Rivastigmine monotherapy and combination therapy with memantine in patients with moderately severe Alzheimer’s disease who failed to benefit from previous cholinesterase inhibitor treatment T. DANTOINE, 1 S. AURIACOMBE, 2 M. SARAZIN, 3 H. BECKER, 4 J-J PERE, 5 I. BOURDEIX 5 De ´partement de Ge ´rontologie Clinique, 1 CHU Limoges, Service de Neurologie, 2 Ho ˆpital Pellegrin Tripode, Bordeaux, Ho ˆpital de Jour Psycho-ge´riatrique, 3 CHU Bretoneau, Paris, Ho ˆpital Pierre Nouveau, 4 Cannes, Novartis Pharma SAS, 5 Rueil-Malmaison, France SUMMARY We investigated the efficacy and safety of rivastigmine alone and combined with memantine in Alzheimer’s disease patients previously failing on donepezil or galantamine. This was a prospective, open-label, multicentre study. After stopping donepezil or galantamine, patients received rivastigmine 3–12 mg/day for 16 weeks. Non-responders to rivastigmine monotherapy at week 16 received meman- tine 5–20 mg/day plus rivastigmine for 12 weeks. The primary efficacy parameter was response (Mini-Mental State Examination equal or better than at week 16) to dual therapy at week 28. Secondary criteria were changes on cognitive and behavioural scales. Two hundred and two patients were included. Ninety-three (46.3%) patients responded to rivastigmine monotherapy. Of 86 patients receiving additional mem- antine for another 12 weeks, 67 (77.9%) responded. Combination therapy caused no apparent safety concerns. When patients fail on donepezil or galantamine, switching to rivastigmine may improve cognition and behaviour. Should they continue to deteriorate, the addition of memantine may be beneficial. Keywords: Cognitive decline; Alzheimer’s disease; rivas- tigmine; memantine; anticholinesterase drugs switch Ó 2006 Blackwell Publishing Ltd INTRODUCTION Alzheimer’s disease (AD) is characterised by progressive decline in neurocognitive functioning. Currently, two classes of drugs are recommended for the symptomatic treatment of AD, each targeting a different neurochemical component thought to underlie the condition. The rationale for the development of cholinesterase inhibitors was the now well- known ‘cholinergic hypothesis’ (1) that the progressive loss of cholinergic neurones seen in the AD brain, and the resulting decline in levels of the neurotransmitter, acetylcholine, corre- lates with cognitive decline. In addition, it has been shown that, in AD, continuous stimulation of N-methyl-D-aspartate (NMDA) receptors by glutamate triggers a cascade of bio- chemical events that damage and kill surrounding neurones. This formed the rationale for developing NMDA receptor antagonists for the treatment of AD (2). The cholinesterase inhibitors are widely recommended for the treatment of mild to moderate AD (3,4). Although all approved cholinesterase inhibitors enhance cholinergic func- tion in the brain by inhibiting the enzyme(s) that degrades acetylcholine, individual agents differ with regard to their pharmacological profiles (5). The three most widely used cholinesterase inhibitors are rivastigmine (Exelon Ò ), a sus- tained inhibitor of acetylcholinesterase (AChE) and butyryl- cholinesterase (BuChE), and the AChE-selective inhibitors, donepezil (Aricept Ò ) and galantamine (Reminyl Ò , Razadyne TM ). The clinical significance of additional BuChE inhibition is still be elucidated, but it has been proposed that pharma- cological differences may differentiate the cholinesterase inhibitors with respect to clinical efficacy and safety (5). Such differences may underlie clinical findings that patients who fail on one agent may benefit from another, leading to the suggestion that patients not responding to one cholinesterase inhibitor should be switched to another agent in the same class (6–9). In 2004, the first NMDA receptor antagonist was approved for the treatment of moderate to severe AD. Memantine (Ebixa Ò ) is believed to replace the magnesium ion in a Correspondence to: Thierry Dantoine, De ´partement de Ge ´rontologie Clinique, Centre Hospitalier Universitaire, 2 Avenue Martin Luther King, 87042 Limoges Cedex, France Tel.: þ 33 5 55 05 65 44 Fax: þ 33 5 55 05 65 45 Email: thierry.dantoine@chu-limoges.fr ª 2006 Blackwell Publishing Ltd Int J Clin Pract, January 2006, 60, 1, 110–118 ORIGINAL PAPER doi: 10.1111/j.1368-5031.2005.00769.x