• Hideyuki Sawada, Tomoko Oeda, Masayuki Kohsaka, Atsushi Umemura, Satoshi Tomita, Kwiyoung Park, Kouichi Mizoguchi, Hidenori Matsuo, Kazuko Hasegawa, Harutoshi Fujimura, Hiroshi Sugiyama, Michikazu Nakamura, Seishi Kikuchi, Kenji Yamamoto, Toshiaki Fukuda, Suminobu Ito, Masashi Goto, Kosuke Kiyohara, and Takashi Kawamura.
• Clinical Research Center and Department of Neurology, Utano National Hospital, Kyoto, Japan sawada.unh@gmail.com.
• J. Neurol. Neurosurg. Psychiatr. 2018 Dec 1; 89 (12): 133213401332-1340.

ObjectivesBrain 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.MethodsA 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.ResultsKaplan-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.ConclusionsAlthough 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 NumberUMIN000005403.© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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