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Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia

Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., Joseph P. McEvoy, M.D., Marvin S. Swartz, M.D., Robert A. Rosenheck, M.D., Diana O. Perkins, M.D., M.P.H., Richard S.E. Keefe, Ph.D., Sonia M. Davis, Dr.P.H., Clarence E. Davis, Ph.D., Barry D. Lebowitz, Ph.D., Joanne Severe, M.S., and John K. Hsiao, M.D., for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators*

N Engl J Med 2005; 353:1209-1223September 22, 2005DOI: 10.1056/NEJMoa051688

Abstract
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References
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Antipsychotic drugs have become the cornerstone of treatment for schizophrenia. The first-generation “conventional” antipsychotic drugs are high-affinity antagonists of dopamine D2 receptors that are most effective against psychotic symptoms but have high rates of neurologic side effects, such as extrapyramidal signs and tardive dyskinesia.1 The introduction of second-generation, or “atypical,” antipsychotic drugs promised enhanced efficacy and safety.2 The atypical agents differ pharmacologically from previous antipsychotic agents in their lower affinity for dopamine D2 receptors and greater affinities for other neuroreceptors, including those for serotonin (5-hydroxytryptamine1A, 2A, 2C, 3, 6, and 7) and norepinephrine (α1 and α2).1

Although studies indicated that the atypical drugs are similar to the conventional drugs in reducing psychotic symptoms and produce few neurologic effects, the evidence of their superior efficacy has been neither consistent nor robust,3-8 with the exception of clozapine, which repeatedly has been effective in patients whose condition is refractory to treatment with other types of agents but has severe side effects that limit its use.9-11 The newer agents appear more efficacious than conventional drugs in reducing negative symptoms (e.g., lack of emotion, interest, and expression), possibly owing to the absence of extrapyramidal symptoms12 or other secondary causes of negative symptoms (e.g., depression) rather than to direct therapeutic effects.13 The results of studies of the effects of treatment on cognitive impairment and mood symptoms have been inconclusive.14,15 The ability of atypical agents to prevent relapse and their effects on social and vocational functioning, quality of life, long-term outcome, and the caregivers' burden have been incompletely explored.8,12,16

The safety advantages of the atypical drugs have been questioned because of their propensity to induce weight gain17 and alter glucose and lipid metabolism.18,19 Nevertheless, these medications are widely used and have a 90 percent market share in the United States,20,21 resulting in burgeoning costs. In the wake of this trend, questions have been raised about the clinical advantages and cost effectiveness of the atypical drugs. We report the primary outcomes of a double-blind, active-control clinical trial sponsored by the National Institute of Mental Health (NIMH) that was designed to compare the effectiveness of atypical and conventional antipsychotic drugs.22,23

Methods

Study Setting and Design

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study was initiated by the NIMH to compare the effectiveness of antipsychotic drugs. Its rationale, design, and methods have been described previously.24-28 The protocol was made available to the public for comment, and a committee of scientific experts, health care administrators, and consumer advocates critiqued the study under the auspices of the NIMH. The study was conducted between January 2001 and December 2004 at 57 clinical sites in the United States (16 university clinics, 10 state mental health agencies, 7 Veterans Affairs medical centers, 6 private nonprofit agencies, 4 private-practice sites, and 14 mixed-system sites). Patients were initially randomly assigned to receive olanzapine, perphenazine, quetiapine, or risperidone under double-blind conditions and followed for up to 18 months or until treatment was discontinued for any reason (phase 1). (Ziprasidone was approved for use by the Food and Drug Administration [FDA] after the study began and was added to the study in January 2002 in the form of an identical-appearing capsule containing 40 mg.) Patients whose assigned treatment was discontinued could receive other treatments in phases 2 and 3.24 The present report is limited to phase 1 results.

Participants

Eligible patients were 18 to 65 years of age; had received a diagnosis of schizophrenia, as determined on the basis of the Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition; and were able to take oral antipsychotic medication, as determined by the study doctor. Patients were excluded if they had received a diagnosis of schizoaffective disorder, mental retardation, or other cognitive disorders; had a history of serious adverse reactions to the proposed treatments; had had only one schizophrenic episode; had a history of treatment resistance, defined by the persistence of severe symptoms despite adequate trials of one of the proposed treatments or prior treatment with clozapine; were pregnant or breast-feeding; or had a serious and unstable medical condition.

