BMJ  2005;330:874 (16 April), doi:10.1136/bmj.38369.459988.8F (published 18 February 2005)

Paper

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

¹ Institute of Psychiatry, King's College, London SE5 8AF, ² Centre for Statistics in Medicine, Oxford University, Oxford OX3 7LF, ³ University of Newcastle, Institute of Ageing, Newcastle General Hospital, Newcastle upon Tyne NE4 4BE, ⁴ Oxfordshire Mental Healthcare NHS Trust, Fiennes Unit, Horton Hospital, Banbury OX16 9BF, ⁵ Oxford University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX

Abstract

Objectives To determine the respective efficacy of quetiapine and rivastigmine for agitation in people with dementia in institutional care and to evaluate these treatments with respect to change in cognitive performance.

Design Randomised double blind (clinician, patient, outcomes assessor) placebo controlled trial.

Setting Care facilities in the north east of England.

Participants 93 patients with Alzheimer's disease, dementia, and clinically significant agitation.

Intervention Atypical antipsychotic (quetiapine), cholinesterase inhibitor (rivastigmine), or placebo (double dummy).

Main outcome measures Agitation (Cohen-Mansfield agitation inventory) and cognition (severe impairment battery) at baseline and at six weeks and 26 weeks. The primary outcome was agitation inventory at six weeks.

Results 31 patients were randomised to each group, and 80 (86%) started treatment (25 rivastigmine, 26 quetiapine, 29 placebo), of whom 71 (89%) tolerated the maximum protocol dose (22 rivastigmine, 23 quetiapine, 26 placebo). Compared with placebo, neither group showed significant differences in improvement on the agitation inventory either at six weeks or 26 weeks. Fifty six patients scored > 10 on the severe impairment battery at baseline, 46 (82%) of whom were included in the analysis at six week follow up (14 rivastigmine, 14 quetiapine, 18 placebo). For quetiapine the change in severe impairment battery score from baseline was estimated as an average of –14.6 points (95% confidence interval –25.3 to –4.0) lower (that is, worse) than in the placebo group at six weeks (P = 0.009) and –15.4 points (–27.0 to –3.8) lower at 26 weeks (P = 0.01). The corresponding changes with rivastigmine were –3.5 points (–13.1 to 6.2) lower at six weeks (P = 0.5) and –7.5 points (–21.0 to 6.0) lower at 26 weeks (P = 0.3).

Conclusions Neither quetiapine nor rivastigmine is effective in the treatment of agitation in people with dementia in institutional care. Compared with placebo, quetiapine is associated with significantly greater cognitive decline.

Introduction

Antipsychotic drugs are commonly prescribed to many people with dementia (up to 45%) in residential or nursing homes,¹ often for prolonged periods. Antipsychotics have modest efficacy² but are commonly associated with substantial adverse effects and, more seriously, an increased risk of stroke has been reported with the atypical antipsychotics, risperidone and olanzapine.³ There are no published randomised controlled trials for other atypical antipsychotics in people with dementia, although a published abstract indicates some benefit of quetiapine in those with agitation,⁴ and preliminary evidence indicates that cholinesterase inhibitors may also improve agitation.⁵

One observational study reported a doubling in the rate of cognitive decline in patients with dementia taking typical antipsychotics,⁶ although the impact on cognition of newer atypical antipsychotics, was not determined.

We compared quetiapine and rivastigmine with placebo in patients with dementia and agitation in nursing homes in a randomised double blind placebo controlled trial over 26 weeks. Our primary objective was to determine whether either drug was better than placebo for agitation. We also evaluated whether there was a significant difference between the individual active treatments and placebo with respect to cognitive change.

View this table: [in this window] [in a new window]   Summary of change from baseline at six weeks and 26 weeks for main outcomes plus comparative statistics

 

Method

Participants were all people with dementia living in care facilities. Our inclusion criteria were a diagnosis of probable or possible Alzheimer's disease; age > 60; clinically significant agitation for at least six weeks using the Cohen-Mansfield agitation inventory,⁷ and the irritability or aberrant motor behaviour scales of the neuropsychiatric inventory; and no use of antipsychotics or cholinesterase inhibitors for four weeks before entry into the study. We excluded patients known to be sensitive to cholinesterase inhibitors or antipsychotics and those with advanced, severe, progressive, or unstable disease or disability that might prevent them from completing study procedures (see bmj.com).

