1. Brandt, Doug

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The research findings were clear. Fifteen of 17 trials examining "atypical" antipsychotic medications showed that, in comparison with placebo, the drugs nearly double an older adult's risk of death. It was a sobering finding; although the drugs are approved only for the treatment of specific conditions, such as schizophrenia, the number of prescriptions written for off-label purposes, such as dementia, delirium, and agitation, is high-more than 25% of nursing home residents on Medicare receive these medications. As a result of those studies, in April 2005 the Food and Drug Administration mandated "black box" warnings on the labels of these newer antipsychotics reporting the increase in risk and reminding providers and patients that the drugs haven't been approved for the treatment of other conditions.


Not the end of the story.

The atypical antipsychotics had been tested against placebo, not against conventional antipsychotics, and there were concerns that prescribers would rush back to the older antipsychotics without knowing whether they also posed a danger. To find out, researchers examined records pertaining to nearly 23,000 Pennsylvania adults 65 years of age or older who were newly prescribed either typical or atypical antipsychotics between 1994 and 2003. The atypical agents (and brands) studied were aripiprazole (Abilify), clozapine (Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon).


The conventional agents were acetophenazine (Tindal), chlorpromazine (Thorazine), fluphenazine (Prolixin, Permitil), mesoridazine (Serentil), perphenazine (Trilafon), thioridazine (Mellaril), trifluoperazine (Stelazine), triflupromazine (Vesprin), chlorprothixene (Taractan), haloperidol (Haldol), loxapine (Loxitane), molindone (Moban), pimozide (Orap), and thiothixene (Navane).


Medicare mortality data revealed that the risk of dying within 180 days of beginning therapy with antipsychotics was 37% higher in the group using conventional agents than in the group taking atypical agents. When broken into smaller time periods, the results were comparable: the risk of death within 40 days of beginning therapy with conventional antipsychotics, as compared with atypical ones, was 56% higher; the risk of dying 40 to 79 days after starting therapy was 37% higher; and the risk of dying 80 to 180 days afterward was 27% higher. The risk was also dosage dependant.


The risk of dying within 180 days of starting high-dosage therapy with conventional agents was 73% higher, as compared with low-dosage therapy (relative risk, 1.14).


The study authors conclude that conventional antipsychotics are not safer than the newer drugs and suggest that the FDA consider adding precautions to the labels of the older drugs as well.


Wang PS, et al. N Engl J Med 2005;353(22): 2,335-41.