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Antipsychotics and Alzheimer's

Tuesday 1 April 2008

“Medication 'worsens Alzheimer's'” reads the headline on the BBC News website today. The BBC reports that a study in 165 people with Alzheimer’s has found that antipsychotics “offered no long-term benefit for most patients with mild symptoms of disturbed behaviour”. It says that about 60% of people with Alzheimer’s in nursing homes are given antipsychotics to control problem behaviours, such as aggression. The Guardian also reports on the study, saying that these types of drugs (neuroleptics) have severe side effects, including stroke and death.

This study has provided evidence about the effects of withdrawing antipsychotics from people with Alzheimer’s disease. It demonstrated that there was no difference in global cognitive function between those who continued with the antipsychotic drugs (which they had been using for behavioural disturbance) for six to 12 months and those who were switched to inactive placebo drugs.

This study did not find that continuing with the antipsychotics worsened the patients’ Alzheimer’s; neither did it examine harmful outcomes of antipsychotics or differences in survival rates between the two groups. The newspapers reported a deterioration in the verbal skills of those who remained on antispsychotics. Although, the study did find that the group on antipsychotics had a slight drop in a score of verbal fluency that was statistically significant, this was not the focus of the study, was assessed in only a small number of patients and may not be robust. It is also not possible to tell whether the difference in verbal score would result in clinically meaningful differences between the patients. Further research that specifically looked at this outcome in Alzheimer’s patients would be needed to clarify this.

This study suggests that stopping, or continuing with, antipsychotics does not affect cognitive function in people with Alzheimer’s disease.

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 the research. The study was funded by the Alzheimer’s Research Trust. It was published in PLoS Medicine, a peer-reviewed open-access journal.

What kind of scientific study was this?

The study was a double-blind randomised controlled trial that assessed the effects of either continuing or stopping antipsychotics in people with Alzheimer’s disease.

The researchers enrolled 165 people with possible or probable Alzheimer’s disease who were living in nursing or residential homes and who had been taking antipsychotics (mainly haloperidol and risperidone) to treat their behavioural or psychiatric disturbance for at least three months. To be eligible, they had to have been taking daily amounts of at least 0.5mg of risperidone, 10mg chlorpromazine or the equivalent.

Eligible patients were randomly assigned to either continuing their antipsychotics for 12 months or were switched to inactive placebo pills. Antipsychotics were given in fixed doses, using very low, low and high doses, to match what the patient had been receiving prior to the study. The participants’ overall cognitive impairment and neuropsychiatric symptoms were measured at the start of the study, and again at six and 12 months using standard measurement scales (Severe Impairment Battery and Neuropsychiatric Inventory respectively). The researchers also looked at a range of secondary outcomes.

The outcomes of those who continued to receive antipsychotics were compared with those receiving placebo. Participants with low and high levels of neuropsychiatric symptoms (low defined as scoring 14 points or less on the NPI, high as 15 points or more) were also analysed separately to see if this had an effect on the outcomes of antipsychotic treatment.

What were the results of the study?

There was a high level of “loss to follow up”, meaning that many of the participants dropped out or died over the 12-month period.

At six months, it was only possible to assess 62% of the original 165 participants for cognitive impairment, and 66% for neuropsychiatric symptoms. At this time, there was no significant difference in the change in cognitive impairment or neuropsychiatric symptoms between those who continued taking antipsychotics and those who switched to placebo.

There was a separate analysis on those who, at the start of the study, had high neuropsychiatric symptoms scores. This showed a tendency for less deterioration in these symptoms in people who continued to take antipsychotics, but this difference did not reach statistical significance.

By 12 months, only about 30% of participants could be assessed. There was still no significant difference in change in cognitive impairment between the groups, but there was less deterioration in neuropsychiatric symptoms in the group that continued antipsychotics, particularly among those with high levels of symptoms at the start of the study.

What interpretations did the researchers draw from these results?

The researchers concluded that stopping antipsychotic drugs in people with Alzheimer’s does not adversely affect cognitive function. There may be some advantages to continuing antipsychotic treatment in people with more severe neuropsychiatric symptoms, but this should be balanced against their potential side effects.

What does the NHS Knowledge Service make of this study?

The advantages of this study are its randomised design and double blinding. However, it also has limitations that need to be considered.

  • The study’s main limitation was the high number of people who dropped out or died during follow up, particularly at 12 months. Because of this, it is not possible to be certain if the results in this very limited group of participants are representative of the results that would have been obtained in the whole group.
  • The study was relatively small, and particularly so after many of the participants dropped out during follow up. As such, it may not have been large enough to detect clinically important differences between the groups.
  • BBC news reported that neuroleptics “were associated with a marked deterioration in verbal skills”. The researchers carried out several assessments on different measures of cognition: function, neuropsychiatric symptoms, and language. The only assessment in which they found a statistically significant difference between antipsychotic and placebo groups was on an assessment of verbal fluency, with those continuing on antipsychotics having a slight drop in score compared to the placebo group. However, the fact that this measure was not the primary outcome being assessed by the researchers, that only 40% of participants were assessed using this measure, and that multiple secondary outcomes were tested makes this result less reliable. It is also not possible to tell whether these differences in verbal score between the groups would result in clinically meaningful differences between the patients.

This study suggests that stopping, or continuing with, antipsychotics does not affect cognitive function in people with Alzheimer’s disease.

Sir Muir Gray adds...

Important study, but as always a single study needs to be set in the context of all other similar studies. This is called a systematic review of the evidence.

Analysis by Bazian
Edited by NHS Website

Links to the headlines

Warning over anti-psychotic drugs.

Channel 4, 1 April 2008

Warning on drugs for Alzheimer's patients in nursing homes.

The Guardian, 1 April 2008

Medication 'worsens Alzheimer's'.

BBC News, 1 April 2008

Links to the science

Ballard C, Waite J, Birks J.

Atypical antipsychotics for aggression and psychosis in Alzheimer's disease.

Cochrane Database Syst Rev 2006, Issue 1

Ballard C, Lana MM, Theodoulou M, et al.

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

PLoS Medicine 2008; Apr 1