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

Date Published: April 1, 2008

Publisher: Public Library of Science

Author(s): Clive Ballard, Marisa Margallo Lana, Megan Theodoulou, Simon Douglas, Rupert McShane, Robin Jacoby, Katja Kossakowski, Ly-Mee Yu, Edmund Juszczak, Carol Brayne

Abstract: BackgroundThere 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 FindingsDesign: 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.ConclusionsFor 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).

Partial Text: Worldwide, there are 25 million people with dementia [1], the majority of whom have Alzheimer disease
(AD). It is a devastating illness that results in a progressive decline in cognitive ability
and functional capacity, causes immense distress to patients, their carers, and families,
and has an enormous societal impact. Currently the most frequent treatment issue for people
with AD presenting to clinical services remains the management of neuropsychiatric symptoms,
such as aggression, agitation, and psychosis. Over 90% of people with dementia
develop these symptoms at some point during their illness [2]. The symptoms are frequently distressing for
the patients who experience them [3] and problematic for their caregivers [4], in whom they are associated with clinically
significant depression [5]. In addition, they are often the precipitant for institutional care
[6].

Because of difficulties in identifying people with Alzheimer disease in nursing homes who
were taking neuroleptics and were able to complete the rigorous cognitive assessments, the
recruitment target sample size based on the power calculation was not attained. However,
despite this drawback, we report the largest and longest-duration randomized placebo
controlled trial of neuroleptic discontinuation. To our knowledge this is the first study of
this type to evaluate outcome over 6 mo and beyond.

Source:

http://doi.org/10.1371/journal.pmed.0050076

 

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