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The story comes from a study comparing survival rates for one group of patients continuing to take their prescribed antipsychotic drugs, and another group that was switched to a placebo for 12 months. After three years, 30% of the antipsychotic group were still alive compared with 59% of those on placebo.
This study was well-designed and provides further evidence about the risks of long-term antipsychotic use in people with dementia. It should be noted that some of the potential side effects of these drugs were already well known prior to this study.
The National Institute for Health and Clinical Excellence (NICE) already recommends that the drugs should be considered for dementia patients with severe psychiatric symptoms, but that these drugs should only be used for limited periods. Doctors should continue to follow this advice.
Dementia care and treatment is being reviewed as part of the Department of Health’s National Dementia Strategy, which is due for publication later this year.
Where did the story come from?
Dr Clive Ballard and colleagues from King’s College London and other universities and hospitals in the UK carried out this research. Dr Ballard is director of research at the Alzheimer's Society. The study was funded by the UK Alzheimer’s Research Trust and published in the peer-reviewed medical journal The Lancet Neurology.
What kind of scientific study was this?
This was a double-blind randomised controlled trial, looking at the effects of discontinuing antipsychotic drug use in people with Alzheimer’s disease. Antipsychotic drugs are used to treat some of the psychiatric symptoms of Alzheimer’s, such as aggressive behaviour.
This trial came about as a result of the findings of short-term trials and a systematic review of related studies on behalf of the Cochrane organisation. These findings had suggested that antipsychotic drugs might increase the risk of adverse events and death in people with Alzheimer’s disease, but their long-term effect was unknown.
The researchers enrolled people with Alzheimer’s who were living in care facilities and had been taking antipsychotics for at least three months for psychiatric and behavioural disturbances. People taking the antipsychotics thiorizadine, chlorpromazine, haloperidol, trifluoperazine or risperidone were eligible for inclusion in the trial.
Enrollment took place between 2001 and 2004 in four regions of the UK (Oxfordshire, the Newcastle and Gateshead area, London and Edinburgh).
People were excluded from the study if they were unable to complete the assessment at the start of the study, or they were likely to experience increased suffering or distress while taking part. Those with certain heart problems were also excluded.
An independent statistician randomly assigned 165 eligible people (average age 84 years) to either continue receiving their antipsychotic treatment, or to switch to an inactive placebo pill for 12 months. Of the 165 people randomised, 128 actually started the study (78%).
For each antipsychotic drug used in this study, three doses were available: very low, low and high. Participants were given the dose nearest to the amount they were already taking.
Most participants (88%) received the low-dose antipsychotics, while the remainder received high doses. No participant received very low-dose antipsychotics. The most commonly used drugs were risperidone (67% of participants) and haloperidol (26%).
The researchers followed up participants for 12 months and assessed their cognitive and psychiatric function (results not reported in this publication). They also identified participants who died, and obtained their death certificates so they could identify the causes of death.
After 12 months, the double-blind treatment period was completed. The researchers carried out a telephone assessment 24 months after enrollment of the last participant (54 months after the first participants) to identify any further deaths. The researchers compared survival rates between the two groups.
What were the results of the study?
Among the 128 people who started the study, the researchers found that 70% of the antipsychotic drug group were still alive after 12 months, compared with 77% of the placebo group. After 24 months, 46% of the antipsychotic drug group were still alive, compared with 71% of the placebo group.
Over the entire period of the study, people who took antipsychotic drugs were about twice as likely to die than those taking a placebo (hazard ratio 0.58, 95% confidence interval 0.35 to 0.95). This result was similar if the researchers only analysed the data on those people who continued to take their assigned medication for the first 12 months of the study, or if they analysed all randomised participants.
What interpretations did the researchers draw from these results?
The researchers concluded that long-term use of antipsychotic drugs increases the risk of death among people with Alzheimer’s disease, and that more research is needed to identify less harmful alternatives.
What does the NHS Knowledge Service make of this study?
This study was designed and conducted well. Although it was relatively small, it does give an indication that risk of death in people with Alzheimer’s increases with long-term use of antipsychotics.
There are a few limitations to note:
Much of the difference in death rates between the two groups occurred after the double-blind period of the trial was completed (12 months). The authors report that the reasons for this are unclear, although it could be that any extremely frail patients enrolled in the study were likely to die within 12 months regardless of which group they were assigned to. Once these patients died, the effects of the treatments themselves could be seen more clearly.
Alternatively, the close monitoring of patients during the first 12 months may have reduced the risk of death in both groups because any adverse effects would be identified and dealt with if possible.
The authors also acknowledge that fewer people were available for follow-up later on, therefore it is possible that differences between the two groups occurred by chance.
After the 12-month study was completed, there may have been changes in medication that could have affected the results. For example, people from the antipsychotic drug group may have stopped taking antipsychotics, while those in the placebo group may have started on antipsychotics again. However, the authors felt that this was unlikely because only a few people from the placebo group were known to have restarted antipsychotics, and the groups were already starting to show a difference in mortality by the end of the initial 12-month period.
These results may not be applicable to all patients with Alzheimer’s, as those with the most severe cognition problems were excluded from the trial. In addition, these results do not apply to people taking antipsychotics for reasons other than dementia, such as schizophrenia.
This study highlights the risks associated with the long-term use of antipsychotic drugs by people with Alzheimer’s disease. It should be noted that some of the potential side effects of these drugs were already known or suspected prior to this study.
The National Institute for Health and Clinical Excellence (NICE) already recommends that the drugs should only be considered in people with dementia if they have severe psychiatric symptoms, and that they should be used for a limited period only, with regular monitoring. At present doctors should continue to follow this advice.
Links to the headlines
Liquid cosh' treatment kills dementia patients.The Independent, January 9 2009
Chemical coshes 'double the chance of Alzheimer's patients dying'.The Daily Telegraph, January 9 2009
Strongest drugs ‘double risk of death’ for dementia sufferers.The Times, January 09 2009
Dementia drug death risk warning.BBC online, January 9 2009
Links to the science
Clive Ballard C, ML Hanney, Theodoulou M,et al. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurology 2009; early online publication, January 9