There is a large increased long-term risk of mortality in patients with Alzheimer's disease (AD) who are prescribed antipsychotic medication. These results, from long-term follow-up of the DART-AD study*, further highlight the need to seek less harmful treatments for neuropsychiatric symptoms in these patients. These are the conclusions of an Article published Online first and in the February edition of The Lancet Neurology, written by Dr Clive Ballard, Wolfson Centre for Age-Related Diseases, King's College London, UK, and colleagues. The study was funded by the UK Alzheimer's Research Trust.
While there is evidence of modest short term (6-12 weeks) benefits of antipsychotic treatment for the neuropsychiatric symptoms of AD, there is also clear evidence of an increase in adverse effects, including parkinsonism, sedation, oedema, chest infections, accelerated decline in brain function, stroke and mortality. However, all the data regarding mortality so far relate to short term follow-up of 12 weeks or less. The authors of this study have provided the first long-term follow-up data for AD patients given antipsychotic drugs.
Between 2001 and 2004, patients with AD aged between 67 and 100 years who resided in facilities in four UK areas** were randomly assigned to continue with their antipsychotic treatment (thioridazine, chlorpromazine, haloperidol, trifluorperazine, 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 enrolment of the last participant (range 24-54 months). Causes of death were obtained from death certificates.
In total, 165 patients were randomised and of these, 128 started treatment – 64 on antipsychotics, 64 on placebo. At 12 months, there was 70% survival in the antipsychotic group compared with 77% in placebo. However, longer term follow-up revealed bigger differences in survival. At 2 years, survival was 46% in the antipsychotic group and 71% in the placebo group, and at 36 months the difference was even greater: 30% antipsychotic versus 59% placebo. Overall, across the whole study period, the risk of death was 42% lower in the placebo group than in the antipsychotic group.
The authors conclude: "Our data add further serious safety concerns about the long-term use of antipsychotics in this population, and clinicians should certainly try to replace antipsychotics with safer management approaches. Several studies have shown that psychological management can replace antipsychotic therapy without any appreciable worsening of neuropsychiatric symptoms; and although cholinesterase inhibitors do not seem to be an effective short-term pharmacological treatment for agitation, there is evidence that memantine or antidepressants such as citalopram might be safer and effective alternatives for some neuropsychiatric symptoms.
"Our opinion is that there is still an important but limited place for atypical antipsychotics in the treatment of severe neuropsychiatric manifestations, particularly aggression, of AD. However, the accumulating safety concerns, including the substantial increase in long-term mortality, emphasise the urgent need to put an end to unnecessary and prolonged prescribing."
The Leading Edge editorial in February's Lancet Neurology, also published Online first, concludes: "The risks and benefits of prescribing antipsychotics to patients with dementia need to be carefully balanced and these drugs should be used only if alternative strategies do not work. To protect the health and dignity of people with dementia and reduce the use of antipsychotic drugs, approaches that make the needs of patients central to decisions about care should be promoted."
Dr Clive Ballard, Wolfson Centre for Age-Related Diseases, King's College London, UK T) +44 (0) 20 7848 6568E) clive.ballard@kcl.ac.uk
The Lancet Neurology Press Office T) +44 (0) 7424 4949 E) pressoffice@lancet.com
For full Article and Leading Edge see: http://press.thelancet.com/TLNantipsychoticsfinal.pdf
Notes to editors: *DART-AD: Dementia antipsychotic withdrawal trial
**Four UK areas: Oxfordshire, Newcastle and Gateshead, London, Edinburgh
Journal
The Lancet Neurology