The study was approved by the institutional review board at each site, and written informed consent was obtained from the patients or their legal guardians.

Interventions

Identical-appearing capsules contained olanzapine (Zyprexa, Eli Lilly) (7.5 mg), quetiapine (Seroquel, AstraZeneca) (200 mg), risperidone (Risperdal, Janssen Pharmaceutica) (1.5 mg), perphenazine (Trilafon, Schering-Plough, at the time of the study) (8 mg), or (after January 2002) ziprasidone (Geodon, Pfizer) (40 mg). The packaging was done by Quintiles. The dose of medications was flexible, ranging from one to four capsules daily, and was based on the study doctor's judgment. Overlap in the administration of the antipsychotic agents that patients received before study entry was permitted for the first four weeks after randomization to allow a gradual transition to study medication. Concomitant medications were permitted throughout the trial, except for additional antipsychotic agents. Patients had monthly visits with study doctors.

Because of product labeling, quetiapine and ziprasidone are given twice daily and olanzapine, perphenazine, and risperidone once daily. To protect blinding, half the patients randomly assigned to perphenazine, olanzapine, and risperidone were assigned to twice-daily dosing and half to once-daily dosing. To minimize initial side effects, patients assigned to quetiapine began treatment by receiving one 100-mg capsule on days 1 and 2, one twice daily on day 3, and one for the first dose of day 4. All patients assigned to twice-daily dosing received five identical-appearing capsules to begin treatment. Patients with current tardive dyskinesia could enroll, but the randomization scheme prevented their assignment to treatment with perphenazine.

Objectives and Outcomes

We hypothesized that there would be significant differences in the overall effectiveness of olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone in treating schizophrenia that reflected variations in efficacy and tolerability. The primary outcome measure was the discontinuation of treatment for any cause, a discrete outcome selected because stopping or changing medication is a frequent occurrence and major problem in the treatment of schizophrenia. In addition, this measure integrates patients' and clinicians' judgments of efficacy, safety, and tolerability into a global measure of effectiveness that reflects their evaluation of therapeutic benefits in relation to undesirable effects. The key secondary outcomes were the specific reasons for the discontinuation of treatment (e.g., inefficacy or intolerability owing to side effects such as weight gain, extrapyramidal signs, or sedation as judged by the study doctor). Additional secondary efficacy outcomes included scores on the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions (CGI) Scale. PANSS scores can range from 30 to 210, with higher scores indicating more severe psychopathology. Scores for the CGI Scale can range from 1 to 7, with higher scores indicating greater severity of illness. Secondary safety and tolerability outcomes, which were evaluated at months 1, 3, 6, 9, 12, 15, and 18, included the incidence of serious adverse events, the incidence of adverse events during treatment, the incidence of neurologic side effects, and changes in weight, electrocardiographic findings, and laboratory analytes.

Statistical Analysis

Randomized patients who received at least one dose of study medication made up the intention-to-treat population. Two hundred thirty-one patients with tardive dyskinesia were excluded from random assignment to perphenazine. Ziprasidone was added to the trial after approximately 40 percent of the patients had been enrolled. Consequently, comparisons involving the perphenazine group were limited to patients without tardive dyskinesia, and comparisons involving the ziprasidone group were limited to the cohort of patients who underwent randomization after ziprasidone was added (the ziprasidone cohort). In general, the trial had a statistical power of 85 percent to identify an absolute difference of 12 percent in the rates of discontinuation between two atypical agents; however, it had a statistical power of 76 percent for comparisons involving perphenazine and of 58 percent for comparisons involving ziprasidone.

We used Kaplan–Meier survival curves to estimate the time to the discontinuation of treatment. Treatment groups were compared with use of Cox proportional-hazards regression models29 stratified according to site, with adjustment for whether the patient had had an exacerbation of schizophrenia in the preceding three months and tardive dyskinesia status (for models excluding perphenazine). Sites with 15 or fewer patients were grouped according to the sites' health care systems.

