Effects of Donepezil on Extrapyramidal Symptoms in Patients with Dementia with Lewy Bodies: A Secondary Pooled Analysis of Two Randomized-Controlled and Two Open-Label Long-Term Extension Studies

Abstract

Background/Aims: The aim of this study was to clarify the effects of donepezil on extrapyramidal symptoms in patients with dementia with Lewy bodies (DLB). Methods: Using pooled datasets from phase 2 and 3, 12-week randomized, placebo-controlled trials (RCT, n = 281) and 52-week open-label long-term extension trials (OLE, n = 241) of donepezil in DLB, the effects of donepezil on the incidence of extrapyramidal adverse events (AEs) and on the Unified Parkinson's Disease Rating Scale (UPDRS) part III were assessed, and potential baseline factors affecting the AEs were explored. Results: The RCT analysis did not show significant differences between the placebo and active (3, 5, and 10 mg donepezil) groups in extrapyramidal AE incidence (3.8 and 6.5%, p = 0.569) and change in the UPDRS (mean ± SD: -0.2 ± 4.3 and -0.6 ± 6.5, p = 0.562). In the OLE analysis (5 and 10 mg donepezil), the incidence did not increase chronologically; all AEs leading to a dose reduction or discontinuation except one were relieved. The UPDRS was unchanged for 52 weeks. An exploratory multivariate logistic regression analysis of the RCTs revealed that donepezil treatment was not a significant factor affecting the AEs. Baseline severity of parkinsonism was a predisposing factor for worsening of parkinsonism without significant interactions between donepezil and baseline severity. Conclusion: DLB can safely be treated with donepezil without relevant worsening of extrapyramidal symptoms, but treatment requires careful attention to symptom progression when administered to patients with relatively severe parkinsonism.

Increased plasma donepezil concentration improves cognitive function in patients with dementia with Lewy bodies: An exploratory pharmacokinetic/pharmacodynamic analysis in a phase 3 randomized controlled trial

“…Although ChEI treatment can theoretically worsen extrapyramidal symptoms, the UPDRS part III scores were not significantly associated with the plasma donepezil concentration in the present analysis. This suggests that increasing the donepezil dose to 10 mg/day would not necessarily exacerbate parkinsonism, as shown previously [9,11,29]. Although no correlation between plasma concentration and worsening of parkinsonism was not demonstrated, it is still important to observe parkinsonism during donepezil treatment in these patients.…”

Adequacy of Using Consensus Guidelines for Diagnosis of Dementia with Lewy Bodies in Clinical Trials for Drug Development

“…The protocols were approved by the institutional review board at each participating centre. The results of the studies have previously been reported [12,13,14,15,16]. …”

“…We have previously conducted 3 clinical trials [12,13,14,15,16] on donepezil for DLB including 2 RCTs [12,14] that enrolled a total of 281 patients diagnosed with probable DLB according to the original consensus criteria [2]. These studies were conducted 3 years apart.…”

Repeated Intrastriatal Botulinum Neurotoxin-A Injection in Hemiparkinsonian Rats Increased the Beneficial Effect on Rotational Behavior

“…Although donepezil was shown as beneficial with respect to cognition in mild to moderate dementia [ 80 , 81 , 82 , 83 ], and also moderate dementia with Parkinson’s disease, donepezil therapy did not change motor PD symptoms [ 84 , 85 ]. Furthermore, donepezil treated dementia with Lewy body, without relevant worsening of extrapyramidal symptoms [ 86 ]. However, others stated that donepezil treatment could cause adverse motor effects in a subset of patients with parkinsonian dementia [ 87 , 88 , 89 , 90 ]; worsened activities of daily living mobility in patients with progressive supranuclear palsy [ 91 ]; and deteriorated motor behavior in patients with dystonic reactions [ 92 ].…”