Dr. Swartz, who served as guest editor of this special section, is affiliated with the Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Box 3173, Durham NC 27710 (email: swart001@mc.duke.edu).

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study was developed in response to a request for proposals issued by the National Institute of Mental Health (NIMH) that sought to examine the comparative effectiveness of second-generation antipsychotic drugs in real-world settings (1). At the time most such U.S. studies had been conducted under pharmaceutical-company sponsorship and were subject to sponsorship bias (2,3). CATIE, in contrast, was envisioned as the largest independent, government-sponsored trial of the comparative effectiveness of second-generation agents in the treatment of schizophrenia.

For many CATIE investigators, the primary question was which second-generation agent was most efficacious. At the time, there was far less interest in whether, as a group, these agents were superior to first-generation antipsychotics—an issue that was seemingly resolved, if for no other reason, by massive shifts in prescribing practices toward newer agents. However, a careful reading of the literature suggests little evidence that, with the exception of clozapine, second-generation antipsychotics confer superior efficacy in ameliorating positive and negative symptoms and improving cognition or that they are more tolerable (2,4,5,6,7,8,9,10,11,12).

The first report of CATIE findings indicated modest superiority of olanzapine over other second-generation agents and the first-generation proxy, perphenazine, in time to all-cause treatment discontinuation, but olanzapine's benefits were offset by weight gain and related metabolic sequelae (1). Further, the authors reported no evidence of superiority of the other second-generation agents over perphenazine—results received with great dismay and even anguish. A New York Times editorial (13) chided policy makers for "wasting billions of dollars on heavily marketed drugs that have never proved themselves in head-to-head competition against cheaper competitors." Advocacy groups despaired that this CATIE finding would buttress attempts to limit access to second-generation antipsychotics in Medicaid formularies, where a large portion of the costs for these agents are borne. Indeed, as states struggle with rising Medicaid expenditures topping all other state expenditures, a major driver of the rising costs are psychotropic medications.

Soon after publication of the initial report, attacks on the CATIE findings and methodology were lobbed from many quarters—many directly from the pharmaceutical industry or industry-sponsored experts. However, an independent study in the United Kingdom came to similar conclusions (14). Unfortunately, too much of the well-deserved debate and discourse on CATIE was thinly veiled industry spin, which left many clinicians and other stakeholders in search of a "spin-free zone" in which to consider the many issues raised by the trial: To whom is CATIE generalizable? Did the complex study design bias the results? Were modest differences in dosing in the trial an important source of bias? Was the exclusion of patients with tardive dyskinesia from treatment with perphenazine another key source of bias?

The articles in this special section are designed to offer such much-needed neutral commentary on the study. In the first article, my colleagues and I (15) provide an overview of the CATIE design and key study outcomes published to date. In the next article, Marisa Domino and I (16) report the results of an analysis of community-based data from the Medical Expenditure Panel Survey from 1996—1997 and 2004—2005 that we conducted in order to examine the rate of first- and second-generation antipsychotic medication use and changes in the characteristics of users. We found that much of the growth in use of second-generation agents during this period occurred not among individuals with schizophrenia but rather among off-label users and as a result of the introduction of new on-label indications.

In the third article, Rosenheck and coauthors (17) discuss the intersection of the science of cost-effectiveness with policy and political decision making in public deliberations about CATIE and suggest methods for guiding psychotropic formularies to better align them with evidence from cost-effectiveness studies. Noting the dearth of real-world head-to-head studies such as CATIE to inform formulary policy discussions, these authors suggest establishing a new federal agency or funding pool that would carry out independent trials comparing different Food and Drug Administration-approved drugs with each other. A commentary in response by Frank (18) suggests caution in using a small number of studies to create formulary policies that could have potentially draconian impact. Further, he suggests specific caution in using CATIE results as the cornerstone of new formulary policies, given what he sees as methodologic limitations of the study.

