The three established AD drugs are cholinesterase inhibitors (ChEIs; see ARF Live Discussion on cholinesterase inhibitors). By contrast, memantine—which won FDA approval last fall and is due in pharmacies next month (see ARF related news story)—is a low-affinity NMDA receptor antagonist that counteracts glutamine-mediated excitotoxicity. The fact that memantine and ChEIs work through separate neurotransmitter systems has raised hope that combination therapy might show either independent additive effects or synergistic effects, which could increase somewhat the modest benefit seen with one drug alone. Previously, a small open-label study had suggested this might be safe (Hartmann and Mobius, 2003), and further trials are ongoing.

The multicenter trial of 404 patients involved adding a six-month course of memantine to the drug regimen of people with moderate or severe AD who already were on stable doses of donepezil, as well as other drugs needed in these sick patients. Study participants were tested at baseline and every four weeks thereafter on cognitive, functional, and global outcomes. Tariot and colleagues report that adding memantine improved the patients’ performance on all primary and secondary outcome measures, which included several test batteries adapted for use in severely demented patients. More patients in the placebo-donepezil group than in the memantine-donepezil group dropped out due to side effects, indicating that the drug combination overall did not add further complications. There were differences on individual side effects, with more confusion and headaches, but less nausea, diarrhea, and incontinence, seen in the memantine than the placebo group.

The trial did not test different doses of memantine; all patients included in the analysis took 20 mg/d, the higher of two doses described in memantine’s FDA documents. It also did not include patients who were on rivastigmine or galantamine, the other two ChEIs. Therefore, this trial alone is insufficient to infer that memantine-ChEI combination therapy for AD is safe and effective in general, the authors note. An open-label extension of the current trial is gathering data on long-term consequences of this combination therapy; other trials are ongoing.—Gabrielle Strobel.

Reference:
Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I; Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004 Jan 21; 291(3): 317-24. Abstract