El CATIE-Que Fue Lo Que Aprendimos

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The NIMH-CATIE Schizphrenia St:What di We learn?

Everyone said, loud enough or the others to hear: Look at the Emperors newclothes.

The Emperors New Clothes, by Hans Christian Anderson

It has been over 10 years since the initiation o the National Institute o Mental Health(NIMH) Clinical Antipsychotic Trials o Intervention Eectiveness (CATIE) study and 5years since the rst publication o its primary results (1). In this period, the initial report

has been cited in the literature over 1,600 times (2) while more than 80 articles rom thestudys extensive database (Table 1), as well as a book serving as an archive o the studys

results and implications (3), have been published. In the meantime, several more ran-domized trials comparing the eectiveness o antipsychotics have been completed (46), meta-analyses that bear on the ndings o the CATIE study have been perormed (7,8), and commentaries on CATIEs ndings and critiques o its methodology have been

published (911). All o these help us to view the CATIE study in a broader context andenable us to determine what we really learned rom it.

When the CATIE study was designed in 19992000, the prevailing opinion o research-

ers and clinicians alike was that the newer (second-generation) antipsychotic drugswere vastly superior to the older (rst-generation) antipsychotic drugs in ecacy and

saety. This largely refected the results o studies spon-sored by the manuacturers o the new drugs (12, 13), mar-keting messages o pharmaceutical companies and the

hopes o many who wanted better treatments. Indeed, thehypothesis and expectation o the CATIE study investiga-tors was that the rst-generation antipsychotic perphen-

azine would be inerior to the newer agents. Consequently,the nding that perphenazine was similar in eectiveness

to most other medications had a proound eect that extended beyond the scienticand psychiatric communities to the lay public and various stakeholder groups. Some-what sensational news reports decried the preerential use and greater cost o the newer

medications and the marketing practices that led to them. For example, the September21, 2005, editorial page oThe New York Timesopined, A government-nanced studyhas provided the strongest evidence yet that the system or approving and promoting

drugs is badly out o whack. The study compared ve drugs used to treat schizophre-nia and ound that most o the newest, most heavily prescribed drugs were no betterthan an older drug that is ar cheaper. The nation is wasting billions o dollars on heav-

ily marketed drugs that have never proved themselves in head-to-head competitionagainst cheaper competitors (14).

But what did we really learn rom the CATIE study? In this commentary, we summa-rize its major implications and their relevance to clinical practice. We will also addresssome o the studys most relevant critiques.

Rests f the CATIE St

The most striking result o the CATIE study, which enrolled almost 1,500 individuals

with chronic schizophrenia, was the high rate o treatment discontinuation (up to 74%)

Commentary

770 ajp.psychiatryonline.org Am J Psychiatry 168:8, August 2011

To the extent that

antipsychotics differ, it ismore in their side effectsthan therapeutic effects.


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Am J Psychiatry 168:8, August 2011 ajp.psychiatryonline.org 771

over the 18-month period o the trial and the short median time to discontinuationo treatment (about 6 months) in all phases o the trial. Treatment discontinuation in

CATIE refected the desire o patients and their clinicians to switch their medicationsor patients nonadherence to treatment. These ndings were surprising to some but

are consistent with those observed in administrative databases that document antipsy-chotic prescribing patterns in state Medicaid programs (15, 16), in Qubec (17), and inthe U.S. Veterans Health Administration (18). In act, the mean duration o treatment

or persons with schizophrenia spectrum disorders who started new antipsychotics inthese analyses o administrative data was shorterthan that or participants in CATIE.

The most controversial nding o the CATIE study was the lack o signicant dier-

ences in eectiveness between most o the second-generation antipsychotics and per-

phenazine, the proxy or the rst-generation antipsychotics. It has been argued thatolanzapine was the most eective antipsychotic medication in the rst phase o thestudy in spite o the lack o a statistically signicant advantage over perphenazine orziprasidone (19). However, olanzapine had the most adverse metabolic eects and

highest discontinuation rate as a result o intolerability. Moreover, the other second-generation antipsychotics were similar to perphenazine in eectiveness. In addition,there were no advantages in ecacy or any o the second-generation antipsychotics

with regard to negative symptoms or cognitive impairment. The most robust dier-ences observed between drugs were in the rates o side eects, particularly weight gainand laboratory measures o cholesterol, triglycerides, and prolactin. Extrapyramidal

symptoms were similar across treatment groups, although more patients receiving per-

phenazine discontinued treatment because o this side eect.

