Treatment response

Cholinesterase inhibitors

In the first placebo-controlled trial of a cholinesterase inhibitor in patients with DLB, 120 patients were treated with rivastigmine (mean dose 7 mg) or placebo for 20 weeks [104]. The primary outcome measure was 30% improvement in a four-item subscore derived from the Neuropsychiatric Inventory (NPI) (delusions, hallucinations, apathy, depression); this was attained by 63% of people treated with rivastigmine and 30% of people treated with placebo, a significant difference on the observed case analysis. On the total NPI, there was a three-point advantage for the rivastigmine-treated patients. Significant improvements were seen in attentional performance on computerized tests, with a non-significant one-point advantage for the rivastigmine-treated patients on the MMSE. More recently, a multicentre trial included 140 patients with DLB, randomized to receive placebo or 3, 5, or 10 mg of donepezil daily for 12 weeks [105]. Donepezil demonstrated significant improvement in MMSE, attention/concentration on the revised Wechsler Memory Scale, and the Wechsler Adult Intelligence Scale (third edition) symbol digit test, but not in verbal fluency or visuoperceptual tests, in a dose-dependent fashion. Neuropsychiatric symptoms assessed by the NPI were also significantly improved, as was caregiver burden and global functioning. Symptoms of parkinsonism were more frequent in the 3- and 5-mg groups than in the placebo group, although the difference did not translate to changes in the mean Unified Parkinson's Disease Rating Scale (UPDRS) part III score. Additionally, some evidence exists for cognitive benefit in DLB patients with galantamine [106].

Two large randomized, placebo-controlled, trials have examined the effect of cholinesterase inhibitors in PD-D. In one, rivastigmine conferred benefit in comparison with placebo over 24 weeks of treatment in 541 patients with PD-D (allocated 2:1 rivastigmine:placebo) [107]. Over the treatment period, the rivastigmine-treated patients had a two-point advantage on the NPI, a one-point advantage on the MMSE, an almost three-point advantage on the Alzheimer’s Disease Assessment Scale—Cognition (ADAS-COG), and also superiority on more specialized assessment of attention and executive function, all differences being statistically significant. Additionally, post-hoc analyses revealed improved outcomes in basic activities of daily living (ADLs) and high-function ADLs [108]. Another trial randomized 550 PD-D patients to 5 or 10 mg of donepezil or placebo [109]: no difference was found in ADAS-COG mean changes in intention- to-treat population, but there were statistically significant differences in favour of donepezil in a post-hoc analysis removing the centre-effect. MMSE and tests of executive function and attention showed significant improvement with donepezil.

Although there are always limitations to the interpretation of comparisons of effect size across trials, the magnitude of benefit of cholinesterase inhibitor treatment in DLB and PD-D appears comparable between studies, and in DLB and PD-D [110]. There are no blinded studies that directly examine cholinesterase inhibitors in DLB and PD-D patients, but open-label trials also suggest that effect sizes and side effects are similar [111].

In both syndromes, sudden withdrawal of cholinesterase inhibitors may be detrimental, and this may be particularly pronounced in PD-D [112].

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