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Zyprexa and Other Drugs for Dementia

Posted by medconsumers on July 1, 2007

The frequently prescribed antipsychotic drugs are causing a slight increase in deaths in demented elderly people, according to a study published recently in Annals of Internal Medicine. You might wonder: Why on earth would a doctor prescribe antipsychotics—drugs that are used to treat schizophrenia and bipolar disorders—to a demented elderly person? In fact, doctors have been prescribing these drugs to demented elderly people for nearly 50 years with little or no evidence to support the practice, and misleading promotion of the newer, far more expensive antipsychotics have made things worse in the last seven years.

The newer antipsychotic drugs, sold under the brand names of Zyprexa, Risperdal and Seroquel, began to come on the market in 1996. Strong promotional campaigns on the part of the drug makers have had their intended effect, and doctors began to favor them over the older drugs because they are thought to have fewer adverse effects. (No head-to-head comparison trial with elderly demented participants has proven this commonly held belief.) The prescription of any antipsychotic for dementia is an off-label use, which means their safety and effectiveness are unproven according to FDA standards. But that rarely stops doctors who can prescribe drugs as they wish.

What’s more, the small increase in deaths associated with the newer antipsychotic drugs has been known for years. Fifteen out of 17 clinical trials reviewed by the FDA in 2005 found a 1.6 to 1.7 higher death rate in people taking one of these drugs compared to people taking a placebo.

The usual next step for the FDA is to mandate a black box warning in the drug “label,” which hardly anyone reads, including most doctors. (A drug label is a 20- to 40-page insert largely aimed at physicians and rarely comes with the drug.) In 2005, the FDA issued a public health advisory, stating that use of all three newer antipsychotics to treat elderly people with dementia is associated with an increased risk of death. The deaths appeared to be heart- or infection-related (mostly pneumonia). The Canadian regulatory agency, Health Canada, issued its own warning to doctors the same year.

The warnings seem to have made only a small difference. Sales temporarily dipped a bit, as some doctors thought it would be safer to switch their demented patients to one of the older antipsychotics like haloperidol (brand name: Haldol).

That brings us back to the latest antipsychotic drug study, which not only confirmed the slight increase in deaths but also found that the mortality risk may be even greater with the older antipsychotics that have been prescribed since 1958. This study involved over 27,000 elderly people living in Ontario, Canada, who were a mixture of people living in nursing homes or in the community.

The research team led by Sudeep S. Gill, MD, drew information from several databases, including pharmacy records, hospitalization records, billing information for health services and death records. From these sources, the researchers identified people with dementia who did and did not receive prescriptions for antipsychotic drugs. They then looked to see if the people were alive at 30, 60, 120, and 180 days after the initial prescription for the antipsychotic. The death rate of those who had received prescriptions was compared with the death rate of those who had not.

What Now?

Will this and the 15 other studies showing an increased death rate make any difference in the way doctors prescribe antipsychotics? Maybe not, but at least there is now an explanation for why they continued to prescribe the drugs despite the warnings. The story became public at the end of last year thanks to The New York Times reporting of the lawsuits against Eli Lilly, maker of Zyprexa.

Fraudulent Promotion

The 18,000 lawsuits were not filed on behalf of demented elderly people, but on behalf of people with schizophrenia and bipolar disorders who developed diabetes as a result of taking Zyprexa. The lawyer representing the plaintiffs provided New York Times reporter, Alex Berenson, with documents that revealed the fraudulent nature of Lilly’s campaign to get doctors to prescribe Zyprexa to a broader segment of the population.

In late 2000, Lilly began a campaign instructing its sales representatives to encourage primary care doctors to treat the symptoms and behaviors of schizophrenia and bipolar disorder, even though this specialty has no training in diagnosing or treating either illness.

According to The New York Times, Lilly’s sales representatives were trained to present physicians with misleading profiles of the perfect candidate for Zyprexa. One of the more outrageous examples was “Donna, a single mother in her mid-30s whose chief complaint is, ‘I feel so anxious and irritable lately.’”

The campaign was successful in increasing sales. By 2005 Zyprexa became Lilly’s best-selling product with $4.2 billion in global sales. Zyprexa and the other newer antipsychotics are three to nine times more expensive than the older drugs like Haldol.

By law, drug makers may promote their drugs only for diseases for which the FDA has found the medicines to be safe and effective. But they are rarely prosecuted for Lilly’s type of fraudulent drug promotion that could result in deaths of people who are not even appropriate candidates for the drug.

All drugs have their risks that must be accepted along with their benefits. So goes the justification for allowing drugs to remain on the market after fatalities are reported. But in the case of antipsychotics for dementia, an important question lingers: What are their benefits? No one tried to answer this question in a systematic way until 2002 when the Cochrane Collaboration published a review of all trials about Haldol, the oldest antipsychotic.

The Cochrane reviewers found that by 1989, there was some evidence that Haldol provided “a modest overall benefit” compared to nothing (i.e., a placebo). But two advances occurred after 1997—better trials were published (five in all, lasting 3-16 weeks) and a better understanding of the various behaviors associated with dementia. As a result, the Cochrane reviewers were able to identify a subgroup of demented people who benefited from Haldol: those whose dementia-related agitation takes the form of aggression.

The drug’s adverse reactions that include Parkinson-like symptoms, such as rigidity, and involuntary movements were found to be acceptable to this subgroup of demented patients as well as their caregivers. In return, Haldol reduced the risk of aggressive behavior.

A more recent Cochrane review, published in 2006, looked at two newer antipsychotics—Zyprexa and Risperdal—for people with Alzheimer’s disease. The review concluded that the adverse effects of these drugs may be too severe to justify their “modest efficacy.”

Maryann Napoli, Center for Medical Consumers ©
July 2007

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