TABlE 1. Ke Pbishe Artices n the CATIE St a

Topic Study Authors Publication

Phase 1 eectiveness Eectiveness o antipsychotic drugs in patients with chronic schizo-phrenia

Lieberman et al. N Engl J Med 2005;353:12091223

Phase 2E eectiveness Eectiveness o clozapine versus olanzapine, quetiapine, and risperi-done in patients with chronic schizophrenia who did not respond toprior atypical antipsychotic treatment

McEvoy et al. Am J Psychiatry 2006;163:600610

Phase 2T eectiveness Eectiveness o olanzapine, quetiapine, risperidone, and ziprasidonein patients with chronic schizophrenia ater discontinuing a previousatypical antipsychotic

Stroup et al. Am J Psychiatry 2006;163:611622

Cost-eectiveness Cost-eectiveness o second-generation antipsychotics and perphen-azine in a randomized trial o treatment or chronic schizophrenia

Rosenheck et al. Am J Psychiatry 2006;163:20802089

Switching eects onmedication treatmentoutcomes

Eectiveness o switching antipsychotic medications Essock et al. Am J Psychiatry 2006;163:20902095

Phase 1B eectiveness Eectiveness o olanzapine, quetiapine, and risperidone in patientswith chronic schizophrenia ater discontinuing perphenazine: a CATIEstudy

Stroup et al. Am J Psychiatry 2007;164:415427

Treatment eects onneurocognition

Neurocognitive eects o antipsychotic medications in patients withchronic schizophrenia in the CATIE trial

Keee et al. Arch Gen Psychiatry2007; 64:633647

Treatment eects on psy-chosocial unctioning

Eects o antipsychotic medications on psychosocial unctioning in pa-tients with chronic schizophrenia: fndings rom the NIMH CATIE study

Swartz et al. Am J Psychiatry 2007;164:428436

Metabolic eects otreatments

Antipsychotic eects on estimated 10-year coronary heart disease riskin the CATIE schizophrenia study

Daumit et al. Schizophr Res 2008;105:175187

Metabolic eects otreatments

Change in metabolic syndrome parameters with antipsychotic treat-ment in the CATIE schizophrenia trial: prospective data rom phase 1

Meyer et al. Schizophr Res 2008;101:273286

Extrapyramidal sideeects o treatments

Extrapyramidal side eects o antipsychotics in a randomized trial Miller et al. Br J Psychiatry 2008;193:279288

Genome-wideassociation study

Genome-wide association or schizophrenia in the CATIE study:results o stage 1

Sullivan et al. Mol Psychiatry 2008;13:570584

Phase 3 eectiveness Results o phase 3 o the CATIE schizophrenia trial Stroup et al. Schizophr Res 2009;107:112

a Articles presented are rom a total o more than 80 published articles on the CATIE study.


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The CATIE study showed that each drug might be most useul in particular situations.For patients whose symptoms did not improve with rst-line treatment, clozapine was

most eective. Olanzapine was eective in all phases o the study, but it and clozapinehad the greatest side eect liabilities. For patients who switched medications becauseo side eects, the best alternative depended on the type o the individual side eects

and the severity o the patients illness. Risperidone was eective overall or people whodiscontinued prior medications as a result o intolerability (and is now available as a

generic). Quetiapine worked well or people who did not tolerate perphenazine. Zipras-idone demonstrated the most avorable metabolic prole. Perphenazine, because itwas priced as a generic, was the most cost-eective drug in the studys main phase.

The essential import o the CATIE study can be summarized as ollows. Antipsychoticdrugs, both old and new, are clearly eective and have been a boon to the treatment oschizophrenia. However, they have substantial limitations in ecacy and saety, which

lead clinicians and consumers to seek better results by switching or adding medica-tions. The numerous antipsychotic drugs, however they might be classied, are moresimilar to than dierent rom each other. To the extent that antipsychotics dier, it is

more in their side eects than therapeutic eects. Nevertheless, there is variation in theeectiveness o antipsychotic drugs, which or individual patients can be substantial,

and what works or one person may not work or another. Consequently, treatments or

schizophrenia must be individualized.

Critiqes f the CATIE St

There is only one thing worse than being talked about and that is not being talkedabout.

Oscar Wilde

The CATIE study has not suered rom lack o attention. O all the issues raised in

the commentary and critiques o the CATIE study, we believe that three are most sa-lient. CATIE used an innovative outcome measure to capture the overall eectivenesso the medications and to refect the input o patients and clinicians on their ecacy

and tolerability: time to all-cause treatment discontinuation. It is important to em-phasize that discontinuation did not mean that patients stopped treatment and let thestudy but that they and/or their clinicians elected to switch or stop the medication to

which they had been randomly assigned. This measure was criticized as being not su-ciently specic or clinically valid (11). However, treatment discontinuation is a discrete

event that may have many clinically important causes that are not mutually exclusiveor specically identied. For example, in everyday practice when patients drop outo treatment or are noncompliant, this is oten because o problems with psychotic

symptoms and/or adverse eects. The measures simplicity and comprehensivenessmake it an attractive primary outcome or eectiveness studies. Patients in CATIE whodiscontinued treatment or any cause had lower quality o lie scores than those who

completed the study, and their quality o lie scores at the time o discontinuation weredecreased rom baseline (20).