The overall difference among the olanzapine, quetiapine, risperidone, and perphenazine groups was evaluated with the use of a test with 3 degrees of freedom (df). If the difference was significant at a P value of less than 0.05, the three atypical-drug groups were compared with each other by means of step-down or closed testing, with a P value of less than 0.05 considered to indicate statistical significance. Each group was then compared with the perphenazine group by means of a Hochberg adjustment for multiple comparisons.30 The smallest resulting P value was compared with a value of 0.017 (0.05 ÷ 3). The ziprasidone group was directly compared with the other three atypical-drug groups and the perphenazine group within the ziprasidone cohort by means of a Hochberg adjustment for four pairwise comparisons. The smallest resulting P value was compared with a value of 0.013 (0.05 ÷ 4).

Successful treatment time was defined as the number of months of treatment during phase 1 in which patients had a CGI Scale score of at least 3 (mildly ill) or a score of 4 (moderately ill) with an improvement of at least two points from baseline. Treatment groups were compared with use of proportional-hazards regression.

A sensitivity analysis of the Cox model for the discontinuation of treatment for any cause evaluated the effects of potentially important baseline covariates and their interaction with the treatment group.

The PANSS total scores and CGI Scale scores over time were compared among the groups with the use of a mixed model including the same fixed covariates as for the time to discontinuation, plus baseline value, time, the interaction between treatment and time, and the interaction between baseline value and time. Time was classified into months (1, 3, 6, 9, 12, 15, and 18). The results of assessments made at the end of phase 1 were assigned to the next interval. The correlation of the repeated measures within each patient was modeled with the use of a random subject intercept and an unstructured covariance matrix.

The study was funded by the NIMH. The pharmaceutical companies whose drugs were included in the study donated drug supplies, and each provided advice on the dose of its own drug; they were otherwise not involved in the design of the study, analyses, or interpretation of results. The manuscript was written solely by the listed authors.

Results

Characteristics and Disposition of Patients

Table 1Table 1Baseline Demographic and Clinical Characteristics of Randomized Patients. shows the baseline demographic and clinical characteristics of the patients. Figure 1Figure 1Enrollment and Outcomes. depicts the enrollment, randomization, and follow-up of study patients; 1493 patients were enrolled in the study and randomly assigned to treatment. All data from one site (33 patients) were excluded before analysis, owing to concern about the integrity of data from that site before the end of the study and before unblinding. The mean modal doses were 20.1 mg per day for olanzapine, 20.8 mg per day for perphenazine, 543.4 mg per day for quetiapine, 3.9 mg per day for risperidone, and 112.8 mg per day for ziprasidone (Table 2Table 2Outcome Measures of Effectiveness in the Intention-to-Treat Population.). Seventy-four percent of patients in the intention-to-treat analysis (1061 of 1432) discontinued their assigned treatment in phase 1 before 18 months (median, 6).

Discontinuation of Treatment

The time to the discontinuation of treatment for any cause was longer in the olanzapine group than in the quetiapine group (hazard ratio, 0.63; P<0.001), the risperidone group (hazard ratio, 0.75; P=0.002), or the perphenazine group (hazard ratio, 0.78; P=0.021) (Table 2). However, the difference between the olanzapine group and the perphenazine group was not significant after adjustment for multiple comparisons (required P value, ≤0.017). Within the cohort of 889 patients who underwent randomization after ziprasidone was added to the trial, those receiving olanzapine had a longer interval before discontinuing treatment for any cause than did those in the ziprasidone group (hazard ratio, 0.76; P=0.028). However, this difference was not significant after adjustment for multiple comparisons (required P value, ≤0.013).

The time to the discontinuation of treatment for lack of efficacy was longer in the olanzapine group than in the perphenazine group (hazard ratio, 0.47; P<0.001), the quetiapine group (hazard ratio, 0.41; P<0.001), the risperidone group (hazard ratio, 0.45; P<0.001), or the ziprasidone group (hazard ratio, 0.59; P=0.026), but the difference between the olanzapine and ziprasidone groups was not significant after adjustment for multiple comparisons (required P value, ≤0.013) (Table 2). There were no significant differences between groups in time until discontinuation owing to intolerable side effects (P=0.054). The time until discontinuation owing to the patient's decision (i.e., the patient independently chose to stop treatment) was similar to that for discontinuation for any cause (Table 2).

