Donepezil for dementia in Parkinson’s disease: a randomized, double blind, placebo controlled, crossover study
Ravina B, Putt M, Siderowf A, Farrar JT, Gillespie M, et al.;
Commented by , 26 Jul 2005
Aim of the study
To study the safety and efficacy of the cholinesterase inhibitor donepezil for the treatment of Parkinson’s disease associated dementia (PDD).
Method
Placebo-controlled, cross-over study with randomization to donepezil 5-10mg/day or placebo for 10 weeks, washout period of 6 weeks, then alternative treatment. The primary outcome was the Alzheimer’s disease Assessment Scale cognitive subscale (ADAS-cog).
Secondary outcome measures included the Mini Mental State Examination (MMSE), the Mattis Dementia Rating Scale (MDRS), the Clinical Global Impression of Change (CGIC), the Brief Psychiatric Rating Scale (BPRS), the United Parkinson’s Disease Rating Scale (UPDRS).
Results
Twenty-two subjects were enrolled and 19 completed the study. The 1.9 point difference in ADAS-cog was not statistically significant (p=0.18). The MMSE score difference of 2 points was significant (p=0.0044), as well as the CGIC difference of 0.37 (p=0.0056) in favor of donepezil. There was no difference in MDRS, BPRS and UPDRS. Carryover between treatment periods was observed but was not statistically significant. Overall tolerability was not different between donepezil and placebo.
Professor Gauthier's comments
Cholinesterase inhibitors such as rivastigmine have been found to be useful and safe in the treatment of cognitive, functional and behavioral symptoms associated with PDD (ref. 1).
The NMDA antagonist memantine has been found to be useful in the treatment of some of the motor symptoms of PD using a cross-over design (ref. 2).
It was thus logical to test donepezil in PDD using the cross-over design. Unfortunately this design has been found to be less useful than the parallel group design in neurodegenerative conditions such as Alzheimer’s disease (AD), predominantly because of carryover effects and the progression of the underlying condition over time that will change baselines at the start of each of the treatment periods (ref. 3).
The choice of outcomes in PDD, Dementia with Lewy Bodies and vascular dementia studies has been greatly influenced by instruments used in AD clinical trials, which are more sensitive to memory and language that executive function, the latter being more relevant to non-AD dementias (ref. 4).
Nevertheless the ADAS-cog and the CGIC have proven sensitive to improvement in these conditions in most of the published studies in non-AD dementias. There is no doubt that a larger sample in this study would have led to a statistically significant difference in ADAS-cog.
References
1. Emre et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med 2004; 351; 2509-2518 (Note: Free full text article) Read also Professor Emre's own summary of this study here on CNSforum.
2. Merello et al. Effect of memantine (NMDA antagonist) on Parkinson's disease: a double-blind crossover randomized study. Clin Neuropharmacol 1999; 22; 273-276
3. Gauthier et al. Tetrahydroaminoacridine-lecithin combination treatment in patients with intermediate-stage Alzheimer's disease. Results of a Canadian double-blind, crossover, multicenter study. N Engl J Med 1990; 322; 1272-1276
4. Cummings. Cholinesterase inhibitors for treatment of dementia associated with Parkinson's disease. J Neurol Neurosurg Psychiatry 2005; 76; 903-904