Evaluations
We assessed all patients before the start of the pharmacological intervention (baseline) and after six and 26 weeks. At 12 weeks participants underwent an additional severe impairment battery⁸ because people with behavioural problems commonly refuse cognitive assessment at least once. Assessors were blind to treatment allocation.

Outcomes
Our primary outcome measure was a validated standardised evaluation of agitation at six weeks.⁷ We used the severe impairment battery for cognitive assessment.⁸ General assessments included electrocardiography, full blood count, and evaluation of severity of dementia (functional assessment staging) at baseline.

Randomisation
We randomly assigned patients in equal numbers to active quetiapine plus placebo rivastigmine; placebo quetiapine plus active rivastigmine; or placebo rivastigmine plus placebo quetiapine (double dummy).

We aimed to attain doses of 25-50 mg quetiapine twice a day and 3-6 mg rivastigmine twice a day by week 12, and doses of 50 mg quetiapine twice a day or 9 mg rivastigmine daily between week 12 and week 26.

Sample size and analysis
We calculated that we needed a sample size of 23 in each group, assuming similar efficacy of active treatments. Allowing for a dropout rate of 25%, we needed 31 patients per treatment group. (See bmj.com for details of participant flow.)

We summarised demographic factors and clinical characteristics. We restricted comparative analysis to those patients who had at least one assessment after randomisation; a modified intention to treat analysis. For the agitation inventory score, for everyone who completed the six week evaluation but dropped out thereafter we carried forward the last total score. For the severe impairment battery, we carried forward the last total score from either the six week or supplementary three month assessment.

For the primary analysis, we summarised the change in the agitation inventory score from baseline to six weeks using the mean (SD). To establish the magnitude and direction of the treatment effect, we used analysis of covariance to compare pairs of treatment groups, giving the mean difference (in change in agitation inventory from baseline to six weeks) between groups (plus 95% confidence intervals) with adjustment for baseline value.

We made no formal adjustment for multiple significance testing. We report our main objective of active treatment versus placebo but also active treatment group comparisons for completeness given the dearth of published data. We also report results at the 26 week follow up to show whether the effects are temporary or sustained. See bmj.com for full details.

Results

Ninety three patients (31 per arm), most with severe dementia were randomised between September 2001 and April 2003, of whom 80 (86%) started treatment (25 rivastigmine, 26 quetiapine, 29 placebo). Seventy one (89%) tolerated the maximum protocol dose (22 rivastigmine, 23 quetiapine, 26 placebo). Eighty seven (94%) completed the agitation inventory assessment at baseline and 80 (86%) did so at six weeks (24 rivastigmine, 27 quetiapine, 29 placebo). Wherever possible we assessed outcomes irrespective of whether a patient commenced treatment.

Demographic characteristics and stage of dementia were similar across the three groups, but there was a slight imbalance on severe impairment battery at baseline (10 point difference in favour of patients in the placebo group) (see bmj.com).

Agitation inventory
There were no significant differences between treatments in the change in agitation inventory scores between baseline and six weeks and baseline and 26 weeks (table).

What is already known on this topic Antipsychotic drugs are widely used for the control of behavioural manifestations in dementia, of which agitation is the most common Central cholinesterase inhibitors are increasingly used to treat the behavioural manifestations of dementia Observational data have suggested that (typical) antipsychotics might accelerate cognitive decline in dementia What this study adds Central cholinesterase inhibitors and atypical antipsychotics are not effective for the treatment of agitation in people with dementia Quetiapine (an atypical antipsychotic) is associated with accelerated cognitive decline

Severe impairment battery
Fifty six of the 93 (60%) participants scored > 10 on the severe impairment battery at baseline (20 rivastigmine, 17 quetiapine, 19 placebo). Forty six (82%) of these patients also completed it at six weeks. For these 46 patients, the mean (SD) scores at baseline were 71.6 (24.6) placebo; 66.6 (21.3) quetiapine and 65.1 (22.6) rivastigmine (2.6, 7.2, and 6.3 points higher, respectively, than the scores at six weeks). This was not explained by those with a poorer cognitive function being more likely to drop out and baseline figures were almost identical for participants who did or did not complete the agitation inventory at six weeks.

