Early use of donepezil against psychosis and cognitive decline in Parkinson's disease: a randomised controlled trial for 2 years

Abstract

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.

Keywords: Parkinson's disease; brain acetylcholinesterase; donepezil.

Figure 1

Flow diagram of the patient recruitment process.

Figure 2

Primary (A and B) and secondary outcome (C–E) measures. (A) The survival curves of psychosis-free patients in the donepezil and placebo groups are shown. The number below the horizontal axis shows the number of patients at risk. Censored case is indicated as vertical lines. (B) HR of psychosis was expressed as a mean with 95% CIs. The horizontal axis has a logarithmic scale. (C) Score changes of PPQ from baseline at V9, V15, V21 and V27, secondary outcomes. Data are expressed as mean and SD. There was a statistically significant difference between donepezil and placebo (p=0.004, GEE). (D) Changes in ESS scores from baseline at V9, V15, V21 and V27, secondary outcomes, expressed as mean and SD. There was a statistically significant difference (p=0.042, GEE). (E) Changes in MMSE from baseline at V9, V15, V21 and V27, secondary outcomes, expressed as mean and SD. There was a statistically significant difference (p=0.032, GEE). (F) Changes in WMS-1 (auditory memory) at V9, V15, V21 and V27, secondary outcomes, expressed as mean and SD. There was a statistically significant difference (p=0.029, GEE). ESS, Epworth Sleepiness Scale; GEE, generalised estimating equation; mH-Y, modified Hoehn-Yahr; MMSE, Mini-Mental State Examination; PPQ, Parkinson’s Psychosis Questionnaire; WMS, Wechsler Memory Scale.

Figure 3

Subgroup analysis by apolipoprotein ε4 (Apo E4) allele. (A and B) Kaplan-Meier curves of psychosis-free patients (A) without ε4 and (B) with the ε4 allele. The curves separate at 48 weeks in the ε4 (−) subgroup but not in the ε4 (+) subgroup. (C and D) Cox proportional hazard models for psychosis development in 48 weeks in patients (C) without ε4 and (D) with the ε4 allele. There was a statistically significant difference between donepezil and placebo groups in the ε4 (−) subgroup (HR=0.31 (95% CI 0.11 to 0.86), p=0.02), but not in the ε4 (+) subgroup (HR=0.85 (95% CI 0.192 to 3.78), p=0.84). (E and F) Changes in total PPQ scores in patients (E) without ε4 and (F) with the ε4 allele. There was a statistically significant difference between donepezil and placebo groups in the ε4 (−) subgroup (p=0.001) but not in ε4 (+) subgroup. (G and H) Change in ESS scores in patients (G) without ε4 and (H) with the ε4 allele. There was a statistically significant difference between donepezil and placebo groups in the ε4 (−) subgroup (p=0.027) but not in ε4 (+) subgroup. ESS, Epworth Sleepiness Scale; mH-Y, modified Hoehn-Yahr; PPQ, Parkinson’s Psychosis Questionnaire.

Figure 4

Changes in UPDRS-III scores and L-Dopa equivalent dose of dopaminergic replacement therapy (LDED). (A) In the donepezil group, UPDRS-III scores were transiently elevated by starting and dose escalation (3–5 mg/day) of donepezil, but then returned to baseline and remained stable. In the placebo group, the scores were stable. There were no statistically significant differences in UDPRS-III changes between donepezil and placebo groups. (B) Dopaminergic drug doses were elevated gradually in both donepezil and placebo groups and were slightly larger with donepezil than with placebo. The difference was not statistically significant. Data represent the mean with 95% CIs.