Donepezil Shows No Effect on Development of Psychosis in Parkinson


The results suggest that early use of donepezil may be efficacious against cognitive decline but not for the prophylaxis of psychosis.

Dr Atsushi Umemura

Despite showing beneficial effects on 2-year score changes for multiple questionnaire measures, donepezil had no preventive impact on psychosis development in patients with Parkinson disease.

Findings in the Journal of Neurology, Neurosurgery, and Psychiatry have suggested that apolipoprotein E4 (APOE4) may be suppressing the antipsychotic effect of the therapy.1 In the analysis, the researchers assessed outcome measures in subgroups according to the E4 allele, which 37 patients possessed total.

Lead author Hideyuki Sawada, MD, PhD, the Deputy Medical Director and Chair of the Department of Neurology at Utano National Hospital in Kyoto, Japan, said the result was surprising, and that, as previous reports have shown psychosis improvements with donepezil, he and his colleagues expected positive prophylactic effects.2

Conducted by Sawada and a team including Atsushi Umemura, MD, PhD, the double-blind, placebo-controlled trial included 145 patients with Parkinson disease without dementia, randomized 1:1 to either donepezil hydrochloride (n = 72) or placebo (n = 73). In total, 34.4% (n = 21) and 25% (n = 16) of each group had APOE4, respectively. In both groups, there were 25 patients with a history of psychosis.

By the end of the trial, 46 patients had developed predefined psychosis. There was no statistically significant difference between the donepezil and placebo groups for this outcome, with a hazard ratio (HR) for psychosis of 0.87 (95% CI, 0.48 to 1.60).

When divvying patients by APOE4, Kaplan-Meier curves split at 48 weeks and joined at 96 weeks. Hazard models displayed a prophylactic effect (HR, 0.31; 95% CI, 0.11 to 0.86; P = .02) against the development of psychosis at 48 weeks in for those without APOE4, though the difference was no longer significant at 96 weeks (HR, 0.63; 95% CI, 0.28 to 1.141; P = .26). Those with APOE4 did not display this difference (HR, 0.85; 95% CI, 0.192 to 3.78; P = .84)

The change in Epworth Sleepiness Scale (ESS) was significantly greater for those in the donepezil group without APOE4 (P = .027), but not for those with APOE4. This was similar with Parkinson’s Psychosis Questionnaire (PPQ) scores, which also displayed significant differences between placebo and donepezil groups (P = .001) for those without APOE4, but not with APOE4. For APOE4 carriers, the adjusted HR was 0.85 (95% CI, 0.19 to 3.79; P = .84) for those on donepezil and 0.86 (95% CI, 0.23 to 3.32; P = .83) for those given placebo for psychosis in 48 and 96 weeks, respectively.

These data, Sawada and colleagues noted, suggest that APOE4 carriers may be more likely to have comorbid amyloid burden causing a cortical dysfunction which prevented the therapy from being as effective as it was in previous cases. They also acknowledged that those who carry APOE4 have been found to have a higher risk of hallucinations and development of dementia, though that association is considered controversial.

With regard to safety, the therapy appeared relatively well tolerated. "Visual hallucinations, auditory hallucinations, or delusions were observed in about 40% of patients with non-demented Parkinson's disease in 2 years," Sawada told Reuters Health.2

Sawada added that physicians should look at the condition of patients and pay attention specifically to detect psychotic symptoms. As systemic inflammation or trigger medications, such as amantadine, dopaminergic antagonists, or anticholinergic drugs can cause psychosis, checking for these factors at the presentation of hallucinations is paramount.

“Although the effects of donepezil, at least at 5 mg/day, were weak and inadequate to provide prophylaxis against the development of psychosis in patients with PD, early use of donepezil improved the scores for PPQ, MMSE and auditory WMS significantly for 2 years in cognitive preserved patients, without worsening of motor symptoms. These results suggest that early use of donepezil may be efficacious against cognitive decline but not for prophylaxis of psychosis,” Swada and colleagues wrote.


1. Sawada H, Oeda T, Kohsaka M, et al. Early use of donepezil against psychosis and cognitive decline in Parkinson’s disease: a randomized controlled trial for 2 years. J Neurol Neurosur PS. Epub August 3, 2018. doi: 10.1136/jnnp-2018-318107.

2. Boggs W. Donepezil slows cognitive decline, does not ward off psychosis in Parkinson's. Psych Congress Network. Published September 27, 2018. Accessed September 28, 2018.

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