Patients who received quetiapine experienced, on average, an estimated mean difference in change in severe impairment battery score from baseline of –14.6 points (95% confidence interval –25.3 to –4.0) compared with the placebo treated group at six weeks; indicating a significantly greater deterioration in the quetiapine group (table and figure). A similar magnitude of difference was evident at 26 weeks. In contrast, the corresponding comparison of change in score from baseline for rivastigmine with placebo was an average of –3.5 points lower at six weeks and –7.5 points lower at 26 weeks.

Discussion

Compared with placebo, the atypical antipsychotic drug quetiapine does not result in significant improvement in agitation in patients with dementia and is associated with a greater decline in cognitive function. This result is consistent with data from previous observational and preliminary clinical trials.⁶ It is unlikely that the differences we found can be explained by any potential confounding factors.

Even though quetiapine has a relatively more favourable pharmacological profile than other antipsychotic agents, it was still associated with a detrimental impact on cognition. One postulated mechanism is suppression of brain derived neurotrophic factor (BDNF), accelerating the accumulation of the core pathological substrates of Alzheimer's disease.⁹ Another possible mechanism involves antimuscarinic properties.¹⁰ Preliminary reports indicate potential cognitive benefits of quetiapine in people with schizophrenia,¹¹ although the mechanisms of cognitive impairment in the two conditions are completely different.

View larger version (27K): [in this window] [in a new window]   Change in score on severe impairment battery (baseline to six weeks) by treatment group

 

Patients in the rivastigmine group did not experience any significant improvement in agitation nor did they seem to experience a significant decline in cognitive function compared with patients in the placebo group.

Strengths and limitations
The improvements seen in the placebo group are consistent with most previous reports² and are probably explained by a Hawthorne effect—residents in an unstimulating environment respond positively to the increased interaction as part of the study procedures. Though our study is limited because of the modest sample size, multiple evaluations, and the substantial proportion of patients who were unable to complete the severe impairment battery, the possible impact of quetiapine on cognition is clinically important.

We did not adjust for multiple significance testing because we considered the six week results would be the most important because of the anticipated dropout rate; comparison of treatment versus placebo was of primary importance, hence the interpretation of the significant result; and comparison of active treatments was always going to be of secondary importance, hence the caution with the six week result for rivastigmine versus quetiapine. When interpreting the cognitive function result for quetiapine compared with placebo, it can be argued that, in the light of a lack of evidence of efficacy, even a suggestion of a decline in what was a secondary outcome is noteworthy. As one could argue that it is not necessary to show significant evidence of harm under these particular circumstances, a formal adjustment was not deemed necessary.

Conclusion
Quetiapine and rivastigmine seemed of no benefit in patients with dementia and agitation in institutional care, and quetiapine was associated with greater cognitive decline than placebo. Our results suggest that quetiapine should not be used in people with dementia and highlight concerns regarding the long term use of antipsychotics in these patients.

---

We thank the Alzheimer's Research Trust for their support in our programme of work to evaluate the impact of antipsychotics on cognition; Alistair Burns for his helpful comments on the manuscript; and Andrea Burton for her helpful advice regarding the sensitivity analysis.

Contributors: See bmj.com Funding: The study was funded largely from general donations to C Ballard's research programme and profits from previously completed commercially funded clinical trials, with additional support from the Alzheimer's Research Trust. Competing interests: C Ballard has received honorariums and research donations to support his general research programme from Astra Zeneca and Novartis.

Ethical approval: The study was approved by a properly constituted local research ethics committee.

This is the abridged version of an article that was posted on bmj.com on 18 February 2005: http://bmj.com/cgi/doi/10.1136/bmj.38369.459988.8F