Next, Carpenter and Buchanan (19) examine take-home lessons from CATIE and note that the study supports the view that both generations of antipsychotics have similar therapeutic properties and, with the exception of clozapine, similar efficacy, but they have diverse adverse effects. These authors underscore the importance of approaches to prescribing that optimize individual benefit-risk profiles, rather than approaches based on unfounded assumptions about differences in efficacy. Covell and colleagues (20) then discuss the implications of the study from the perspective of mental health services researchers who study how prescribers, patients, and systems of care function and change over time. Eschewing interpretations of CATIE findings that would support "fail-first" formulary policies, these authors see a need to develop data-monitoring systems to track prescriber behavior and measure the impact of interventions designed to influence prescriber behavior and improve outcomes. They suggest that such data analyses could identify suboptimal practices and direct interventions that support practice improvement.

In a commentary from the United Kingdom, Owens (21), a clinician and clinical researcher, welcomes the eroding distinction between first- and second-class agents, the end of the preferred status of the newer drugs, and the debunking of extrapyramidal symptoms as the "uniquely frightening bogey-man." Like Carpenter and Buchanan, Owens calls for patient-centered tailored prescribing irrespective of anachronistic generational denotations.

The final two articles summarize the perspectives of other important stakeholders. Parks and colleagues (22), representing state mental health policy makers, note that political forces were influential in placing a high value on maintaining unlimited access to second-generation antipsychotics for a relatively small number of Medicaid beneficiaries. Many states took this approach rather than considering potential trade-offs in allowing broader access to more beneficiaries with a more limited formulary. These authors call for a shift in formulary policy making to an outcomes-based payment system. Finally, Duckworth and Fitzpatrick (23), speaking from a patient advocacy perspective, caution against restrictive antipsychotic formulary policies. They call for more research on patient-treatment matching, barriers to treatment adherence, the role of side effects, and real-world treatment effectiveness.

Our hope is that these articles will serve as a compendium of stakeholder perspectives about the CATIE study, even though not all perspectives are fully or adequately represented. Of the myriad lessons to be taken home from CATIE perhaps the most enduring is the need to critically and dispassionately evaluate unbiased empirical data and use the best tools available to drive evidence-based policy and practice. As the United States inevitably wrestles with the twin issues of achieving universal health coverage and containing health care costs, questions about how to use studies such as CATIE to rationally and conscionably formulate policy on psychotropic medications will become a central discussion for all who care about vulnerable citizens with mental illness.