A second criticism was that the dose ranges o the study drugs were not equivalent.However, the doses selected were based on those used in clinical practice. Moreover, nostudies at the time o the trial, or subsequently, have demonstrated clear dierences in

dose response rom those used in the trial. In addition, the dose o the rst-generationdrug, perphenazine, was administered at the low end o the recommended dose range.This was done to minimize the potential extrapyramidal side eects, but the drug still

proved to be therapeutically comparable to the second-generation medications.A more cogent criticism is that the study was not powered or nonineriority. This is

accurate but does not negate the results. The act that the study was powered or supe-

riority refects the investigators a priori belie that the second-generation drugs would


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prove superior. The act that the new drugs did not show statistical superiority (or evennumerical superiority in all cases except olanzapine) over perphenazine indicates that

i there were an eectiveness dierence, which the study did not reveal because o pow-er limitations, the magnitude o the eect must be small. In addition, the conrmatory

pattern o results rom subsequent studies and meta-analyses urther supports the va-lidity o the CATIE results.

Effect f the CATIE St

Given its startling results and the extraordinary attention that it attracted, one might

have expected the CATIE study to have had a proound eect on clinical practice. How-ever, prescribing patterns have not markedly changed in the ways suggested by theCATIE studys results. For example, since 2006, among New York State Medicaid recipi-

ents with schizophrenia or schizoaective disorder, clozapine use is fat, olanzapineuse has declined, quetiapine use is up, and risperidone use has declinedeven thoughit became generic during this timewhile its branded metabolite, paliperidone, has

gained considerable use. Meanwhile, use o perphenazine and all other mid- and low-potency rst-generation antipsychotic drugs remains rare (Figure 1).

On the other hand, the CATIE results have clearly aected the debate about the rela-

tive eectiveness o antipsychotic drugs and our understanding o the true value andreal role o the dierent types o antipsychotics. Moreover, the CATIE study has dra-

matically demonstrated the value and importance o independently sponsored andconducted comparative eectiveness trials to inorm clinicians, consumers, and policymakers o the relative value o marketed treatments or medical disorders. In particu-

lar, policy makers need inormation to make rational decisions about whether to adopt

FIguRE 1. Antipschtic Prescriptins Fie fr New yrk Meicai Recipients With SchizphreniaSpectrm disrers (20062009)a

8,000

7,000

6,000

5,000

4,000

3,000

2,000

1,000

02006 2007 2008 2009

Year

NumberofPatients

W

ithPrescriptionsFilled

Aripiprazole

Clozapine

Fluphenazine

Haloperidol

Long-Acting Injectables

Olanzapine

Paliperidone

Quetiapine

Risperidone

Ziprasidone

Other (Any other

oral antipsychotic)

a Antipsychotic prescriptions flled indicates the number o patients who flled at least one prescription or a speci-fed drug in the calendar year.


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expensive new treatments that have not been compared with cheaper existing ones.The importance o comparative eectiveness research is evident in recent legislation.

In 2009, the American Recovery and Reinvestment Act provided or the development oan inrastructure or the ongoing generation and dissemination o inormation on com-parative eectiveness. In 2010, the Patient Protection and Aordable Care Act estab-

lished the Patient-Centered Outcomes Research Institute to identiy national prioritiesor research and to establish, update, and carry out a national comparative outcomes

research project agenda.CATIE helped to demonstrate that, although the introduction o second-generation

antipsychotic drugs brought new options or the treatment o psychosis, the major ad-

vance many had hoped or remains elusive. By revealing the truth about the emperorsnew clothes, CATIE has helped to reocus eorts on the need or truly innovative treat-ments and strategies that can make signicant advances or persons with schizophre-

nia and related psychoses.

References

1. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keee RS, Davis SM, Davis CE,

Lebowitz BD, Severe J, Hsiao JK: Eectiveness o antipsychotic drugs in patients with chronic schizophrenia.