References

1. McGrath AM, Jackson GA. Survey of prescribing in residents of nursing homes in Glasgow. BMJ 1996;314: 611-2.
2. Ballard C, O'Brien J. Treating behavioural and psychological signs in Alzheimer's disease. BMJ 1999;319: 138-9.[Free Full Text]
3. Committee on Safety of Medicines. Atypical antipsychotic drugs and stroke. www.mca.gov.uk (accessed 9 March 2004).
4. Tariot P. Atypical antipsychotics for the treatment of BPSD. Int Psychogeriatr (in press).
5. Cummings JL. Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Am J Psychiatry 2003;11: 131-45.
6. McShane R, Keene J, Gedling K, Fairburn C, Jacoby R, Hope T. Do neuroleptic drugs hasten cognitive decline in dementia? Prospective study with necropsy follow up. BMJ 1997;314: 266-70.[Abstract/Free Full Text]
7. Cohen-Mansfield J. Assessment of disruptive behaviour/agitation in the elderly: function, methods, and difficulties. J Geriatr Psychiatry Neurol 1995;8: 52-60.
8. Saxton J, McGonigle-Gibson K, Swihart A, Miller M, Boller F. Assessment of severely impaired patients: description and validation of a new neuropsychological test battery. Psychol Assess 1990;2: 298-303.[CrossRef]
9. Coffey ET, Akerman KE, Courtney MJ. Brain derived neurotrophic factor induces a rapid upregulation of synaptophysin and tau proteins via the neurotrophin receptor TrkB in rat cerebellar granule cells. Neurosci Lett 1997;227: 177-80.[CrossRef][Web of Science][Medline]
10. Perry EK, Kilford L, Lees AJ, Burn DJ, Perry RH. Increased Alzheimer pathology in Parkinson's disease related to antimuscarinic drugs. Ann Neurol 2003;54: 235-8.[CrossRef][Web of Science][Medline]
11. Fleming K, Thyrum P, Yeh C, Vargo DL, Potkin SG. Cognitive improvements in psychotic subjects treated with "Seroquel" (quetiapine fumarate): an exploratory study. J Clin Psychopharmacol 2001;21: 527-9.[CrossRef][Web of Science][Medline]

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

Relevant Articles

Quetiapine and rivastigmine may not work for dementia
BMJ 2005 330: 0. [Full Text]

Drugs for Alzheimer's disease and related dementias

Serge Gauthier
BMJ 2005 330: 857-858. [Extract] [Full Text] [PDF]

Quality of care in private sector and NHS facilities for people with dementia: cross sectional survey

Clive Ballard, Jane Fossey, Ramilgan Chithramohan, Robert Howard, Alistair Burns, Peter Thompson, George Tadros, and Andrew Fairbairn
BMJ 2001 323: 426-427. [Extract] [Full Text] [PDF]

Treating behavioural and psychological signs in Alzheimer's disease

Clive Ballard and John O'Brien
BMJ 1999 319: 138-139. [Extract] [Full Text] [PDF]

Do neuroleptic drugs hasten cognitive decline in dementia? Prospective study with necropsy follow up

Rupert McShane, Janet Keene, Kathy Gedling, Christopher Fairburn, Robin Jacoby, and Tony Hope
BMJ 1997 314: 266. [Abstract] [Full Text]

Survey of neuroleptic prescribing in residents of nursing homes in Glasgow

Alice M McGrath and Graham A Jackson
BMJ 1996 312: 611-612. [Extract] [Full Text]

This article has been cited by other articles:

