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Research paper
Early use of donepezil against psychosis and cognitive decline in Parkinson’s disease: a randomised controlled trial for 2 years
  1. Hideyuki Sawada1,
  2. Tomoko Oeda1,
  3. Masayuki Kohsaka1,
  4. Atsushi Umemura1,
  5. Satoshi Tomita1,
  6. Kwiyoung Park1,
  7. Kouichi Mizoguchi2,
  8. Hidenori Matsuo3,
  9. Kazuko Hasegawa4,
  10. Harutoshi Fujimura5,
  11. Hiroshi Sugiyama1,6,
  12. Michikazu Nakamura7,
  13. Seishi Kikuchi8,
  14. Kenji Yamamoto1,
  15. Toshiaki Fukuda1,
  16. Suminobu Ito9,
  17. Masashi Goto10,
  18. Kosuke Kiyohara11,
  19. Takashi Kawamura12
  1. 1 Clinical Research Center and Department of Neurology, Utano National Hospital, Kyoto, Japan
  2. 2 Department of Neurology, Shizuoka Medical Institute of Epilepsy and Neurological Disorders, Shizuoka City, Japan
  3. 3 Department of Neurology, Nagasaki Kawatana Medical Center, Nagasaki, Japan
  4. 4 Department of Neurology, Sagamihara National Hospital, Sagamihara, Japan
  5. 5 Clinical Research Center and Department of Neurology, Toneyama National Hospital, Toyonaka, Japan
  6. 6 Department of Neurology, Minami-Kyoto National Hospital, Joyo, Japan
  7. 7 Department of Neurology, Kyoto Medical Center, Kyoto, Japan
  8. 8 Department of Neurology, Hokkaido Medical Center, Sapporo, Japan
  9. 9 Clinical Research Center, National Hospital Organization, Meguro, Japan
  10. 10 Division of General Internal Medicine, Kyoto Medical Center, Kyoto, Japan
  11. 11 Department of Public Health, Tokyo Women’s Medical University, Shinjuku-ku, Japan
  12. 12 Health Center, Kyoto University, Kyotoi, Japan
  1. Correspondence to Dr Hideyuki Sawada, Clinical Research Center and Department of Neurology, Utano National Hospital, Kyoto 6168255, Japan; sawada.unh{at}


Objectives Brain acetylcholine is decreased even in patients with cognitively preserved Parkinson’s disease (PD). We investigated whether early and long-term use of donepezil prevents psychosis in non-demented PD patients.

Methods A double-blinded, placebo-controlled trial was conducted. A total of 145 non-demented PD patients were randomly assigned to receive 5 mg/day donepezil (n=72) or placebo (n=73) for 96 weeks. Medications for PD were not restricted, but antipsychotic drugs were not permitted throughout the study. The primary outcome measure was survival time to psychosis that was predefined by Parkinson’s Psychosis Questionnaire (PPQ) B score ≥2 or C score ≥2. Secondary outcome measures included psychosis developing within 48 weeks, total PPQ score, Mini-Mental State Examination (MMSE), Wechsler Memory Scale (WMS) and subgroup analysis by apolipoprotein ε4 genotyping.

Results Kaplan-Meier curves for psychosis development were very similar between the two groups, and the Cox proportional hazard model revealed an adjusted HR of 0.87 (95%CI 0.48 to 1.60). The changes in MMSE and WMS-1 (auditory memory) were significantly better with donepezil than in placebo. In the subgroup analysis, donepezil provided an HR of 0.31 (0.11–0.86) against psychosis in 48 weeks for apolipoprotein ε4 non-carriers.

Conclusions Although donepezil provided beneficial effects on PPQ, MMSE and auditory WMS score changes in 2 years, it had no prophylactic effect on development of psychosis in PD. Apolipoprotein ε4 may suppress the antipsychotic effect of donepezil.

Trial registration number UMIN000005403.

  • donepezil
  • brain acetylcholinesterase
  • Parkinson's disease

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  • Correction notice Since this article was first published online the author Dr Kukuchi has been updated. The surname now reads Kikuchi.

  • Contributors HS had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: HS and TO. Acquisition of data: HS, TO, MK, AU, ST, KP, KM, HM, KH, HF, HS, MN and SK. Analysis and interpretation of data: HS, TO, MK, AU, ST, KP, KM, HM, KH, HF, HS, MN, SK, TF and SI. Drafting of the manuscript: HS and TO. Critical revision of the manuscript for important intellectual content: HS, TO, HF, MN and TK. Statistical analysis: HS, TO, MG and TK. Administrative, technical or material support: TF, KK and SI. Study supervision: HS, TO and SI.

  • Funding The study was registered with the University hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) (UMIN000005403) and the Pharmaceutical and Medical Devices Agency, Japan (#22-4018) and approved by the National Hospital Organization Central Review Board (NHO-CRB, Tokyo, Japan). The study was supported by a Grant for the Designated Clinical Research from the National Hospital Organization, Tokyo, Japan. Eisai Pharmaceutical Company supplied donepezil hydrochloride tablets (3 mg and 5 mg) and placebo tablets (3 mg and 5 mg) in the study. No salaries or stipends were paid. The trial drugs were donated by Eisai Pharmaceutical Company.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The National Hospital Organization Central Review Board, Tokyo, Japan (NHO-CRB).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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