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Richard S. E. Keefe, PhD; Robert M. Bilder, PhD; Sonia M. Davis, DrPH; Philip D. Harvey, PhD; Barton W. Palmer, PhD; James M. Gold, PhD; Herbert Y. Meltzer, MD; Michael F. Green, PhD; George Capuano, PhD; T. Scott Stroup, MD, MPH; Joseph P. McEvoy, MD; Marvin S. Swartz, MD; Robert A. Rosenheck, MD; Diana O. Perkins, MD, MPH; Clarence E. Davis, PhD; John K. Hsiao, MD; Jeffrey A. Lieberman, MD; for the CATIE Investigators and the Neurocognitive Working Group

Arch Gen Psychiatry. 2007;64(6):633-647.

Context  Neurocognitive impairment in schizophrenia is severe and is an important predictor of functional outcome. The relative effect of the second-generation (atypical) antipsychotic drugs and older agents on neurocognition has not been comprehensively determined.

Objective  To compare the neurocognitive effects of several second-generation antipsychotics and a first-generation antipsychotic, perphenazine.

Design  Randomized, double-blind study of patients with schizophrenia assigned to receive treatment with olanzapine, perphenazine, quetiapine fumarate, or risperidone for up to 18 months as reported previously by Lieberman et al. Ziprasidone hydrochloride was included after its approval by the Food and Drug Administration.

Setting  Fifty-seven sites participated, including academic sites and treatment mental health facilities representative of the community.

Patients  From a cohort of 1460 patients in the treatment study, 817 completed neurocognitive testing immediately prior to randomization and then after 2 months of treatment.

Main Outcome Measures  The primary outcome was change in a neurocognitive composite score after 2 months of treatment. Secondary outcomes included neurocognitive composite score change at 6 months and 18 months after continued treatment and changes in neurocognitive domains.

Results  At 2 months, treatment resulted in small neurocognitive improvements of z = 0.13 for olanzapine (P<.002), 0.25 for perphenazine (P<.001), 0.18 for quetiapine (P<.001), 0.26 for risperidone (P<.001), and 0.12 for ziprasidone (P<.06), with no significant differences between groups. Results at 6 months were similar. After 18 months of treatment, neurocognitive improvement was greater in the perphenazine group than in the olanzapine and risperidone groups. Neurocognitive improvement predicted longer time to treatment discontinuation, independently from symptom improvement, in patients treated with quetiapine or ziprasidone.

Conclusions  After 2 months of antipsychotic treatment, all groups had a small but significant improvement in neurocognition. There were no differences between any pair of agents, including the typical drug perphenazine. These results differ from the majority of previous studies, and the possible reasons are discussed.

Author Affiliations: Departments of Psychiatry and Behavioral Sciences (Drs Keefe, McEvoy, and Swartz) and Biological Psychiatry, John Umstead Hospital (Dr McEvoy), Duke University Medical Center, Durham, NC; Departments of Psychiatry and Biobehavioral Sciences (Drs Bilder and Green) and Psychology (Dr Bilder), University of California, Los Angeles, Neuropsychiatric Institute; Quintiles Inc, Research Triangle Park, NC (Dr Davis); Department of Psychiatry, Mount Sinai School of Medicine, New York, NY (Dr Harvey); Department of Psychiatry, University of California, San Diego (Dr Palmer); Maryland Psychiatric Research Center, Baltimore (Dr Gold); Department of Psychiatry, Vanderbilt University Medical Center, Nashville, Tenn (Dr Meltzer); Department of Psychiatry, School of Medicine (Drs Capuano, Stroup, and Perkins), and Department of Biostatistics (Dr Davis), University of North Carolina at Chapel Hill; Department of Psychiatry, Yale University School of Medicine, New Haven, Conn (Dr Rosenheck); Adult Psychopharmacology Program, Adult Treatment and Preventive Intervention Research Branch, Division of Services and Intervention Research, National Institute of Mental Health, Bethesda, Md (Dr Hsiao); and Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, New York (Dr Lieberman).

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