• Jalbert, J. J., Daiello, L. A., Lapane, K. L. (2008). Dementia of the Alzheimer Type. Epidemiol Rev 30: 15-34 [Abstract] [Full text]  
• Wood-Mitchell, A., James, I. A., Waterworth, A., Swann, A., Ballard, C. (2008). Factors influencing the prescribing of medications by old age psychiatrists for behavioural and psychological symptoms of dementia: a qualitative study. Age Ageing 37: 547-552 [Abstract] [Full text]  
• Qaseem, A., Snow, V., Cross, J. T. Jr., Forciea, M. A., Hopkins, R. Jr., Shekelle, P., Adelman, A., Mehr, D., Schellhase, K., Campos-Outcalt, D., Santaguida, P., Owens, D. K., the Joint American College of Physicians/American, (2008). Current Pharmacologic Treatment of Dementia: A Clinical Practice Guideline from the American College of Physicians and the American Academy of Family Physicians. ANN INTERN MED 148: 370-378 [Abstract] [Full text]  
• Raina, P., Santaguida, P., Ismaila, A., Patterson, C., Cowan, D., Levine, M., Booker, L., Oremus, M. (2008). Effectiveness of Cholinesterase Inhibitors and Memantine for Treating Dementia: Evidence Review for a Clinical Practice Guideline. ANN INTERN MED 148: 379-397 [Abstract] [Full text]  
• (2007). How safe are antipsychotics in dementia?. DTB 45: 81-85 [Abstract] [Full text]  
• Howard, R. J., Juszczak, E., Ballard, C. G., Bentham, P., Brown, R. G., Bullock, R., Burns, A. S., Holmes, C., Jacoby, R., Johnson, T., Knapp, M., Lindesay, J., O'Brien, J. T., Wilcock, G., Katona, C., Jones, R. W., DeCesare, J., Rodger, M., the CALM-AD Trial Group, (2007). Donepezil for the Treatment of Agitation in Alzheimer's Disease. NEJM 357: 1382-1392 [Abstract] [Full text]  
• Kurlan, R., Cummings, J., Raman, R., Thal, L., For the Alzheimer's Disease Cooperative Study Grou, (2007). Quetiapine for agitation or psychosis in patients with dementia and parkinsonism. Neurology 68: 1356-1363 [Abstract] [Full text]  
• Blaszczyk, A. T., Mathys, M. (2007). Treatment of Cognitive Decline and Psychiatric Disturbances Associated With Alzheimer's Dementia. Journal of Pharmacy Practice 20: 13-28 [Abstract]  
• Beier, M. T. (2007). Pharmacotherapy for behavioral and psychological symptoms of dementia in the elderly. Am J Health Syst Pharm 64: S9-S17 [Abstract] [Full text]  
• Livingston, G, Walker, A E, Katona, C L E, Cooper, C (2007). Antipsychotics and cognitive decline in Alzheimer's disease: the LASER-Alzheimer's disease longitudinal study. J. Neurol. Neurosurg. Psychiatry 78: 25-29 [Abstract] [Full text]  
• Friedman, J. H. (2006). Atypical antipsychotics in the elderly with Parkinson disease and the "black box" warning.. Neurology 67: 564-566 [Abstract] [Full text]  
• Gill, S., Marras, C., Anderson, G. M., Lee, P. E., Gurwitz, J. H., Rochon, P. A. (2006). Atypical Antipsychotics Have Very Different Adverse Effect Profiles and Should Not Be Lumped Together--Reply. Arch Intern Med 166: 586-587 [Full text]  
• Aupperle, P. (2006). Management of aggression, agitation, and psychosis in dementia: Focus on atypical antipsychotics. AM J ALZHEIMERS DIS OTHER DEMEN 21: 101-108 [Abstract]  
• Schneider, L. S., Dagerman, K. S., Insel, P. (2005). Risk of Death With Atypical Antipsychotic Drug Treatment for Dementia: Meta-analysis of Randomized Placebo-Controlled Trials. JAMA 294: 1934-1943 [Abstract] [Full text]  
• (2005). Which Drugs (or None) for Alzheimer Disease?. Journal Watch Dermatology 2005: 9-9 [Full text]  
• (2005). Which Drugs (or None) for Alzheimer Disease?. JWatch General 2005: 1-1 [Full text]  
• Gauthier, S. (2005). Drugs for Alzheimer's disease and related dementias. BMJ 330: 857-858 [Full text]  

Rapid Responses:

Read all Rapid Responses

correction: this could be low DHEA...

James M. Howard
bmj.com, 18 Feb 2005 [Full text]

Cognitive changes could be explained by reversible acute sedative effects

Erick H Turner
bmj.com, 20 Feb 2005 [Full text]

Agitation in patients with dementia

Zafeer H.K Barki
bmj.com, 9 Mar 2005 [Full text]

Quetiapine for Lewy Body

B. Andrew Farah
bmj.com, 14 Mar 2005 [Full text]

Safety and efficacy of atypical antipsychotics in the treatment of patients with behavioural symptoms of dementia

Peter Paul De Deyn
bmj.com, 17 Mar 2005 [Full text]

The Cognitive Decline Associated with Quetiapine in Alzheimer’s disease

ARUNRAJ BALAKRISHNA KAIMAL, MRCPsych, et al.
bmj.com, 12 Apr 2005 [Full text]

Quetiapine and cognitive decline: apply caution

Ajit K Shah
bmj.com, 16 Apr 2005 [Full text]

Mechanisms of cognitive decline

Simon R Wright
bmj.com, 19 Apr 2005 [Full text]

Confusion around the scales and interpretation of the results

Thomas Marshall
bmj.com, 21 Apr 2005 [Full text]

Conclusion based on insufficient power

Lena Palaniyappan, et al.
bmj.com, 6 May 2005 [Full text]

Rivastigmine - thoughts of a journal club

Jonathan C Haynes, et al.
bmj.com, 9 May 2005 [Full text]

Concerns regarding the article

JANAKIRAMAN RAGURAMAN
bmj.com, 23 Aug 2005 [Full text]

Online poll

Find out more >>