A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial)


Clive Ballard1*, Marisa Margallo Lana2, Megan Theodoulou3, Simon Douglas4, Rupert McShane5, Robin Jacoby3, Katja Kossakowski1, Ly-Mee Yu6, Edmund Juszczak6, on behalf of the Investigators DART AD

1 Wolfson Centre for Age-Related Diseases, King’s College London, London, United Kingdom, 2 Northgate Hospital, Morpeth, Northumberland, United Kingdom, 3 Department of Psychiatry, University of Oxford, The Warneford Hospital, Oxford, United Kingdom, 4 Department of Psychiatry, Newcastle University, Newcastle upon Tyne, United Kingdom, 5 Oxfordshire and Buckinghamshire Mental Health NHS Trust and University of Oxford, Department of Psychiatry, Fulbrook Centre, Oxford, United Kingdom, 6 Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom

Background

There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease.

Methods and Findings

Design: Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial.

Setting: Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom.

Participants: Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo.

Interventions: Continue neuroleptic treatment for 12 mo or switch to an identical placebo.

Outcome measures: Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI).

Results: 165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) −0.4 (95% confidence interval [CI] −6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) −2.4 (95% CI −8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI ≥ 15 benefited on neuropsychiatric symptoms from continuing treatment.

Conclusions

For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy.

Trial registration: Cochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).

Funding: The DART-AD project was made possible by a grant from The Alzheimer’s Research Trust, Cambridge, UK (http://www.alzheimers-research.org.uk) to Profs Ballard and Jacoby and to RM. The peer review process undertaken by the funder did result in some modifications to the study design. The funder has no other role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: CB has received honoraria from Novartis, Pfizer, Shire, Lundbeck, Myriad, Janssen, Astra Zeneca, and Servier pharmaceutical companies and research grants from Novartis, Lundbeck, Astra-Zeneca, and Janssen pharmaceuticals. The remaining authors have declared that they have no competing interests.

Academic Editor: Carol Brayne, University of Cambridge, United Kingdom

Citation: Ballard C, Lana MM, Theodoulou M, Douglas S, McShane R, et al. (2008) A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial) . PLoS Med 5(4): e76 doi:10.1371/journal.pmed.0050076

Received: May 31, 2007; Accepted: February 15, 2008; Published: April 1, 2008

Copyright: © 2008 Ballard et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abbreviations: AD, Alzheimer disease; ANCOVA, analysis of covariance; BADLS, Bristol Activities of Daily Living Scale; CGIC, Clinician’s Global Impression of Change; CI, confidence interval; DMC, data-monitoring committee; EPS, extrapyramidal signs and symptoms; FAS, Verbal Fluency Task; FAST, Functional Assessment Staging; IQR, interquartile range; NPI, Neuropsychiatric Inventory; SD, standard deviation; SIB, Severe Impairment Battery; (S)MMSE, (Standardised) Mini Mental State Examination; STALD, Sheffield Test for Acquired Language Disorders; UPDRS, Unified Parkinson’s Disease Rating Scale

* To whom correspondence should be addressed. E-mail: clive.ballard@kcl.ac.uk

Editors’ Summary

Background

The number of people with dementia (currently 25 million worldwide) is expected to increase by 5 million each year. The risk of dementia, including Alzheimer disease, increases sharply with age: Alzheimer’s Disease International estimates that 1.4% of people 65–69 have dementia, whereas almost a full quarter of those over the age of 85 years are affected. Almost all older dementia patients will experience, along with the cognitive and functional decline typical of the illness, some neuropsychiatric symptoms. These symptoms can include agitation, aggression, and psychosis, and are often devastating for the older patient and his or her family and caregiver. Managing these symptoms is often a prime concern for health-care providers and families. Neuroleptics (sometimes called antipsychotics) are the class of drugs often used to manage or control neuropsychiatric problems, but there have been questions about their safety and appropriateness. Safety concerns involve risk of stroke, parkinsonism, sedation, edema, and chest infections but also include a worsening of cognitive decline with prolonged use of neuroleptics.

Why Was the Study Done?

Previous studies on the effectiveness and safety of neuroleptics in older people have been short term. Ballard and colleagues wanted to study over a longer period of time the impact of neuroleptic drugs on elderly patients with dementia. Specifically, they wanted to know if being on a neuroleptic was associated with more cognitive decline than coming off the drug. They also wanted to investigate whether discontinuing the drug exacerbated any neuropsychiatric symptoms, Parkinson disease-like symptoms, or other functional, language, and cognition difficulties frequently associated with dementia.

What Did the Researchers Do and Find?

The researchers recruited older patients with Alzheimer disease from across England who had been on neuroleptics for at least three months. They randomised patients to one of two groups: the first group continued taking the same neuroleptic at the same dosage level while the second group was switched to an identical-looking placebo. The researchers assessed the patients’ cognitive status and neuropsychiatric symptoms upon their entry into the study. Six and 12 months later the researchers assessed any cognitive decline and the level of neuropsychiatric and other problems that patients were experiencing.

At both 6 and 12 months, the researchers found that there were no differences between the two groups (continued treatment and placebo) in terms of cognitive decline. The placebo group may have had less cognitive decline, but this was not statistically significant. They also found no overall differences between the two groups in the change in the number of neuropsychiatric symptoms over these time periods. Patients with severe neuropsychiatric problems at the outset of the trial did better on continued neuroleptic therapy, but this advantage was not statistically significant. There was a significant decline on the verbal fluency language tests among the patients who continued on their neuroleptic.

What Do these Findings Mean?

The researchers report perhaps the first trial of this duration on continued versus withdrawn neuroleptic treatment among older dementia patients. The findings do not indicate any benefit of continuing neuroleptic therapies in older patients on either cognitive or neuropsychiatric outcomes. The researchers conclude that neuroleptics, with their known safety issues, should not be used as first-line treatment to manage problems such as agitation or aggression. For older dementia patients whose neuropsychiatric symptoms are not remedied by nonpharmaceutical treatments, the researchers advise caution. More studies are urgently needed to find better solutions to help older patients with dementia who have agitation, aggression, and psychosis.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050076.

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3 Responses to A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial)

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