Abstract
Objective: To evaluate the effect of memantine added to cholinesterase inhibitors (ChEIs) on agitation, other neuropsychiatric symptoms, and related caregiver burden in patients with Alzheimer’s disease (AD) experiencing agitation. Background: Agitation, a common, problematic neuropsychiatric symptom associated with AD, can increase caregiver burden and costs. Memantine and its extended-release formulation are approved for moderate-to-severe AD; ChEIs are additionally approved in mild AD. Previous studies suggest that ChEIs, memantine, and memantine added to ChEIs provide benefits for neuropsychiatric symptoms in AD. Design/Methods: Data were pooled from three phase 3, randomized, double-blind, placebo-controlled 24-week trials evaluating memantine for patients with moderate-to-severe or mild-to-moderate AD receiving concurrent ChEIs. Inclusion for these analyses required Neuropsychiatric Inventory-agitation (NPI-agitation) scores >0 at baseline or end-of-treatment. A mixed-effect repeated-measure model evaluated least squares mean differences (LSMD) between groups on NPI-agitation and NPI Caregiver Distress-agitation (NPI-D-agitation), as well as total and subdomain scores, from baseline to weeks 12 and 24, with alpha 0.05. Effect sizes were estimated with Cohen’s d. Results: Of 1140 patients, 532 had symptomatic agitation and were analyzed (mean age±SEM 76.10±0.349 years; mean baseline MMSE±SEM 10.83±0.137): 269 placebo/ChEIs, 263 memantine/ChEIs. Memantine/ChEIs significantly improved NPI-agitation at weeks 12 (P=0.0003; d,−0.3193) and 24 (P=0.0001; d, −0.3554) compared with placebo/ChEIs. Similar between-group effects were observed for NPI-D-agitation at week 12 (P=0.0067; d, −0.3346) and week 24 (P=0.0147; d,−0.3126). Congruent benefits of memantine were observed for NPI total score (week 12: P=0.0003; d,−0.3174; week 24: P=0.0004; d,−0.3213), NPI-delusion (week 12: P=0.0217; d,−0.2016; week 24: P=0.0365; d,−0.1913), NPI-D-delusion (week 12: P=0.0191; d,−0.2894), NPI-irritability/lability (week 12: P=0.0001; d,−0.3400; week 24: P=0.0013; d,−0.2933), NPI-D-irritability/lability (week 12: P=0.0109; d,−0.3152), and NPI-anxiety and NPI-apathy/indifference (week 24: P=0.0400; d,−0.1875; P=0.0127; d,−0.2287). Conclusions: Memantine added to ChEIs may substantially reduce agitation and other behavioral disturbances in AD patients who experience agitation, and also may reduce caregiver burden related to these symptoms.