Thirteen studies were included in the review; five RCTs (three blinded (1,059 patients), two open label (433 patients)), four open-label non-RCTs (314 patients), and four cohort studies (1,082 patients). One blinded RCT was at low risk of bias, the remaining two blinded RCTs had undetermined risk. The six open label studies were all at high risk of bias.
Completion rates in the blinded RCTs ranged between 74% and 89.4%. Completion rates in the open label studies ranged between 64% and 95.3%. Drop-out rates were reported in two of four cohort studies and ranged from 21% to 34%.
Cognitive function (three blinded RCTs): Only subgroup analyses in moderate to severe patients showed statistically significant improvements in cognitive function when combination therapy was used compared to both memantine (SMD 0.52, 95% CI 0.35 to 0.69; two RCTs; I²=0%) and donepezil (SMD 0.45, 95% CI 0.27 to 0.63; two RCTs; I²=5%).
Functional outcomes (three blinded RCTs): Combination therapy statistically significantly improved functional outcomes in mild to severe patients when compared to donepezil monotherapy (SMD 1.07, 95% CI 0.26 to 1.89; three RCTs; I²=0%).
Behavioural outcomes (three blinded RCTs): The authors stated that there were no statistically significant differences between treatment groups across mild to severe patients. However, forest plots suggested that combination therapy compared to donepezil showed a small but statistically significant improvement (SMD 3.00, 95% CI 0.22 to 5.78; three RCTs; I²=79%). Subgroup analyses showed that combination therapy statistically significantly improved behavioural outcomes in patients with moderate to severe Alzheimer's Disease compared to monotherapy with memantine (SMD 3.7, 95% CI 1.98 to 5.43; two RCTs; I²=0%) or donepezil (SMD 4.40, 95% CI 3.01 to 5.79; two RCTs; I²=0%).
There were no statistically significant differences between treatment groups for global outcomes (two blinded RCTs), quality of life (one blinded RCT) or adverse events.
Three of six open-label studies and four cohort studies suggested benefit with combined therapy.