CATIE was supported by grant N01-MH-90001 from the National Institute of Mental Health (NIMH). The project was carried out by principal investigators from the University of North Carolina, Duke University, the University of Southern California, the University of Rochester, and Yale University in association with Quintiles, Inc.; the program staff of the Division of Interventions and Services Research of NIMH; and investigators from 56 U.S. sites (CATIE Study Investigators Group).The investigators are Lawrence Adler, M.D., Clinical Insights, Glen Burnie, Md.; Mohammed Bari, M.D., Synergy Clinical Research, Chula Vista, Calif.; Irving Belz, M.D., Tri-County Mental Health and Mental Retardation Services, Conroe, Tex.; Raymond Bland, M.D., Southern Illinois University School of Medicine, Springfield; Thomas Blocher, M.D., Mental Health and Mental Retardation Authority of Harris County, Houston; Brent Bolyard, M.D., Cox North Hospital, Springfield, Mo.; Alan Buffenstein, M.D., Queen's Medical Center, Honolulu; John Burruss, M.D., Baylor College of Medicine, Houston; Matthew Byerly, M.D., University of Texas Southwestern Medical Center at Dallas; Jose Canive, M.D., Albuquerque Department of Veterans Affairs (VA) Medical Center, Albuquerque, N.M.; Stanley Caroff, M.D., Behavioral Health Service, Philadelphia; Charles Casat, M.D., Behavioral Health Center, Charlotte, N.C.; Eugenio Chavez-Rice, M.D., El Paso Community Mental Health and Mental Retardation Center, El Paso, Tex.; John Csernansky, M.D., Washington University School of Medicine, St. Louis, Mo.; Pedro Delgado, M.D., University Hospitals of Cleveland, Cleveland, Ohio; Richard Douyon, M.D., VA Medical Center, Miami; Cyril D'Souza, M.D., Connecticut Mental Health Center, New Haven; Ira Glick, M.D., Stanford University School of Medicine, Palo Alto, Calif.; Donald Goff, M.D., Massachusetts General Hospital, Boston; Silvia Gratz, M.D., Eastern Pennsylvania Psychiatric Institute, Philadelphia; George T. Grossberg, M.D., St. Louis University School of Medicine-Wohl Institute, St. Louis. Mo.; Mahlon Hale, M.D., New Britain General Hospital, New Britain, Conn.; Mark Hamner, M.D., Medical University of South Carolina and VA Medical Center, Charleston; Richard Jaffe, M.D., Belmont Center for Comprehensive Treatment, Philadelphia; Dilip Jeste, M.D., University of California-San Diego, and VA Medical Center, San Diego; Anita Kablinger, M.D., Louisiana State University Health Sciences Center, Shreveport; Ahsan Khan, M.D., University of Kansas School of Medicine, Wichita; Steven Lamberti, M.D., University of Rochester Medical Center, Rochester, N.Y.; Michael T. Levy, M.D., Staten Island University Hospital, Staten Island, N.Y.; Jeffrey Lieberman, M.D., University of North Carolina School of Medicine, Chapel Hill; Gerald Maguire, M.D., University of California-Irvine, Orange; Theo Manschreck, M.D., Corrigan Mental Health Center, Fall River, Mass.; Joseph McEvoy, M.D., Duke University Medical Center, Durham, N.C.; Mark McGee, M.D., Appalachian Behavioral Healthcare, Athens, Ohio; Herbert Meltzer, M.D., Vanderbilt University Medical Center, Nashville, Tenn.; Alexander Miller, M.D., University of Texas Health Science Center at San Antonio; Del D. Miller, M.D., University of Iowa, Iowa City; Henry Nasrallah, M.D., University of Cincinnati Medical Center, Cincinnati, Ohio; Charles Nemeroff, M.D., Ph.D., Emory University School of Medicine, Atlanta, Ga.; Stephen Olson, M.D., University of Minnesota Medical School, Minneapolis; Gregory F. Oxenkrug, M.D., St. Elizabeth's Medical Center, Boston; Jayendra Patel, M.D., University of Massachusetts Health Care, Worcester; Frederick Reimher, M.D., University of Utah Medical Center, Salt Lake City; Silvana Riggio, M.D., Mount Sinai Medical Center-Bronx VA Medical Center, Bronx, N.Y.; Samuel Risch, M.D., University of California-San Francisco, San Francisco; Bruce Saltz, M.D., Henderson Mental Health Center, Boca Raton, Fla.; Thomas Simpatico, M.D., Northwestern University, Chicago; George Simpson, M.D., University of Southern California Medical Center, Los Angeles; Michael Smith, M.D., Harbor-UCLA Medical Center, Torrance, Calif.; Roger Sommi, Pharm.D., University of Missouri, Kansas City; Richard M. Steinbook, M.D., University of Miami School of Medicine, Miami; Michael Stevens, M.D., Valley Mental Health, Salt Lake City, Utah; Andre Tapp, M.D., VA Puget Sound Health Care System, Tacoma, Wash.; Rafael Torres, M.D., University of Mississippi, Jackson; Peter Weiden, M.D., SUNY Downstate Medical Center, Brooklyn, N.Y.; and James Wolberg, M.D., Mount Sinai Medical Center, New York City.

Dr. Swartz has been a consultant for, speaker for, or has received research funding from Eli Lilly and Company, Pfizer, and Bristol-Myers Squibb.