All patients included in this trial were on the acetylcholinesterase inhibitor, donepezil, and previous reports indicate that acetylcholinesterase inhibitors reduce behavioral abnormalities in patients with AD.20
Some patients with AD may not experience sustained clinical benefit from acetylcholinesterase inhibitor treatment owing to “lack-of-benefit” or “loss-of-response” after long-term treatment or tolerance issues. Therefore, changing acetylcholinesterase inhibitor therapy may benefit patients with AD who initially respond to acetylcholinesterase inhibitor treatment but then experience a decline in cognition, behavior, or activities of daily living, or who experience persistent adverse events.22
No adverse effects of the study drugs, such as nausea and vomiting, were reported in the Galantamine Switch study. In the DIAM study, only one patient (6.3%) in the donepezil increase group and two patients (11.8%) in the additional memantine group discontinued the study due to adverse drug effects. The incidence of adverse effects reported was less frequent than previously reported in patients receiving memantine alone.6
Donepezil and galantamine are widely used to slow the rate of cognitive and behavioral decline in patients with AD. These agents have the same mechanism of action, but galantamine also has allosteric-modulating activity at nicotinic receptors.5
Galantamine is effective and safe in patients with AD, regardless of previous exposure to acetylcholinesterase inhibitors. In a previous study, patients who were taking galantamine and had been previously exposed to an acetylcholinesterase inhibitor achieved significant improvements in cognition compared with those who received placebo.23
The sample size of the current study was limited, so no differences were seen for cognitive improvements from baseline. However, this study did demonstrate a reduction in agitation on the CMAI in the group that switched from donepezil to galantamine. The CMAI consists of 29 agitation behavior items with a total score in the range of 0–203; therefore, this scale is well suited for discriminating small changes in agitation behavior. The NPI also includes an agitation domain, but the scoring range is small (severity 0–3, frequency 0–4) and did not show any differences compared with baseline and when the two groups were compared. Similarly, Howard et al24
used the CMAI in patients with AD and reported that donepezil treatment for 12 weeks was not more effective than placebo for the treatment of agitation. Therefore, the results of this study suggest that switching from donepezil to galantamine is beneficial for improving agitation in patients with AD.
Galantamine is a rather weak acetylcholinesterase inhibitor, but has additional allosteric potentiating effects at nicotinic receptors. This allosteric potentiation contributes not only to neuronal protection against several neurotoxic stimuli but also to enhanced release of neurotransmitters, including dopamine, noradrenaline, glutamate, and γ-aminobutyric acid. In patients with AD, a positive correlation has been seen between aggressive behavior and magnitude of cell loss in the rostral locus coeruleus.25
The locus coeruleus is the major nucleus of origin of noradrenergic fibers in the mammalian brain. Therefore, galantamine-induced allosteric potentiation at nicotinic receptors may result in suppression of agitation.
have reported that for patients with AD, addition of memantine to an established donepezil regimen resulted in better outcomes for cognition and activities of daily living, compared with placebo. Further, addition of memantine reduced agitation, irritability, and appetite/eating disturbances, as measured by the NPI. Memantine reduced agitation in patients who were agitated at baseline and delayed the emergence of agitation in those who were free of agitation at baseline. Data from the current study demonstrated a reduction in agitation in the additional memantine group compared with the donepezil increase group, using both the CMAI and NPI scales. The mechanism by which memantine produces psychotropic benefits is not clear. It is hypothesized that memantine blocks the excitotoxicity associated with chronic low-level glutamate stimulation.28
Glutamate excitotoxicity has been associated with the tau hyperphosphorylation required in the production of neurofibrillary tangles and is thought to be a significant executioner pathway. Neurofibrillary tangles have been linked to frontal lobe dysfunction and agitation,29
so it is likely that, through a decrease in glutamate toxicity and tau deposition, memantine would have an effect on frontally mediated behaviors.
The results of this study must be viewed in light of its limitations. This study was limited by small sample sizes. Previous reports have demonstrated the cognitive benefits of switching to galantamine from donepezil and the addition of memantine to donepezil.9
The current results demonstrated an improvement in suppression of agitation in patients in both the Galantamine Switch and DIAM studies, but improvements in cognition compared with baseline were not demonstrated.
Behavior symptoms in patients with AD increase the direct costs of care. For example, a one-point increase in the NPI score was calculated to be equivalent to an increased cost of $247–$409 in total annual direct costs.31
Therefore, the addition of memantine to established therapy is an effective way to suppress agitation compared with an increase in the donepezil dose. In summary, switching to galantamine from donepezil and addition of memantine in patients with AD receiving donepezil were both safe and meaningful treatment options, and particularly efficacious for suppression of agitation.