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Antipsychotic Drugs May Improve Neurocognition in Patients With Chronic Schizophrenia

  • Authors: News Author: Laurie Barclay, MD
    CME Author: Charles Vega, MD
  • CME Released: 6/5/2007
  • Valid for credit through: 6/5/2008
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Target Audience and Goal Statement

This article is intended for primary care clinicians, psychiatrists, neurologists, and other specialists who care for patients with schizophrenia.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. List potential limitations of previous research about the role of antipsychotics in improving neurocognitive function among patients with schizophrenia.
  2. Compare first- vs next-generation antipsychotics in terms of their effects on cognition among patients with schizophrenia.


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  • Laurie Barclay, MD

    Laurie Barclay is a freelance reviewer and writer for Medscape.


    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

CME Author(s)

  • Charles P Vega, MD

    Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine


    Disclosure: Charles Vega, MD, has disclosed an advisor/consultant relationship to Novartis, Inc.

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Antipsychotic Drugs May Improve Neurocognition in Patients With Chronic Schizophrenia

Authors: News Author: Laurie Barclay, MD CME Author: Charles Vega, MDFaculty and Disclosures

CME Released: 6/5/2007

Valid for credit through: 6/5/2008


June 5, 2007 — After 2 months of treatment with various antipsychotic drugs, patients with chronic schizophrenia had small but significant improvements in neurocognition, according to the results of a randomized, double-blind study reported in the May issue of the Archives of General Psychiatry.

"Neurocognitive impairment in schizophrenia is severe and is an important predictor of functional outcome," write Richard S.E. Keefe, PhD, and colleagues from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators and the Neurocognitive Working Group. "The relative effect of the second-generation (atypical) antipsychotic drugs and older agents on neurocognition has not been comprehensively determined."

The objective of this study was to compare the neurocognitive effects of several second-generation antipsychotics (olanzapine, quetiapine fumarate, or risperidone) and a first-generation antipsychotic, perphenazine, used for up to 18 months. After its approval by the US Food and Drug Administration, the second-generation antipsychotic, ziprasidone hydrochloride, was also included.

Of 1493 patients randomized to treatment at 57 academic sites and treatment mental health facilities, 817 completed neurocognitive testing immediately before randomization and then after 2 months of treatment. The main endpoint was change in a neurocognitive composite score after 2 months of treatment, and secondary outcome measures included neurocognitive composite score change at 6 and 18 months after continued treatment, and changes in neurocognitive domains.

At 2 months, treatment resulted in small neurocognitive improvements: z = 0.13 for olanzapine (P < .002), z = 0.25 for perphenazine (P < .001), z = 0.18 for quetiapine (P < .001), z = 0.26 for risperidone (P < .001), and z = 0.12 for ziprasidone (P < .06). There were no significant differences between groups, and results were similar at 6 months.

Neurocognitive improvement after 18 months of treatment was greater in the perphenazine group than in the olanzapine and risperidone groups. In patients treated with quetiapine or ziprasidone, neurocognitive improvement predicted longer time to treatment discontinuation, independent of symptom improvement.

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

The authors further note that the lack of a neurocognitive advantage for second-generation antipsychotics in this study suggests that the positive findings from earlier studies may not generalize well to the type of everyday clinical practice studied in the CATIE trial. Differing results may be explained in part by methodologic differences between the studies.

Study limitations include exclusion of patients with schizoaffective disorder, those with only 1 schizophrenic episode, or those who had adverse reactions to any of the treatments or were treatment resistant, limiting generalizability; randomization precluding assignment of a medication known to be more effective for certain subgroups of patients; randomization scheme preventing patients with tardive dyskinesia from receiving treatment with perphenazine; only 56% of the 1460 patients in the trial generated neurocognitive data at baseline and only 303 patients (21%) generated neurocognitive data after having been treated with the same antipsychotic for 18 months; and the possibility that neurocognitive improvement was related solely to practice effects or expectation bias.

The National Institute of Mental Health; AstraZeneca Pharmaceuticals LP, the maker of quetiapine fumarate; Bristol-Myers Squibb Co; Forest Pharmaceuticals, Inc; Janssen Pharmaceutica Products, the maker of risperidone; Eli Lilly and Co, the maker of olanzapine; Otsuka Pharmaceutical Co Ltd; Pfizer Inc, the maker of ziprasidone; Schering-Plough, the maker of perphenazine; and Zenith Goldline Pharmaceuticals, Inc, supported this study and/or provided medications. Some of the authors have disclosed financial relationships with AstraZeneca Pharmaceuticals LP, Eli Lilly and Co, Janssen Pharmaceutica, Pfizer Inc, Forest Labs, GlaxoSmithKline, Johnson & Johnson, Repligen, Abbott Pharmaceuticals, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Lundbeck/Solvay/Wyeth, Memory Pharmaceuticals, Merck, Orexigen, Otsuka Pharmaceutical Co Ltd, Saegis, Sanofi/Aventis, Xenoport, ACADIA, Cypress Bioscience, Cogtest Inc, and/or other pharmaceutical companies.

"The small but statistically significant associations between symptomatic and cognitive improvement in the CATIE trial are consistent with the idea that decreases in distress and psychopathologic features lead to enhanced performance," R. Walter Heinrichs, PhD, from York University in Toronto, Ontario, Canada, writes in an accompanying commentary. "Therefore, many avenues of influence may exist, some related to the psychological and biological conditions that optimize or reduce performance and others involving the neural operations underlying performance itself. The unselective and modest cognitive effects of existing medications are a spur to the exploration of these avenues and hence to the discovery of more powerful and focused treatments for schizophrenia."

Dr. Heinrichs has disclosed no financial relationships.

Arch Gen Psychiatry. 2007;64:631-632, 633-647.

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