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FDA warns about using antipsychotic drugs for dementia

BMJ 2005; 330 doi: (Published 21 April 2005) Cite this as: BMJ 2005;330:922
  1. Jeanne Lenzer
  1. New York

    The US Food and Drug Administration issued a public health advisory warning of fatal adverse events in demented patients treated with atypical antipsychotic drugs. Seventeen controlled studies of elderly demented patients have shown that patients treated with the drugs were 1.6 to 1.7 times more likely to die than patients given placebo. The causes of death included congestive heartfailure, sudden death, and infections, such as pneumonia.

    The FDA asked manufacturers to place a “black box” warning on drug labels—indicating an adverse reaction that may result in death or serious injury—noting the increased death rates and that “these drugs are not approved for the treatment of behavioural symptoms in elderly patients with dementia.”

    The drugs affected include aripiprazole (Abilify), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), clozapine (Clozaril), and ziprasidone (Geodon). A drug used for depression associated with bipolar disorder, olanzapine (Symbyax), was included in the advisory warning.

    Warnings about atypical antipsychotic drugs have been issued in recent years after reports of increased rates of stroke, obesity, and diabetes. Last year, doctors in Europe and Canada received warnings about olanzapine as an intramuscular injection, but doctors in the United States did not. At the request of the regulatory authorities, Eli Lilly, the drug's manufacturer, sent doctors in Canada and Europe letters warning about the risks of fatal cardiovascular and respiratory events.

    The failure to warn US doctors triggered consternation. Michael Allen, director of psychiatric emergency services and associate professor of psychiatry at the University of Colorado Health Science Center in Denver, last week told the American Psychiatric Association's newspaper, Psychiatric News, “Why would fatalities be of less interest to US physicians? I can't understand why we would receive less information than our European colleagues” (

    In response to Dr Allen's concerns, Lilly spokesperson, Valerie Erb Tully, told the BMJ: “A letter was not required by the FDA in the US.” She said, “Lilly updated the product labelling in September 2004 and provided those physicians most likely to prescribe Zyprexa IM with written information on proper dosing. We have been working closely with the FDA to determine whether any education beyond what we have already done is deemed appropriate.”

    However, Dr Allen told the BMJ that he became aware of the problem only through email from Europeans. “My colleagues [in the US] asked how I knew about this,” he said, adding, “Even doctors close to Eli Lilly didn't know about it.”

    Dr Allen acknowledged that Lilly did update its labelling but said that Lilly's change of wording – that was not highlighted and presented as a warning – was insufficient. US doctors, unlike their European and Canadian colleagues, said Dr Allen, were not warned that fatalities and severeadverse reactions in patients taking olanzepine could be due to relatively modest dose increases or concomitant use of benzodiazepines. Such a warning is important, he said, since doctors often use higher doses of antipsychotic drugs, including olanzapine, and often in combination with benzodiazepines. “If it's important not to use intramuscular olanzapine the same waywe have used it orally, the way we use other intramuscular antipsychotics, we really need to knowthat.”

    Several of the atypical antipsychotic drugs have achieved blockbuster status. The top seller, olanzapine, sold $2.4bn (£1.3bn; €1.9bn) in 2004 in the United States, accounting for 15% of Eli Lilly's sales that year. It was the world's fourth biggest selling drug of any class in 2003, making $4.3bn in global sales. Johnson & Johnson's respiradone ranked second among the atypical antipsychotic drugs, making $2.5bn in sales in the US in 2004.

    This rapid rise of atypical antipsychotic drugs to blockbuster status is troubling, said Stefan Kruszewski, former clinical professor of psychiatry at Penn State Medical School. He told the BMJ, “The drugs were adopted almost as quickly as they came out.” He added that some atypical antipsychotic drugs were the only other class of drugs besides HIV medicines to be covered under a special pharmaceutical benefits programme that facilitated the rapid and incautious rise in the use of the drugs. The FDA said that it is currently examining whether older antipsychotic agents are also associated with higher death rates and that a review of the data is still ongoing.