The duration of successful treatment was significantly longer in the olanzapine group than in the quetiapine group (hazard ratio, 0.53; P<0.001), the risperidone group (hazard ratio, 0.69; P=0.002), or the perphenazine group (hazard ratio, 0.73; P=0.013) and was significantly longer in the risperidone group than in the quetiapine group (hazard ratio, 0.77; P=0.021).

Adjustment of Outcomes for Covariates

An exploratory analysis identified the following predictors of an earlier time to discontinuation: higher baseline PANSS score (P=0.001), younger age (P<0.001), longer duration since the first use of antipsychotic medication (P=0.057), and the antipsychotic drug taken before study entry (P=0.001). Baseline antipsychotic agents were grouped into six categories (Table 1). Patients receiving olanzapine or risperidone before enrollment stayed in phase 1 of the trial longer than those taking no antipsychotic agents, those taking combination treatments, or those receiving a single antipsychotic agent excluding olanzapine, quetiapine, or risperidone; pairwise hazard ratios ranged from 0.68 (P<0.001) to 0.80 (P<0.02). No interactions with treatment group were significant at a P value of less than 0.10. After adjustment for these predictors of discontinuation, the results of treatment-group comparisons were similar to the primary results.

Efficacy Measures

Total PANSS scores improved over time in all groups (Figure 2Figure 2Outcome Measures of Effectiveness.). The mixed model revealed significant variation in treatment effects over time (P=0.002). Improvement was initially greatest in the olanzapine group, but its advantage diminished over time. The pattern of change in the scores for the CGI Scale was similar to that for the PANSS scores (P=0.004 for the interaction between treatment and time).

Adverse Events

The rates of adverse events and side effects are listed in Table 3Table 3Outcome Measures of Safety among Randomized Patients.. Fewer patients in the olanzapine group than in the other four groups were hospitalized for an exacerbation of schizophrenia (11 percent vs. 15 to 20 percent, P<0.001). After adjustment for the different durations of treatment, the olanzapine group had a risk ratio for hospitalization of 0.17 per person-year of treatment, as compared with risk ratios of 0.30 to 0.44 in the other groups.

The rates of treatment discontinuation due to intolerable side effects differed between treatments (P=0.04). Risperidone had the lowest rate (10 percent), and olanzapine had the highest rate (18 percent). Moreover, more patients discontinued olanzapine owing to weight gain or metabolic effects (9 percent vs. 1 percent to 4 percent with the other four drugs, P<0.001) and more patients discontinued perphenazine owing to extrapyramidal effects (8 percent vs. 2 percent to 4 percent, P=0.002).

Patients in the olanzapine and quetiapine groups had lower rates of insomnia (16 and 18 percent, respectively) than did patients in the other groups (24 percent in the risperidone group, 25 percent in the perphenazine group, and 30 percent in the ziprasidone group). Quetiapine was associated with a higher rate of anticholinergic effects than were the other drugs (31 percent vs. 20 to 25 percent, P<0.001).

Neurologic Side Effects

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.

Weight Gain and Metabolic Changes

Patients in the olanzapine group gained more weight than patients in any other group, with an average weight gain of 2 lb (0.9 kg) per month. A larger proportion of patients in the olanzapine group than in the other groups gained 7 percent or more of their baseline body weight (30 percent vs. 7 to 16 percent, P<0.001).

Olanzapine had effects consistent with the potential development of the metabolic syndrome and was associated with greater increases in glycosylated hemoglobin, total cholesterol, and triglycerides after randomization than the other study drugs, even after adjustment for the duration of treatment. Ziprasidone was the only study drug associated with improvement in each of these metabolic variables. Only risperidone was associated with a substantial increase in prolactin levels.

Other Potential Adverse Events

There were no substantially different effects of the medications on the corrected QT interval on electrocardiography, and torsades de pointes did not develop in any patients. There were no significant differences among the groups in the incidence of new cataracts. There were no significant differences among the groups in the rates of suicide attempts or suicidal ideation reported as serious adverse events.

