as well as perphenazine,are really good choices, because risperidone had thelowest rate of discontinuation due to side effects and ziprasidonehad the least amount of weight and metabolic effects along with perphenazine."

In the PT interview, Liebermanwarned against using the Phase I results of CATIE "to restrict options or torestrict formularies. If anything, they suggest that doctors and patients needto have a range of choices, because of the variability among the antipsychoticdrugs with regard to efficacy and side effects, and among patients in terms oftheir response characteristics and side effect sensitivities." Additionally, hesaid, "it is premature to come to any kind of decision about possible policyimplications until the results of the rest of the study come out, particularlythe cost-effectiveness data."

More Data and New Research

Much more data are expected from the CATIE trial. We are experiencing the "firstfruits of what we expect to be a very bountiful harvest," said Insel.

Within the next six months, the CATIE investigators plan to publish data oncost-effectiveness, cognitive function outcomes and the Phase II results,Lieberman told PT. For patients whohad to switch medications in Phase I because of failure to control theirsymptoms adequately, Phase II examined what happened when they werere-randomized to one of the other atypical antipsychoticsthey had not previously received or clozapine. Forpatients who stopped their medicines because of side effects, Phase II examinedwhat happened when they were re-randomized to either ziprasidoneor one of the other second-generation medications they had not taken in PhaseI. Once that information is disseminated, there will be a substantial number ofadditional reports. Phase III results, for example, will report on patients whodiscontinued their Phase II treatment and were given open treatment with clozapine, one of the atypicals, fluphenazine decanoate (Prolixin) or dual antipsychotic therapy (risperidone or perphenazineaugmentation of a current atypical drug).

Part of NIMH's role is to focus research onaspects of this illness that have not been addressed sufficiently, Insel said at the press conference. According to Insel, NIMH is focusing on a new generation of compoundsthat may address the cognitive deficits that often accompany schizophrenia.

"One of the reasons that so many people with schizophrenia are unable towork [only 15% are employed at any given time] even after they have control ofsome of their most intense psychotic symptoms is because there are residualproblems with disordered thinking that are not affected by the first-generationor second-generation atypical antipsychotics. So thehope is now to come up with yet a new class with a different set of clinicaltargets and perhaps a different mechanism that will begin to help people inthat dimension. We have a large effort underway. Some of this will undoubtedlybe a public-private partnership working with industry," explained Insel.

Meanwhile, the search continues for efficacious antipsychoticsthat do not carry such side effects as weight gain or neurologiceffects.

"One can look at drug development for antipsychotic medications asproceeding on two parallel tracks," said Lieberman. One track is "drugs thatare being developed using a tried-and-true formula, which [are] drugs that haveaffinity for the dopamine 2 receptor and possibly affinity for some of theother neurotransmitter receptors ... like serotonin or norepinephrine.There are several of such drugs in Phase II or Phase III development, but noneshould be out before 2008 or 2009. The other track is the more innovative trackfor drug development. Currently, there are a couple of leading strategies, one is a drug that has affinity to anotherneurotransmitter receptor class called the neurokininreceptors. An alternative strategy has been to develop drugs that have affinityfor the muscarinic acetylcholine receptors, notacting as antagonists but as agonists. And then there has also been an effortto develop compounds that have affinity for the cannabinoidreceptors. The problem is, from the standpoint of the pharmaceutical industry,this is a high-risk strategy, because over the 50 years that we have had thesegroups of medications, there has never been an antipsychotic drug that has notworked by the traditional mechanism, so it is a big hurdle to get over."

There may not be a magic bullet for schizophrenia, Inselsaid. Similar to the treatment of hypertension, which involves multiplemedications to address the different aspects, schizophrenia may involve finding"ways of combining treatments to get the maximal impact on this very disablingdisease."

It seems from the Phase I results, that "no single compound is going to beable to alleviate all aspects of schizophrenia syndrome by itself," Liebermantold PT. "But," he added, "that doesn'tmean that combining two current antipsychotic drugs is going to be the standardof practice, and it doesn't mean that two antipsychotic drugs are necessarilygoing to do any better than one."

He predicted that the field is probably going to move toward rational polypharmacy. "That is, combining agents to addressspecific parts of the schizophrenia syndrome, meaning psychosis, negativesymptoms, cognitive deficits and enhancing theantipsychotic effects," he said.

Other Effectiveness Trials

Beyond the CATIE trial, some other NIMH-sponsored effectiveness trialsshould be completed within the next year, according to Insel.These include the Systematic Treatment Enhancement Program for Bipolar Disorder(STEP-BD) and the Sequenced Treatment Alternatives to Relieve Depression(STAR-D).

Results from two other effectiveness studies, the Clinical AntipsychoticTrials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) and theTreatment of Adolescents with Depression Study (TADS) have already been sharedwith the psychiatric community. The TADS study evaluated the short- andlong-term effectiveness of four treatments for adolescents with majordepressive disorder: fluoxetine (Prozac),cognitive-behavioral therapy (CBT), their combination and, acutely, pillplacebo. Compared with fluoxetine alone (p=0.02) and CBT alone (p=0.01), treatment of fluoxetine with CBT was superior (March et al., 2004; TADSTeam, 2005).

Some results of the CATIE-AD have been presented at professional meetings,such as the American Psychiatric Association. In that study, researchers soughtto find the most effective medications for treating patients with Alzheimer'sdisease who developed delusions, agitation, aggressive behavior orhallucinations. Researchers found that compared to placebo, olanzapine,risperidone and quetiapinewere associated with greater effectiveness, reduced burden for the caregiverand improved neuropsychiatric symptoms (Schuster,2005).

"The compelling need for effectiveness studies or practical clinical trialshas become increasingly apparent in the last decade and a half," Liebermansaid. "As newer medicines are produced, there is not a clear mechanism todetermine what their relative effectiveness is to each other, and this istremendously important to do."

References:

References

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Freedman R (2005), The choice of antipsychoticdrugs for schizophrenia. N Engl J Med353(12):1286-1288.

2.

Lieberman JA, Stroup TS, McEvoy JP et al. (2005),Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353(12):1209-1223.

3.

March J, Silva S, Petrycki S et al. (2004), Fluoxetine, cognitive-behavioral therapy, and theircombination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial.JAMA 292(7):807-820 [see comments].

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Schuster L (2005), Medscape Medical News: atypicalantipsychotics may offer benefits for AD. Availableat: www.medscape.com/viewarticle/505789_print. Accessed Sept.26.

5.

TADS Team (2005), The Treatment for Adolescents WithDepression Study (TADS): demographic and clinical characteristics. J Am Acad Child Adolesc Psychiatry44(1):28-40.