Abstract
Altered expression of central muscarinic and nicotinic acetylcholine receptors in hippocampal and cortical regions may contribute to the cognitive impairment exhibited in patients with schizophrenia. Increasing cholinergic activity through the use of a cholinesterase inhibitor (ChEI) therefore represents a possible strategy for cognitive augmentation in schizophrenia. We examined the efficacy and safety of the ChEI donepezil as cotreatment for mild to moderate cognitive impairment in schizophrenia or schizoaffective disorder in a prospective, 12-week, placebo-controlled, double-blind, parallel-group study. In total, 250 patients (18–55 years) with schizophrenia or schizoaffective disorder who were clinically stabilized on risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole, alone or in combination, were enrolled at 38 outpatient psychiatric clinics in the United States. Patients were randomized to donepezil 5 mg q.d. for 6 weeks then 10 mg q.d. for 6 weeks, or placebo administered as oral tablets. The primary outcome measure was the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) neurocognitive battery composite score. In the intent-to-treat sample (donepezil, n=121; placebo, n=124), both treatments showed improvement in the composite score from baseline to week 12. At week 12, cognitive improvement with donepezil was similar to that with placebo (last-observation-carried-forward effect size, 0.277 vs 0.411; p=0.1182) and statistically significantly inferior for the observed-cases analysis (0.257 vs 0.450; p=0.044). There was statistically significant improvement in the Positive and Negative Syndrome Assessment Scale negative symptoms score for placebo compared with donepezil, while total and positive symptom scores were similar between both treatments. Statistically significant improvements in positive symptoms score and Clinical Global Impression-Improvement for donepezil compared with placebo were noted at Week 6. Treatment-emergent adverse events (AEs) were observed for 54.5% of donepezil- and 61.3% of placebo-treated patients; most AEs were rated as mild to moderate in severity. Donepezil was safe and well-tolerated but was not effective compared with placebo as a cotreatment for the improvement of cognitive impairment in this patient population. A significant and surprisingly large placebo/practice effect was observed among placebo-treated patients, and is a serious consideration in future clinical trial study designs for potential cognitive enhancing compounds in schizophrenia.
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This study was supported by Eisai Inc. and Pfizer Inc. Editorial support was provided by Lisa Thomas at PAREXEL and was funded by Eisai Inc. and Pfizer Inc.
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Richard Keefe has received grant/research support from Astra-Zeneca, Eli Lilly, Johnson & Johnson, Pfizer, and NIMH, as well as providing educational services to Astra-Zeneca, Eli Lilly, Forest Labs, GlaxoSmithKline, Johnson & Johnson, Pfizer, and Repligen. He has also served as a consultant and on advisory boards for various pharmaceutical companies as follows: Abbott Pharmaceuticals (advisory board), Astra-Zeneca (advisory board, consultant), Bristol Myers Squibb (advisory board), Dainippon Sumitomo Pharma. (consultant), Eli Lilly (advisory board, consultant), Forest Labs (consultant), GlaxoSmithKline (consultant), Johnson & Johnson (advisory board, consultant), Lundbeck/Solvay/Wyeth (advisory board), Memory Pharmaceuticals (advisory board), Merck (advisory board, consultant), Orexigen (advisory board, consultant), Otsuka (consultant), Pfizer (advisory board, consultant), Repligen (consultant), Saegis (advisory board, consultant), Sanofi/Aventis (advisory board, consultant), and Xenoport (consultant). In addition, Dr Keefe receives royalties from the Brief Assessment of Cognition testing battery and the MATRICS Battery (BACS Symbol Coding). Anil K Malhotra has received grant/research support, has served as a consultant and on speakers bureau for Pfizer Inc. Herbert Meltzer has served as a consultant for and been awarded grants from ARYx Therapeutics, Bristol Myers Squibb, Eli Lilly and Company, Janssen, Memory, Pfizer Inc., and in addition has also served as a lecturer for Solvay Pharmaceuticals. He has also served as a consultant for CogTest. John M Kane has served as a consultant for Abbott, Astra-Zeneca, Bristol-Myers Squibb, Janssen, Eli Lilly and Company, Pfizer Inc., and Wyeth Pharmaceticals and on Speakers Bureau for Bristol-Myers Squibb, Janssen, and Astra-Zeneca. Robert W Buchanan received no funds for his involvement in the current project. Dr Buchanan has received grant/research support from Ortho-McNeil who supplied study medications for a foundation supported clinical trial of galantamine, an acetylcholinesterase inhibitor and Janssen who supplied study medications for a NIMH-supported clinical trial of risperidone, an antipsychotic used in the treatment of schizophrenia. Dr Buchanan has also served as a consultant and on advisory boards for various pharmaceutical companies as follows: Pfizer (advisory board), Pfizer is a sponsor of the current study; Organon (consultant), Organon is developing drugs for the treatment of schizophrenia; Merck (Advisory Board), Merck is developing a drug for the treatment of schizophrenia; Glaxo-Smith-Kline (consultant), Glaxo-Smith-Kline is developing a drug for the treatment of schizophrenia; Astra-Zeneca (Advisory Board), Astra-Zeneca is developing a drug for the treatment of schizophrenia; Solvay Pharmaceuticals, Inc. (Advisory Board), Solvay is developing a drug for the treatment of schizophrenia; Roche (consultant), Roche is developing a drug for the treatment of schizophrenia. Dr Buchanan works with Pfizer as a DSMB member for two studies of ziprasidone, an antipsychotic used in the treatment of schizophrenia and with Wyeth as a DSMB member for study examining experimental drug for the treatment of schizophrenia. Dr Buchanan has not been involved in Speakers Bureaus and is not a major stock holder. Anita Murthy is an employee of Eisai Inc., and Mindy Sovel, Chunming Li, and Robert Goldman are employees of Pfizer Inc., the Pharmaceutical companies that manufacture and market donepezil.
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Keefe, R., Malhotra, A., Meltzer, H. et al. Efficacy and Safety of Donepezil in Patients with Schizophrenia or Schizoaffective Disorder: Significant Placebo/Practice Effects in a 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial. Neuropsychopharmacol 33, 1217–1228 (2008). https://doi.org/10.1038/sj.npp.1301499
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DOI: https://doi.org/10.1038/sj.npp.1301499
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