Concomitant Medications

There were few substantial differences among the groups in the rates or types of medications added during the study. Patients in the olanzapine and risperidone groups were the least likely to have anxiolytic agents added (9 and 10 percent, respectively, vs. 14 to 15 percent). Fewer patients receiving quetiapine were prescribed anticholinergic drugs (3 percent vs. 8 to 10 percent).

Discussion

All second-generation antipsychotic drugs were included in phase 1 of this study except aripiprazole (which was approved by the FDA in November 2002) and clozapine, which was included in phase 2 for patients who discontinued phase 1 of treatment owing to lack of efficacy of the assigned drug. Although haloperidol is the first-generation agent most commonly used for comparison, we chose to use perphenazine because of its lower potency and moderate side-effect profile.31

Only a minority of patients in each group took their assigned drug for the duration of phase 1 (rates of discontinuation ranged from 64 to 82 percent). This outcome indicates that antipsychotic drugs, though effective, have substantial limitations in their effectiveness in patients with chronic schizophrenia. Although the rates of discontinuation may have been increased by the fact that patients were participating in a blinded, controlled trial, the rates are generally consistent with those previously observed.5 Within this limited range of effectiveness, the olanzapine group had the lowest rate of discontinuation, which might lead one to consider olanzapine the most effective of the medications studied. Its apparent superior efficacy is also indicated by the greater reduction in psychopathology, longer duration of successful treatment, and lower rate of hospitalizations for an exacerbation of schizophrenia. The results for the other second-generation antipsychotic agents and the representative conventional drug, perphenazine, were similar in most respects. It is important to note that the differences between olanzapine and perphenazine were moderate. Although there were no significant differences in the time until discontinuation owing to intolerable side effects, there were differences in rates. Moreover, olanzapine was associated with greater increases in weight and indexes of glucose and lipid metabolism than the other treatments.

Dose could have been a factor in the performance of the various agents studied. The dose ranges approved by the FDA for quetiapine and ziprasidone may be below their optimal therapeutic doses, and the recommended doses of risperidone (6 mg per day or less), intended to limit extrapyramidal symptoms, may not encompass its full therapeutic range.32,33 However, the dose ranges we used were based on information from the manufacturer of each medication plus knowledge of clinical practice patterns. Moreover, the average prescribed doses of these drugs in the United States for patients with schizophrenia during the period in which the study was conducted (14 mg of olanzapine per day, 3.8 mg of risperidone per day, 388 mg of quetiapine per day, and 125 mg of ziprasidone per day) were generally similar to the ones we used.34 The fact that a higher proportion of patients assigned to quetiapine and ziprasidone received the maximal dose allowed in the study suggests that these agents are either less effective or require higher doses (Table 2). The dose range of perphenazine was chosen to minimize the potential for extrapyramidal symptoms that may have biased previous comparisons of first- and second-generation drugs.4,7,31

The use of low-dose perphenazine appears to have diminished the frequency of extrapyramidal side effects in patients who received the first-generation drug. In contrast to previous studies,35 the proportion of patients with extrapyramidal symptoms did not differ significantly among those who received first-generation and second-generation drugs in our study. Despite this finding, more patients discontinued perphenazine than other medications owing to extrapyramidal effects.

As in other studies, we found that risperidone was associated with hyperprolactinemia and olanzapine was associated with substantial weight gain in addition to adverse changes in glucose and lipid metabolism — all features of the metabolic syndrome. Concerns about potential prolongation of the corrected QT interval with ziprasidone and of cataracts with quetiapine were not realized in this study.

We used broad inclusion and minimal exclusion criteria and allowed the enrollment of patients with coexisting conditions and those who were taking other medications. The study was conducted in a variety of clinical settings in which people with schizophrenia are treated. These “real-world” features of the study, which were intended to make the results widely applicable, may account for the differences in results between this and previous studies comparing first- and second-generation antipsychotic agents.

