The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease.
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.


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


METHODS
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.


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


METHODS
1. Two reviewers extracted data from included trials2. Data were pooled where possible, and analysed using appropriate statistical methods3. Analysis included patients treated with an atypical antipsychotic, compared with placebo


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 olanzpaine treated patients had a significantly higher incidence of serious adverse cerebrovascular events (including stroke), extra-pyramidal 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.


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 extra-pyramidal 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 marked risk or severe distress. 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 (using data not in the public domain) suggested a significant increase in mortality (OR 1.7).
Ballard
C
C
Kings College London, Wolfson Centre for Age-Related Diseases, Wolfson Wing, Hodgkin Building, Guy's Campus, London, UK, SE1 1UL. clive.ballard@kcl.ac.uk
Waite
J
J
D000374:Aggression; D000544:Alzheimer Disease / Q000523:psychology*; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D000068180:Aripiprazole; D001569:Benzodiazepines / Q000627:therapeutic use; D003987:Dibenzothiazepines / Q000627:therapeutic use; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy*; D000077152:Olanzapine; D010879:Piperazines / Q000627:therapeutic use; D011595:Psychomotor Agitation / Q000188:drug therapy*; D011618:Psychotic Disorders / Q000188:drug therapy; D000069348:Quetiapine Fumarate; D015363:Quinolones / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D018967:Risperidone / Q000627:therapeutic use
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D010879:Piperazines; D015363:Quinolones; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D000068180:Aripiprazole; D018967:Risperidone; D000077152:Olanzapine