NEW ORLEANS (FRONTLINE MEDICAL NEWS)The combination of memantine and a cholinesterase inhibitor improved behavioral symptoms in patients with moderate-severe Alzheimer’s dementia, according to two pooled, post hoc analyses.

The combination not only significantly improved total scores on the Neuropsychiatric Inventory ( NPI ), but individual scores on agitation/aggression, elation/euphoria, emotional lability, and appetite, Suzanne Hendrix, Ph.D., reported in two posters presented at the annual meeting of the American Association for Geriatric Psychiatry.

The studies, sponsored by the Forest Research Institute, examined pooled data from five randomized, placebo-controlled trials; three of these were included in both analyses.

The first study comprised a total of about 1,250 patients with moderate-severe Alzheimer’s included in three placebo-controlled trials. The first randomized patients to 10 mg memantine or placebo plus donepezil. The second randomized to 20 mg memantine or placebo plus any existing cholinesterase inhibitor (ChEI). The third randomized to extended-release 28 mg memantine or placebo plus any existing ChEI. All were 24 weeks’ duration.

The primary outcome was change on the total NPI; the secondary outcomes were changes in individual subscores.

Patients were a mean age of 75 years. Total NPI scores ranged from 14 to 17; only 7%-14% had an NPI of 0.

By week 24, all memantine doses combined with ChEI had significantly outperformed ChEI alone on both the total NPI score and on the subscores for delusions, agitation/aggression, irritability/lability, and nighttime behaviors. The mean total score improvement was about 2.25 points.

When considering only those patients who were symptomatic at baseline, combination therapy also significantly outperformed ChEI alone in total NPI and on the subscores for agitation/aggression, irritability/lability, and appetite – all by about 0.5 points. Aberrant motor behavior improved by a nearly statistically significant amount with a P value of .051.

The second analysis comprised about 1,800 patients with moderate-severe disease. Its primary endpoint was change agitation among the subset of patients who did not display this symptom or who displayed clinically insignificant symptoms (474 with NPI 1, 2, or 3; 596 with NPI 1, 2, 3, or 4). It included the previous three trials, plus two more, both of which randomized to 10 mg memantine twice a day or placebo. Patient characteristics were similar in all the studies. Comparisons were made between combination therapy, placebo plus ChEI, and placebo only.

By week 12, mean agitation/aggression scores were unchanged in those on combination therapy and nonsignificantly worse for those taking either memantine alone or ChEI alone. Agitation/aggression scores had worsened by almost 0.6 points among those taking placebo – a significant difference from combination therapy.

By the end of the studies, the mean score among those with NPI scores of 1-3 who took combination therapy actually had improved significantly from baseline (about 0.5 points). Patients taking either monotherapy remained unchanged, while those taking only placebo worsened by almost a full point.

Findings were similar among those with NPI scores of 1-4. By the end of the studies, those taking combination therapy experienced a mean improvement of almost 1 point, while those taking placebo worsened by a mean of 0.6 points. Scores in the monotherapy groups remained unchanged.

Given the expected worsening of agitation and aggression as AD progresses, the results suggest a clinical benefit of memantine when added to existing cholinesterase inhibition, Dr. Hendricks said.

“This argues for the potential benefit of earlier addition of memantine. This may in turn prevent the expected worsening of agitation/aggression, delay considerably additional diagnoses, and also delay the introduction of other medications.”

The Forest Research Institute supported the analysis. Dr. Hendricks is president of the Pentara Corp., which consults with pharmaceutical companies and nonprofit or academic groups in Alzheimer’s disease clinical study design and analysis. On Twitter @alz_gal