In summary, patients with chronic schizophrenia in this study discontinued their antipsychotic study medications at a high rate, indicating substantial limitations in the effectiveness of the drugs. Within this limited range of effectiveness, olanzapine appeared to be more effective than the other drugs studied, and there were no significant differences in effectiveness between the conventional drug perphenazine and the other second-generation drugs. There were no significant differences among the drugs in the time until discontinuation of treatment owing to intolerable side effects. However, olanzapine was associated with greater weight gain and increases in glycosylated hemoglobin, cholesterol, and triglycerides, changes that may have serious implications with respect to medical comorbidity such as the development of the metabolic syndrome. How clinicians, patients, families, and policymakers evaluate the trade-offs between efficacy and side effects, as well as drug prices, will determine future patterns of use.

Supported by a grant (N01 MH90001) from the NIMH and by the Foundation of Hope of Raleigh, N.C. AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Forest Pharmaceuticals, Janssen Pharmaceutica, Eli Lilly, Otsuka Pharmaceutical, Pfizer, Zenith Goldline Pharmaceuticals, Schering-Plough, and Novartis provided medications for the studies.

Dr. Lieberman reports having received research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceutica, and Pfizer and consulting and educational fees from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Novartis, Pfizer, and Solvay. Dr. Stroup reports having received research funding from Eli Lilly and consulting fees from Janssen Pharmaceutica, GlaxoSmithKline, and Bristol-Myers Squibb. Dr. McEvoy reports having received research funding from AstraZeneca, Forest Research Institute, Eli Lilly, Janssen Pharmaceutica, and Pfizer; consulting or advisory-board fees from Pfizer and Bristol-Myers Squibb; and lecture fees from Janssen Pharmaceutica and Bristol-Myers Squibb. Dr. Swartz reports having received research funding from Eli Lilly and consulting and educational fees from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, and Pfizer. Dr. Rosenheck reports having received research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, and Eli Lilly and consulting fees from Bristol-Myers Squibb, Eli Lilly, and Janssen Pharmaceutica. Dr. Perkins reports having received research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Otsuka Pharmaceutical, Eli Lilly, Janssen Pharmaceutica, and Pfizer and consulting and educational fees from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceuticals, and Pfizer. Dr. Keefe reports having received research funding from AstraZeneca, Eli Lilly, and Janssen Pharmaceutica; consulting or advisory-board fees from Forest Pharmaceuticals, Eli Lilly, Janssen Pharmaceutica, Pfizer, and Bristol-Myers Squibb; and lecture fees from Eli Lilly and Janssen Pharmaceutica. Dr. Sonia Davis is an employee of Quintiles. Dr. Clarence Davis reports having received consulting fees from Eli Lilly and Quintiles. Dr. Lebowitz is a former employee and Ms. Severe and Dr. Hsiao are current employees of the NIMH.

This article (10.1056/NEJMoa051688) was updated on September 8, 2010, at NEJM.org.

We are indebted to the 1493 participants in the CATIE study; to the late Mahmoud A. Parsa, M.D., of the Department of Psychiatry, Case Western Reserve University, Cleveland; to Grayson S. Norquist, M.D., M.S.P.H., previously director of the Division of Services and Intervention Research, NIMH, and currently chairman of the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson; to Ingrid Rojas-Eloi, B.S., project manager of the CATIE study, and Tiffany Harris, staff assistant, Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill; to Allison Andors, Ph.D., director of Grants Development at the Research Foundation for Mental Hygiene, New York State Psychiatric Institute; and to the Quintiles CATIE project team.

Source Information

From the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, New York (J.A.L.); the Department of Psychiatry, School of Medicine (T.S.S., D.O.P.), and the Department of Biostatistics, School of Public Health (S.M.D., C.E.D.), University of North Carolina at Chapel Hill, Chapel Hill; Quintiles, Research Triangle Park, N.C. (S.M.D.); the Department of Biological Psychiatry, John Umstead Hospital, Butner, N.C. (J.P.M.); the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, N.C. (J.P.M., M.S.S., R.S.E.K.); the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (R.A.R.); and the Division of Services and Intervention Research, National Institute of Mental Health, National Institutes of Health, Bethesda, Md. (B.D.L., J.S., J.K.H.).

Address reprint requests to Dr. Lieberman at the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, 1051 Riverside Dr., New York, NY 10032, or at .

The CATIE investigators are listed in the Appendix.

