Psychopharmacology Research Tutorial

Memantine for Dementia-Related Aggression

Consultant, Worldwide Drug Development

First published in Psychiatry Weekly, Volume 3, Issue 23, on June 23, 2007

Memantine, a N-methyl-d-aspartate (NMDA) receptor antagonist, is the first of a new class of agents for the treatment of Alzheimer’s disease that acts on the glutamatergic system. It is approved for treatment of patients with moderately severe and severe Alzheimer’s disease.

Memantine acts as a non-competitive, low potency antagonist at NMDA receptors and inhibits prolonged influx of calcium ions, causing neuronal excitotoxicity. In general, memantine therapy is well tolerated clinically because it has low potency as an NMDA receptor antagonist and differs from treatment with the more potent NMDA antagonists, which offer neuroprotective effects but often have unacceptable side effects.

Memantine treatment produces improvement in multiple domains, including global, cognitive, functional, and behavioral. A recent retrospective meta-analysis of pooled data from the efficacy trials examines outcomes in patients with agitation, aggression, or psychosis before trial entry. Patients who scored =1 on any of three Neuropsychiatric Inventory (NPI) items assessing agitation/aggression, delusions, or hallucinations within 4 weeks of entry into the trial were analyzed separately. Of the 983 patients in the total study population, 593 (60%) manifested agitation, aggressive behavior, or psychosis prior to treatment (placebo=287, memantine=306). This subgroup with pre-existing behavioral symptoms resembled the overall patient sample in demographics, Mini-Mental Status Exam scores, and symptom severity (except for NPI score).

Across the trials, 454 patients had pre-existing agitation/aggression, 336 delusions, and 172 hallucinations. Improvement on the NPI behavioral symptom cluster was significantly better with memantine than with placebo treatment at both 3 months (P=.0014) and 6 months (P=.0004). At 6 months, memantine treatment showed significant benefit compared with placebo on measures of cognition (P<.001), activities of daily living (P<.001), and clinician/caregiver impression of change in clinical status (P<.001). In addition, memantine treatment was tolerated better than placebo treatment, with fewer discontinuations from the study treatment over the 6 months. The incidence of withdrawals due to agitation and psychosis among placebo-treated patients was 3-fold higher than with memantine treatment (7.5% versus 2.6%, respectively, P<.01).

For patients randomized to placebo treatment in the trials, behaviorally disturbed patients at trial entry experienced significantly greater decline in clinical status and activities of daily living than placebo-treated patients without pre-existing symptoms. For those patients with neither prior agitation/aggressive behavior or psychosis, significantly fewer memantine-treated patients (P<.01) went on to develop behavioral symptoms during the 6 months of treatment compared with placebo, indicating preventive benefit with memantine therapy.

Conclusion

Although safety concerns about increased mortality and stroke, and changes in product labeling have tempered their use, antipsychotics remain the mainstays of drug therapy for these symptoms of dementia in the elderly. As for memantine, a pooled analysis of efficacy trials indicates that it is superior to placebo for treating and preventing behavioral symptoms in Alzheimer’s disease patients. The therapeutic benefit, however, appears to be modest.

Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, CeNeRx, Epix, Genaissance, Johnson and Johnson, PGxHealth, Phizer, Schering Plough, Somerset, and Takeda.