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Cited by 567Dementia and Cognitive Impairment ResearchPharmaceutical Practices and Patient OutcomesSchizophrenia research and treatment

The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial

Open access
Ballard, Clive, Hanney, Maria Luisa, Theodoulou, Megan, Douglas, Simon, McShane, Rupert, Kossakowski, Katja, Gill, Randeep, Juszczak, Edmund +2 more·2009·The Lancet Neurology
DOI 10.1016/s1474-4422(08)70295-3
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Abstract

Background Data from 12-week placebo-controlled trials have led to mounting concerns about increased mortality in patients with Alzheimer's disease (AD) who are prescribed antipsychotics; however, there are no mortality data from long-term placebo-controlled trials. We aimed to assess whether continued treatment with antipsychotics in people with AD is associated with an increased risk of mortality.Methods Between October, 2001, and December, 2004, patients with AD who resided in care facilities in the UK were enrolled into a randomised, placebo-controlled, parallel, two-group treatment discontinuation trial. Participants were randomly assigned to continue with their antipsychotic treatment (thioridazine, chlorpromazine, haloperidol, trifluoperazine, or risperidone) for 12 months or to switch their medication to an oral placebo. The primary outcome was mortality at 12 months. An additional follow-up telephone assessment was done to establish whether each participant was still alive 24 months after the enrollment of the last participant (range 24-54 months). Causes of death were obtained from death certificates. Analysis was by intention to treat (ITT) and modified intention to treat (mITT). This trial is registered with the Cochrane Central Registry of Controlled Trials/National Research Register, number ISRCTN33368770.Findings 165 patients were randomised (83 to continue antipsychotic treatment and 82 to placebo), of whom 128 (78%) started treatment (64 continued with their treatment and 64 received placebo). There was a reduction in survival in the patients who continued to receive antipsychotics compared with those who received placebo. Cumulative probability of survival during the 12 months was 70% (95% CI 58-80%) in the continue treatment group versus 77% (64-85%) in the placebo group for the mITT population. Kaplan-Meier estimates of mortality for the whole study period showed a significantly increased risk of mortality for patients who were allocated to continue antipsychotic treatment compared with those allocated to placebo (mITT log rank p=0.03; ITT p=0.02). The hazard ratio for the mITT group was 0.58 (95% CI 0.35 to 0.95) and 0.58 (0.36 to 0.92) for the ITT population. The more pronounced differences between groups during periods of follow up longer than 12 months were evident at specific timepoints (24-month survival 46%vs 71%; 36-month survival 30%vs 59%).Interpretation There is an increased long-term risk of mortality in patients with AD who are prescribed antipsychotic medication; these results further highlight the need to seek less harmful alternatives for the long-term treatment of neuropsychiatric symptoms in these patients.Funding UK Alzheimer's Research Trust.

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Crossref · 10.1016/s1474-4422(08)70295-3

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  • Clinical outcomes of pharmacological treatment of agitation are poor and undesired side effects (including cognitive worsening, confusion, and extrapyramidal signs) are frequent, even with the use of the newer atypical drugs.

    “However, clinical outcomes are poor and undesired side effects (including cognitive worsening, confusion, and extrapyramidal signs) are frequent, even with the use of the newer atypical drugs [14].”

    From Nonpharmacological Interventions to Reduce Behavioral and Psychological Symptoms of Dementia: A Systematic Review (2015) · cites this paper as [14]

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Authors
Ballard, C., Hanney, M. L., Theodoulou, M., Douglas, S., McShane, R., Kossakowski, K., Gill, R., Juszczak, E., Yu, L.-M., & Jacoby, R.
Affiliations
  • King's College London (GB)
  • Northgate Hospital (GB)
  • Warneford Hospital (GB)
  • Newcastle University (GB)
  • Oxford Health NHS Foundation Trust (GB)
  • University of Oxford (GB)
Corresponding author
Ballard, Clive
ORCID
Venue
The Lancet Neurology
Publisher
Elsevier BV
Published
2009-02
Volume
8
Issue
2
Pages
151-157
ISSN
1474-4422 (ISSN-L)
DOI
10.1016/s1474-4422(08)70295-3
OpenAlex
W2143521222
Cited by
567
References
29
Citations by year
2026: 8 · 2025: 11 · 2024: 11 · 2023: 14 · 2022: 15 · 2021: 16 · 2020: 28 · 2019: 24 · 2018: 36 · 2017: 36 · 2016: 49 · 2015: 37 · 2014: 40 · 2013: 44 · 2012: 44
FWCI
40.69
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • The Lancet Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • Newcastle University ePrints (Newcastle Univesity)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
antipsychotic drugs, Alzheimer's disease, dementia, mortality, antipsychotic withdrawal, treatment discontinuation, long-term survival, thioridazine, chlorpromazine, haloperidol, trifluoperazine, risperidone, care homes, causes of death, antipsychotic safety, behavioural and psychological symptoms
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Dementia, Female, Follow-Up Studies, Humans, Male, Risk, Antipsychotic Agents, Kaplan-Meier Estimate

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