Appendix

The CATIE Study Investigators Group includes the following: L. Adler, Clinical Insights, Glen Burnie, Md.; M. Bari, Synergy Clinical Research, Chula Vista, Calif.; I. Belz, Tri-County/Mental Health and Mental Retardation Services, Conroe, Tex.; R. Bland, Southern Illinois University School of Medicine, Springfield; T. Blocher, Mental Health and Mental Retardation Authority of Harris County, Houston; B. Bolyard, Cox North Hospital, Springfield, Mo.; A. Buffenstein, Queen's Medical Center, Honolulu; J. Burruss, Baylor College of Medicine, Houston; M. Byerly, University of Texas Southwestern Medical Center at Dallas, Dallas; J. Canive, Albuquerque Veterans Affairs Medical Center, Albuquerque, N.M.; S. Caroff, Behavioral Health Service, Philadelphia; C. Casat, Behavioral Health Center, Charlotte, N.C.; E. Chavez-Rice, El Paso Community Mental Health and Mental Retardation Center, El Paso, Tex.; J. Csernansky, Washington University School of Medicine, St. Louis; P. Delgado, University Hospitals of Cleveland, Cleveland; R. Douyon, Veterans Affairs Medical Center, Miami; C. D'Souza, Connecticut Mental Health Center, New Haven; I. Glick, Stanford University School of Medicine, Stanford, Calif.; D. Goff, Massachusetts General Hospital, Boston; S. Gratz, Eastern Pennsylvania Psychiatric Institute, Philadelphia; G.T. Grossberg, Saint Louis University School of Medicine–Wohl Institute, St. Louis; M. Hale, New Britain General Hospital, New Britain, Conn.; M. Hamner, Medical University of South Carolina and Veterans Affairs Medical Center, Charleston; R. Jaffe, Belmont Center for Comprehensive Treatment, Philadelphia; D. Jeste, University of California, San Diego, Veterans Affairs Medical Center, San Diego; A. Kablinger, Louisiana State University Health Sciences Center, Shreveport; A. Khan, Psychiatric Research Institute, Wichita, Kans.; S. Lamberti, University of Rochester Medical Center, Rochester, N.Y.; M.T. Levy, Staten Island University Hospital, Staten Island, N.Y.; J.A. Lieberman, University of North Carolina School of Medicine, Chapel Hill; G. Maguire, University of California Irvine, Orange; T. Manschreck, Corrigan Mental Health Center, Fall River, Mass.; J. McEvoy, Duke University Medical Center, Durham, N.C.; M. McGee, Appalachian Psychiatric Healthcare System, Athens, Ohio; H. Meltzer, Vanderbilt University Medical Center, Nashville; A. Miller, University of Texas Health Science Center at San Antonio, San Antonio; D.D. Miller, University of Iowa, Iowa City; H. Nasrallah, University of Cincinnati Medical Center, Cincinnati; C. Nemeroff, Emory University School of Medicine, Atlanta; S. Olson, University of Minnesota Medical School, Minneapolis; G.F. Oxenkrug, St. Elizabeth's Medical Center, Boston; J. Patel, University of Massachusetts Health Care, Worcester; F. Reimherr, University of Utah Medical Center, Salt Lake City; S. Riggio, Mount Sinai Medical Center–Bronx Veterans Affairs Medical Center, Bronx, N.Y.; S. Risch, University of California, San Francisco, San Francisco; B. Saltz, Mental Health Advocates, Boca Raton, Fla.; T. Simpatico, Northwestern University, Chicago; G. Simpson, University of Southern California Medical Center, Los Angeles; M. Smith, Harbor–UCLA Medical Center, Torrance, Calif.; R. Sommi, University of Missouri, Kansas City; R.M. Steinbook, University of Miami School of Medicine, Miami; M. Stevens, Valley Mental Health, Salt Lake City; A. Tapp, Veterans Affairs Puget Sound Health Care System, Tacoma, Wash.; R. Torres, University of Mississippi, Jackson; P. Weiden, SUNY Downstate Medical Center, Brooklyn, N.Y.; J. Wolberg, Mount Sinai Medical Center, New York.

Chinese Translation 中国翻译

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