Atypical antipsychotics benefit people with dementia but the risks of adverse events may outweigh the benefits, particularly with long term treatment

Atypical antipsychotics have become the pharmacological treatment of choice for many clinicians in the treatment of behavioural and psychiatric symptoms in people with dementia, and the largest evidence base for double blind placebo controlled trials in this area is for risperidone. Particularly in view of recent safety concerns, a meta-analysis of efficacy and adverse events to inform clinical practice is timely. Modest efficacy is evident, but the elevated risk of cerebrovascular adverse events, mortality, upper respiratory infections, oedema and extrapyramidal symptoms is a concern, particularly as selective reporting makes interpretation of other potential adverse outcomes impossible.

Authors' conclusions: 

Evidence suggests that risperidone and olanzapine are useful in reducing aggression and risperidone reduces psychosis, but both are associated with serious adverse cerebrovascular events and extrapyramidal symptoms. Despite the modest efficacy, the significant increase in adverse events confirms that neither risperidone nor olanzapine should be used routinely to treat dementia patients with aggression or psychosis unless there is severe distress or risk of physical harm to those living and working with the patient. Although insufficient data were available from the considered trials, a meta-analysis of seventeen placebo controlled trials of atypical neuroleptics for the treatment of behavioural symptoms in people with dementia conducted by the Food and Drug Administration suggested a significant increase in mortality (OR 1.7). A peer-reviewed meta-analysis (Schneider 2005) of 15 placebo controlled studies (nine unpublished) found similarly increased risk in mortality (OR=1.54, 95% CI 0.004 to 0.02, p=0.01) for the atypical neuroleptics.

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Background: 

Aggression, agitation or psychosis occur in the majority of people with dementia at some point in the illness. There have been a number of trials of atypical antipsychotics to treat these symptoms over the last five years, and a systematic review is needed to evaluate the evidence in a balanced way.

Objectives: 

To determine whether evidence supports the use of atypical antipsychotics for the treatment of aggression, agitation and psychosis in people with Alzheimer's disease.

Search strategy: 

The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 7 December 2004 using the terms olanzapine, quetiapine, risperidone, clozapine, amisulpride, sertindole, zotepine, aripiprazole, ziprasidone. This Register contains articles from all major healthcare databases and many ongoing trials databases and is updated regularly.

Selection criteria: 

Randomised, placebo-controlled trials, with concealed allocation, where dementia and psychosis and/or aggression were assessed.

Data collection and analysis: 

1. Three reviewers extracted data from included trials
2. Data were pooled where possible, and analysed using appropriate statistical methods
3. Analysis included patients treated with an atypical antipsychotic, compared with placebo

Main results: 

Sixteen placebo controlled trials have been completed with atypical antipsychotics although only nine had sufficient data to contribute to a meta-analysis and only five have been published in full in peer reviewed journals. No trials of amisulpiride, sertindole or zotepine were identified which met the criteria for inclusion.
The included trials led to the following results:
1. There was a significant improvement in aggression with risperidone and olanzapine treatment compared to placebo.
2. There was a significant improvement in psychosis amongst risperidone treated patients.
3. Risperidone and olanzapine treated patients had a significantly higher incidence of serious adverse cerebrovascular events (including stroke), extrapyramidal side effects and other important adverse outcomes.
4. There was a significant increase in drop-outs in risperidone (2 mg) and olanzapine (5-10 mg) treated patients.
5. The data were insufficient to examine impact upon cognitive function.

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