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

Abstract

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.

Effect of biological treatments on psychotic symptoms in lewy body disease: A systematic review and meta‐analysis of randomized controlled trials

“…Forty‐four full‐text articles were retrieved and assessed for eligibility but 25 were excluded due to the behavioral and psychological measure being of a more general nature and not specific to psychosis (n = 11), 15‐25 having no placebo control (n = 10), 26‐35 and having a sample size < 20 (n = 4) 36‐39 . This resulted in 19 trials 40‐58 meeting eligibility for inclusion. Four of these 55‐58 did not report data suitable for inclusion in the quantitative analyses, resulting in 15 trials and 16 datasets (Breier et al 40 reported results from two trials conducted in the United States and Europe) available for meta‐analysis.…”

“…Most studies were conducted in the United States or the United Kingdom/Europe. The mean age of participants was over 70 years of age in all but three trials 46,47,53 . The choice of intervention varied, with most trials using an antipsychotic medication (n = 12) 40,42,43,45‐52,54 or an acetylcholinesterase inhibitor (n = 2) 41,53 .…”

“…The mean age of participants was over 70 years of age in all but three trials 46,47,53 . The choice of intervention varied, with most trials using an antipsychotic medication (n = 12) 40,42,43,45‐52,54 or an acetylcholinesterase inhibitor (n = 2) 41,53 . One trial investigated the role of transcranial direct current stimulation (tDCS) in 40 individuals with DLB over 5 days compared with control, but did not find a favorable effect after 1 and 3 months 44 .…”

“…The most frequently used rating scale was the Scale for the Assessment of Positive Symptoms, 43,45‐48 followed by the Brief Psychiatric Rating Scale (BPRS), 40,50,52,54,57 and the Neuropsychiatric Inventory (NPI) 41,42,44 . Trial durations ranged from as little as 5 days 44 to 96 weeks 53 …”

Current treatment of behavioral and cognitive symptoms of Parkinson's disease

“…Patients with PD dementia and visual hallucinations had better effects from rivastigmine than those without visual hallucinations [122]. However, a recently published randomized double-blind study that evaluated the early use of another cholinesterase inhibitor, donepezil (5 mg per day), in 145 non-demented PD patients during a two-year period did not prove any prophylactic effect of the drug on development of psychosis in PD [123]. Significant improvements in visual hallucinations during memantine treatment was reported for DLB but not PDD [124,125].…”