N Engl J Med 2005; 353:12091223

2. Google Scholar: http://scholar.google.com3. Stroup TS, Lieberman JA: Antipsychotic Trials in Schizophrenia: The CATIE Study. New York, Cambridge Uni-

versity Press, 2010

4. Sikich L, Frazier JA, McClellan J, Findling RL, Vitiello B, Ritz L, Ambler D, Puglia M, Maloney AE, Michael E,

De Jong S, Slika K, Noyes N, Hlastala S, Pierson L, McNamara NK, Delporto-Bedoya D, Anderson R, Hamer

RM, Lieberman JA: Double-blind comparison o frst- and second-generation antipsychotics in early on-

set-schizophrenia and schizoaective disorder: fndings rom the Treatment o Early-Onset Schizophrenia

Spectrum Disorders (TEOSS) study. Am J Psychiatry 2008; 165:14201431 (Erratum in Am J Psychiatry 2008;

165:1495)

5. McEvoy JP, Lieberman JA, Perkins DO, Hamer RM, Gu H, Lazarus A, Sweitzer D, Olexy C, Weiden P, Strakowski

SD: Efcacy and tolerability o olanzapine, quetiapine, and risperidone in the treatment o early psychosis:

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Rssler A, Grobbee DE; EUFEST study group: Eectiveness o antipsychotic drugs in frst-episode schizophre-

nia and schizophreniorm disorder: an open randomized clinical trial. Lancet 2008; 371:10851097

7. Leucht S, Komossa K, Rummel-Kluge C, Corves C, Hunger H, Schmid F, Asenjo Lobos C, Schwarz S, Davis

JM: A meta-analysis o head-to-head comparisons o second-generation antipsychotics in the treatment o

schizophrenia. Am J Psychiatry 2009; 166:152163

8. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM: Second-generation versus frst-generation antipsychotic

drugs or schizophrenia: a meta-analysis. Lancet 2009; 373:3141

9. Tandon R, Belmaker RH, Gattaz WF, Lopez-Ibor JJ Jr, Okasha A, Singh B, Stein DJ, Olie JP, Fleischhacker

WW, Moeller HJ; Section o Pharmacopsychiatry, World Psychiatric Association: World Psychiatric Association

Pharmacopsychiatry Section statement on comparative eectiveness o antipsychotics in the treatment o

schizophrenia. Schizophr Res 2008; 100:2038

10. Kane JM: Commentary on the clinical antipsychotic trials o intervention eectiveness (CATIE). J Clin Psychia-

try 2006; 67:831832

11. Kraemer HC, Glick ID, Klein DF: Clinical trials design lessons rom the CATIE study. Am J Psychiatry 2009;

166:12221228

12. Lewis S, Lieberman JA: CATIE and CUtLASS: can we handle the truth? Br J Psychiatry 2008; 192:16116313. Heres S, Davis J, Maino K, Jetzinger E, Kissling W, Leucht S: Why olanzapine beats risperidone, risperidone

beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis o head-to-head comparison

studies o second-generation antipsychotics. Am J Psychiatry 2006; 163:185194

14. New York Times: Comparing Schizophrenia Drugs (editorial). New York Times, Sept 21, 2005

15. Rothbard AB, Kuno E, Foley K: Trends in the rate and type o antipsychotic medications prescribed to per-

sons with schizophrenia. Schizophr Bull 2003; 29:531540

16. Chen L, McCombs JS, Park J: Duration o antipsychotic drug therapy in real-world practice: a comparison

with CATIE trial results. Value Health 2008; 11:487496

17. Moisan J, Gregoire JP: Patterns o discontinuation o atypical antipsychotics in the province o Qubec: a

retrospective prescription claims database analysis. Clin Ther 2010; 32(suppl 1):S21S31

18. Kilzieh N, Todd-Stenberg JA, Kennedy A, Wood AE, Tapp AM: Time to discontinuation and sel-discontinua-

tion o olanzapine and risperidone in patients with schizophrenia in a naturalistic outpatient setting. J Clin

Psychopharmacol 2008; 28:7477

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20. Davis SM, Stroup ST, Koch GG, Davis CE, Rosenheck RA, Lieberman JA: Time to all-cause treatment discon-

tinuation as the primary outcome in the Clinical Antipsychotic Trials o Intervention Eectiveness (CATIE)

Schizophrenia Study. Stat Biopharmaceut Res 2011; 3:253265

JEFFREy A. lIEBERMAN, M.d.

T. SCoTT STRouP, M.d., M.P.H.

Address correspondence to Dr. Stroup ([email protected]). Editorial accepted or publication April

2011 (doi: 10.1176/appi.ajp.2011.11010039).

Dr. Lieberman serves on the advisory boards o Bioline, Intracellular Therapies, Pierre Fabre, and PsychoGen-

ics; he receives grant support rom Allon, Eli Lilly, F. Homan-La Roche, GlaxoSmithKline, Merck, Novartis,

Pzer, LTD, Sepracor (Sunovion), and Targacept; and he holds a patent with Repligen. Dr. Stroup has received

research support rom the National Institute o Mental Health and the Foundation or the National Institutes

o Health; in the last 3 years, he has received consulting ees rom Janssen and Lilly. Dr. Freedman has re-

viewed this editorial and ound no evidence o infuence rom these relationships.

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