CRD summary

This review assessed the risk of death associated with atypical antipsychotic drugs, compared with placebo, for patients with dementia. The authors concluded that there may be a small increase in the risk of death with such treatment, which should be considered in a wider medical context. This was a well-conducted review and the authors' conclusions are likely to be reliable.

Authors' objectives

To determine whether atypical antipsychotic drug treatment for people with dementia resulted in an increase in mortality.

Searching

MEDLINE (1966 to April 2005) and the Cochrane Controlled Trials Register (Issue 1, 2005) were searched. In addition, the authors handsearched conference programmes, abstract books, conference proceedings, abstracts, poster presentations and slides from geriatric medicine, psychiatric, neurological and geriatric psychiatric professional society meetings since 1999. Pharmaceutical companies manufacturing atypical antipsychotics were also contacted.

Study selection

Assessment of study quality

The trials were required to be double-blind in order to be eligible for inclusion in the review. In addition, the studies were required to report methods of randomisation and the numbers of drop-outs. The assessment method formed part of the process by which papers were selected for the review, but the authors did not state who performed the validity assessment.

Data extraction

One reviewer extracted the data and a second reviewer checked them. Data were extracted on all-cause drop-outs and deaths occurring within the trial period or 30 days of its conclusion. Dosage groups were aggregated within trials. Odds ratios (ORs) and absolute risk differences were calculated for drop-outs and deaths.

Methods of synthesis

Results of the review

Fifteen studies with 16 contrasts of antipsychotic drugs with placebo, and involving a total of 5,387 patients, were included in the review.

Death.

The pooled OR for all 15 trials was 1.54 (95% confidence interval, CI: 1.06, 2.23, P=0.02) in favour of placebo, with no significant heterogeneity among the studies.

In trials (n=3) using aripiprazole versus placebo, the risk difference was 0.01 (95% CI: -0.01, 0.03, P=0.20) in favour of placebo.

In trials (n=5) using olanzapine versus placebo, the risk difference was 0.01 (95% CI: -0.00, 0.07) in favour of placebo.

In trials (n=3) using quetiapine versus placebo, the risk difference was 0.02 (95% CI: -0.01, 0.05, P=0.22) in favour of placebo.

In trials (n=5) using risperidone, the risk difference was 0.01 (95% CI: -0.01, 0.02, P=0.33) in favour of placebo.

Drop-outs.

There was no significant difference in drop-outs between the drug and placebo groups, although there was significant heterogeneity among the trials and between drugs.

Other analyses.

The ad hoc analysis of death rates by length of exposure favoured placebo (pooled RR 1.65, 95% CI: 1.19, 2.29). The sensitivity analyses found no significant differences between groups.

Authors' conclusions

Atypical antipsychotic drugs may be associated with a small increase in risk of death in comparison with placebo.

CRD commentary

The review question and the inclusion criteria were clear. The search was adequate and included unpublished material. The authors assessed publication bias but did not report whether they found any evidence of it. The use of language restrictions was not reported, so bias is unlikely to have been introduced in this way. The authors also did not report using methods to minimise bias and error when selecting studies for their review, and the validity assessment inherent in this process, although such methods were employed in the data extraction. The statistical analysis, which including meta-analysis, was appropriate and thorough. This was a well-conducted systematic review and the authors' conclusions are likely to be reliable.

Implications of the review for practice and research

Practice: The authors stated that the small increased risk of death should be considered within the context of medical need for the drugs involved, evidence of their efficacy, medical co-morbidity, and the efficacy and safety of alternatives.

Research: The authors stated that individual patient analyses modelling survival and causes of death are required.

Funding

Alzheimer's Disease Centers of California, grant number 03-75274; University of Southern California Alzheimer's Disease Research Center, grant number NIH AG 05142.

Bibliographic details

Schneider L S, Dagerman K S, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005; 294(15): 1934-1943. [PubMed: 16234500]

Original Paper URL

http://jama.ama-assn.org/

Other publications of related interest

This additional published commentary may also be of interest. Hirsch C. Review: atypical antipsychotic drugs increase risk for death in dementia. ACP J Club 2006;144:36.

Indexing Status

Subject indexing assigned by NLM

MeSH

Antipsychotic Agents /adverse effects; Cerebrovascular Disorders /chemically induced /mortality; Dementia /drug therapy /mortality; Humans; Randomized Controlled Trials as Topic; Risk

AccessionNumber

12005008533

Database entry date

28/02/2006

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.