The presence of cholinergic deficiency in brain regions regulating behaviour has led to interest in the potential value of cholinesterase (ChE) inhibitors for the treatment of these symptoms.
Studies with the acetylcholinesterase (AChE)-selective inhibitor, donepezil, have produced variable results. A 52-week study in mild to moderate AD, showed no significant behavioural benefit for donepezil over placebo using the NPI.1 In a 24-week study in moderate to severe AD, a significant benefit for donepezil over placebo was observed on the NPI total score, and on the items anxiety, depression and apathy.2,3 There was no notable reduction in the concomitant use of psychoactive medication in donepezil-treated patients and benefit was only noted in patients that were not on psychotropic drugs at randomisation.2,3 In moderate to severe nursing home patients, a 24-week study showed no significant separation between donepezil and placebo, although agitation/aggression was significantly improved in the donepezil group.4
In a 5-month study in mild to moderate AD patients with a low baseline level of behavioural disturbances, the AChE-selective inhibitor, galantamine, significantly stabilised behavioural symptoms, compared with placebo, indicating a delay in the emergence of psychopathology.5 Post-hoc analysis of data in ‘advanced moderate’ AD confirmed this effect.6
In a 26-week placebo-controlled study in mild to moderately severe AD patients, rivastigmine, a dual inhibitor of AChE and butyrylcholinesterase (BuChE), significantly improved global ratings of the CIBIC-plus behavioural domain.7 An open-label extension up to 2 years in the same patients demonstrated significant improvements in mood disturbances and hallucinations.7 In moderately severe AD patients, a post-hoc analysis of placebo-controlled studies showed significant improvement in aggressiveness after 26 weeks.8 Open-label studies conducted in nursing home patients with moderate to severe AD,9,10 demonstrated significant improvements across multiple behavioural symptoms after 26 weeks. These effects were sustained up to 52 weeks,11 and a large proportion of patients were able to reduce/discontinue use of concomitant psychotropic medication.12 Of the patients with no behavioural symptoms present at baseline, only 7% went on to develop symptoms, suggesting that rivastigmine may delay emergence of behavioural symptoms.10
In summary, ChE inhibitors show promise for the treatment of behavioural symptoms of AD. Specific inhibition of AChE clearly provides efficacy across certain behavioural symptoms (particularly apathy, anxiety and depression), with the possibility of additional behavioural effects with dual AChE and BuChE inhibition. This will be examined in an ongoing 2-year head-to-head study (EXCEED) comparing the efficacy of rivastigmine and donepezil in AD patients.
1Winblad B, et al. Neurology 2001;57(3):489-95 2Feldman H, et al. Neurology 2001;57(4):613-20 3Gauthier S et al. Int Psychogeriatrics 2002;14(4):389-404 4Tariot P, et al. JAGS 2001;49:1590-9 5Tariot PN, et al. Neurology 2000;54:2269–76 6Wilkinson D, et al. Int Psychogeriatrics 2001;13(Suppl 2):509-14 7Rosler M, et al. Behav Neurol 1998/1999;11:211–216 8Burns A, et al. Int J Geriatr Psychiatry. Submitted 9Cummings J et al. 2000 (poster) 10Bullock R, et al. 2001 (poster) 11Cummings J et al. 2000 (poster) 12Messina J et al. 2000 (poster)
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