BMJ  2005;330:857-858 (16 April), doi:10.1136/bmj.330.7496.857

Editorial

Drugs for Alzheimer's disease and related dementias

Clear rules about stopping treatment in individual patients are needed

The article by Ballard et al in this issue (p 874) offers an opportunity to discuss the role of drugs in the treatment of Alzheimer's disease and related dementias.¹ This investigator driven randomised clinical trial has tested the hypothesis that the atypical neuroleptic quetiapine and the cholinesterase inhibitor rivastigmine would be better than placebo for treating agitation in institutionalised patients in severe stages of Alzheimer's disease. Using measures of agitation (the Cohen-Mansfield agitation inventory) and cognition (the severe impairment battery) appropriate for this stage of dementia, the authors showed that agitation improved equally in the three arms of the trial but a measurable decline in cognition occurred in patients taking quetiapine. They conclude that these two drugs seemed of no benefit in patients with dementia and agitation in institutional care, and that quetiapine should not be used as alternative treatment to risperidone or olanzapine in people with dementia.

Showing the benefit of drugs on behaviour has been difficult in nursing home settings. Patients with moderate to severe Alzheimer's disease living in the community who were treated with the cholinesterase inhibitor donepezil over 24 weeks have shown an improvement, compared with placebo, in the total score as well as on the apathy, depression, and anxiety items of the neuropsychiatric inventory.² However, when the same drug and outcome were used, no such benefit occurred for patients at a similar severity of disease living in a nursing home setting.³ Is this difference related to an observer bias, since behavioural problems in dementia are best assessed by interviewing informants who know the patient well—for example, are family members better than professional caregivers at detecting behavioural changes?⁴ This is not an issue in Ballard et al's study since all treated patients lived in institutions, and recent data showed good correlation between informant rating and direct observation of behaviours.⁵

Was it appropriate to target agitation in this study? Clearly yes, since agitation is one of the behaviours most commonly related to severity in dementia of various causes and has a marked impact on caregivers,⁶ and because uncertainty exists about the best management of agitation, pharmacological or otherwise.⁷

Does the publication by Ballard et al mean that rivastigmine and quetiapine should be avoided in dementia? Evidence from a recently published randomised controlled trial shows that rivastigmine is useful and well tolerated in dementia associated with Parkinson's disease,⁸ and in an open label trial quetiapine has been shown to improve psychotic symptoms and cognition in this condition.⁹ The evidence for efficacy of rivastigmine and other cholinesterase inhibitors in mild to moderate Alzheimer's disease is established, even by the current report from the National Institute for Clinical Excellence.¹⁰ The issue is whether they are worth their costs from society's point of view.

From a clinical perspective, cholinesterase inhibitors are helpful in the management of many of the symptoms associated with dementia for individual patients. The art of treatment is to use the right drug for the right symptoms at the proper stage of disease, starting low and going slow. Perhaps clear stopping rules for drugs used in dementia based on evidence from randomised controlled trials and taking into account individual patients' responses to treatment will resolve the current debate about drugs for Alzheimer's disease and related dementias. Ballard et al have added useful information to the body of evidence from randomised controlled trials.

McGill Center for Studies in Aging, 6825 LaSalle Blvd, Verdun (Montréal), Québec, Canada H4H 1R3 (Serge.gauthier{at}mcgill.ca)

---

Competing interests: SG has accepted honorariums for lectures and is on the scientific advisory board of most companies doing research in dementia including Pfizer, Novartis, Janssen-Cilag, Neurochem, Lundbeck, Merz, Roche, Lilly.

Papers p 874

References

1. Ballard C, Margallo-Lana M, Juszczak E, Douglas S, Swann A, Thomas A, et al. Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial. BMJ 2005;330: 874-7.[Abstract/Free Full Text]
2. Gauthier S, Feldman H, Hecker J, Vellas B, Ames D, Subbiah P, et al. Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease. Int Psychogeriatrics 2002;14: 389-404.
3. Tariot PN, Cummings JL, Katz IR, Mintzer J, Perdomo CA, Schwam EM, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting. J Am Geriatr Soc 2001;49: 1590-9.[CrossRef][ISI][Medline]
4. Aalten P, de Vugt ME, Lousberg R, Korten E, Jaspers N, Senden B, et al. Behavior problems in dementia: as factor analysis of the neuropsychiatric inventory. Dement Geriatr Cogn Disord 2003;15: 99-105.[CrossRef][ISI][Medline]
5. Cohen-Mansfield J, Libin A. Assessment of agitation in elderly patients with dementia: correlations between informant rating and direct observation. Int J Geriatr Psychiatry 2004;19: 881-91.[Medline]
6. Senanarong V, Cummings JL, Fairbanks L, Mega M, Masterman DM, O'Connor SM, et al. Agitation in Alzheimer's disease is a manifestation of frontal lobe dysfunction. Dement Geriatr Cogn Disord 2004;17: 14-20.[CrossRef][Medline]
7. Profenno LA, Tariot PN. Pharmacologic management of agitation in Alzheimer's disease. Dement Geriat Cogn Disord 2004;17: 65-77.
8. Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, De Deyn PP, et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med 2004;351: 2509-18.[Abstract/Free Full Text]
9. Juncos JL, Roberts VJ, Evatt ML, Jewart RD, Wood CD, Potter LS, et al. Quetiapine improves psychotic symptoms and cognition in Parkinson's disease. Movement Disorders 2003;19: 29-35.
10. National Institute for Health and Clinical Excellence (NICE). Appraisal consultation document: Alzheimer's disease—donepezil, rivastigmine, galantamine and memantine (review). www.nice.org.uk/page.aspx?o=245912 (accessed 11 Apr 2005).

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related Articles

Hit parade
BMJ 2005 330: 1396. [Extract] [Full Text]

Say no to the free lunch

Fiona Godlee
BMJ 2005 330: 0. [Extract] [Full Text] [PDF]

Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial

Clive Ballard, Marisa Margallo-Lana, Edmund Juszczak, Simon Douglas, Alan Swann, Alan Thomas, John O'Brien, Anna Everratt, Stuart Sadler, Clare Maddison, Lesley Lee, Carol Bannister, Ruth Elvish, and Robin Jacoby
BMJ 2005 330: 874. [Abstract] [Full Text] [PDF]

This article has been cited by other articles:

• Samuel, M., Maidment, I., Boustani, M., Fox, C. (2006). Clinical management of Parkinson's disease dementia: pitfalls and progress. Adv. Psychiatr. Treat. 12: 121-129 [Abstract] [Full text]  
• (2005). Which Drugs (or None) for Alzheimer Disease?. Journal Watch Dermatology 2005: 9-9 [Full text]  
• (2005). Hit parade. BMJ 330: 1396-1396 [Full text]  
• (2005). Which Drugs (or None) for Alzheimer Disease?. JWatch General 2005: 1-1 [Full text]