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Antipsychotic Drugs in Patients with Dementia: Minimal Benefit

Atypical antipsychotics were not much better than placebo, and they may be associated with increased mortality.

Although the atypical antipsychotic drugs such as olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal) are FDA-approved only for treatment of schizophrenia and bipolar mania, clinicians frequently use them to treat agitation in patients with dementia. However, in April 2005, the FDA issued an advisory about increased mortality in elderly demented patients with behavioral disorders who are treated with atypical antipsychotic drugs; this advisory resulted in a black-box warning now included in the prescribing information for these drugs. Later in 2005, a published meta-analysis reached a similar conclusion, based on death rates of 3.5% in patients receiving atypical antipsychotic drugs and 2.3% in placebo recipients in 15 trials of 6 to 26 weeks’ duration (JAMA 2005 Oct 19; 294:1934).

If atypical antipsychotic drugs treated agitation effectively in patients with dementia, one might consider a small increase in mortality to be an acceptable tradeoff. But an NIH-sponsored study published in 2006 raised questions about their effectiveness in this setting (Journal Watch Oct 11 2006). In a 36-week double-blind randomized trial, 421 outpatients with Alzheimer disease and psychosis, agitation, or aggression received olanzapine, quetiapine, risperidone, or placebo. The primary outcome, drug discontinuation for any reason, captured both of the reasons that clinicians and patients stop drugs — side effects and lack of efficacy. Median time to discontinuation was similar in the four groups (5–8 weeks), and by the end of the study, about 80% of patients in each group had stopped taking their assigned drugs. Drugs were stopped because of lack of efficacy less often in the active treatment groups than in the placebo group, but this advantage was offset by more frequent drug discontinuation because of side effects in the active treatment groups.

These results should lead clinicians to think twice before prescribing atypical antipsychotic drugs for agitated outpatients with dementia. Clinicians who consider using these drugs should discuss their limitations and risks with patients' caregivers and should not prescribe them indefinitely.

Finally, given the FDA advisory on atypical antipsychotic drugs, one might be tempted to consider the older, conventional agents as safer alternatives. However, in a retrospective study of 23,000 elderly recipients of antipsychotic drugs, researchers found mortality risks to be slightly higher with conventional agents than with atypical agents (Journal Watch Dec 16 2005). The retrospective nature of this study is an important limitation, but the findings serve as another reminder to use any of these drugs judiciously.

— Allan S. Brett, MD

Published in Journal Watch General Medicine December 28, 2006