N-methyl-D-aspartate (NMDA) antagonists and dopaminergic drugs

The NMDA antagonist memantine is approved for the treatment of moderate to severe AD. Conflicting results have been described in the few case reports or case series in patients with DLB, reporting both worsening or improvement in equal measure [30, 31]. Three double-blind, randomized controlled studies comparing memantine with placebo have been reported. The first, a study of 22 weeks’ duration, included 25 patients with PD-D [32]. At the end of the study there were no significant differences between the two groups on any efficacy parameters; however, 6 weeks after withdrawal more patients who had been treated with memantine deteriorated on a global scale (p = 0.04), suggesting that they had had some beneficial effects while being treated. The second study lasted 24 weeks and included 72 patients with either PD-D or DLB of mild to moderate severity randomized either to memantine 20 mg daily or placebo. [33]. The primary end point, the CGIC score was significantly in favour of memantine (p = 0.03) and the effect was stronger in the PD-D group. Except for the improved speed in an attentional task in the memantine group, there were no other significant differences in secondary outcome measures between the two groups. The treatment was well tolerated with similar withdrawals in both groups.

In another study of similar design, 199 patients with mild to moderate PD-D or DLB were randomized either to memantine 20 mg once daily given in the morning or placebo. The mean CGIC score was lower (better) in the total population on memantine treatment, but this difference was not statistically significant except in the DLB group who also showed a statistically significant improvement in total NPI score at 24 weeks compared with patients treated with placebo. There were no consistent effects of memantine on cognitive tests, nor on ADL scores in either PD-D or DLB [34].

Taken together these latter two trials suggest a possible benefit of memantine in patients with Lewy body dementias but there is no consistent message as to which patients might benefit (DLB or PD-D) or which symptoms might improve. There were minor differences in the trial populations, most notably the use of ChE-Is in the former but not the latter study, but these are likely insufficient to explain the variable results. A more plausible explanation is that there is considerable heterogeneity within both DLB and PD-D groups, with different patterns of response in different individuals which are not adequately captured by a pooled-group design. The same response heterogeneity is also seen with antipsychotics and ChE-Is and argues that individual case studies or responder analysis might prove better ways of determining treatment effects in the Lewy body dementias.

The effects of dopaminergic treatment on mental functions have barely been studied in patients with PD-D, most formal studies having been performed in patients without dementia. The results have been equivocal, describing either no effects or improvement in some and worsening in other functions. In one of the few studies which specifically included patients with dementia, subjects with PD, PD-D, or DLB were tested for cognitive functions and behavioural symptoms after acute levodopa challenge and following 3 months of treatment. After acute challenge, patients reported improvement in subjective alertness, but fluctuations increased; reaction time and accuracy remained unchanged in those with PD-D. After 3 months of treatment neuropsychiatric scores improved in both PD and PD-D, mean global cognitive score was better, but attention and memory scores were worse in PD patients without dementia. Reaction time became slower in those with PD-D, but no patients showed a marked deterioration [35].

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