Though the health risks of antipsychotic drugs for elderly patients have been previously documented, the study, published in this week's New England Journal of Medicine, was one of the largest to date, and it found dangers for younger adults, too.
The study's findings add to a growing body of research questioning the safety, cost and effectiveness of so-called atypical antipsychotic drugs. In 2007, U.S. sales of all antipsychotic drugs were $13.23 billion, up 12% from $11.81 billion in 2006, according to IMS Health Inc., a health-care information and consulting company. Atypical drugs were the driving force behind that growth; such medications had U.S. sales of about $13 billion through the first 11 months of 2008.
The atypical drugs used in the study were Seroquel, made by AstraZeneca PLC; Zyprexa, made by Eli Lilly & Co.; Risperdal, made by Johnson & Johnson; and Clozaril, made by Novartis AG. The "typical" drugs used for comparison were haloperidol and thioridazine, both generics.
An editorial accompanying the new study said the use of such drugs should be "reduced sharply" among children and elderly patients. Jerry Avorn, a professor of medicine at the Harvard Medical School and co-author of the editorial, said atypical antipsychotic drugs have been marketed as a safer alternative to older, more conventional medicines. "Now we understand that they have their own problems that are quite substantial," said Dr. Avorn, who was not involved with the study.
The growing use of such drugs has sparked widespread debate in the medical world. In November, a panel of outside advisers urged the Food and Drug Administration to discourage doctors from prescribing atypical antipsychotic drugs for children. Meanwhile, Connecticut, Arkansas and other states have sued various drug makers, alleging that they marketed such drugs for uses not authorized by the FDA and didn't adequately disclose potential side effects, such as weight gain and diabetes.
The FDA approves drugs for specific uses. Doctors can prescribe them for other treatments, but drug makers can't promote them for unapproved uses.
Conventional, or typical, antipsychotic drugs like chlorpromazine, known by the brand name Thorazine, have been used to treat conditions such as schizophrenia since the 1950s. But their side effects include involuntary tremors and tics that are sometimes irreversible. Studies have also linked them to sudden cardiac death, an abrupt and unexpected loss of heart function.
First introduced in 1989, the atypical drugs caused fewer of the involuntary-movement problems. Researchers say they were also thought to be much safer. But in recent years, that view has come into question.
After reviewing various studies, the FDA in 2005 began requiring makers of atypical drugs to put a so-called "black-box" warning on labels to indicate that elderly patients with dementia taking such drugs had a higher risk of premature death. The FDA hasn't approved the use of such drugs by dementia patients. The studies reviewed indicated the deaths were primarily related to heart-related causes and infections. Last year, the agency began requiring a similar black-box warning for older, typical antipsychotic drugs.
A small study published this month in Lancet Neurology, a British medical journal, found that the long-term use of any antipsychotic medication by 165 Alzheimer's-disease patients doubled their death rate after one year.
In 2006, a large federally funded study into the treatment of schizophrenia found that the heavily promoted atypical drugs were no more effective than the old ones and cost up to 30% more.
While FDA authorizations vary by drug, atypical drugs are approved for treating schizophrenia, bipolar disorder and irritability associated with autism in children as young as 5. Researchers say they are widely prescribed for off-label treatment of dementia in nursing-home patients and attention deficit hyperactivity disorder, or ADHD, in children.
For the new study, researchers at Vanderbilt University in Nashville, Tenn., reviewed the medical records of about 277,000 Tennessee Medicaid enrollees for the years 1990 to 2005. Of them, about 46,000 were taking atypical antipsychotic drugs and 44,000 were taking typical antipsychotic drugs. About 187,000 weren't taking any of the drugs. Patients ranged in age from 30 to 74 years; the average age was about 46.
Researchers said that among patients taking the antipsychotic drugs, there were about three sudden cardiac deaths for every 1,000 patient-years included in the study. A patient-year is one patient taking the medication for one year. Although patients taking atypical drugs had a slightly higher death rate than those taking the older medicines, researchers said the difference was not statistically significant. The death rate was about half that level for the control group of patients who weren't taking any antipsychotics, the study said.
The study also found that the risk of death increased for patients receiving larger doses of both kinds of drugs. "It suggests that the drugs, when used, should be used at the lowest possible dose," said Wayne Ray, the lead investigator.
Dr. Ray, a professor of preventive medicine at Vanderbilt University, said he believes the study will affect the practice of medicine and prompt physicians to be as careful about prescribing the atypical drugs as they are about using the problematic older typical medications. "The thinking that these atypical drugs were free of risk of sudden cardiac death seems to be incorrect," he said.
An Eli Lilly spokesman said the study provides information physicians should consider when prescribing such drugs but added that Zyprexa has helped millions with serious mental illnesses regain control of their lives. A J&J spokesman said the study "adds important new information" to related research and that atypical drugs offer "significant benefits" to many patients with severe and debilitating symptoms.
Novartis said it places the highest priority on patient safety and is evaluating the study's findings. An AstraZeneca spokesman said the company believes Seroquel is safe and effective but won't comment on the study until it has reviewed it in detail.
In a disclosure published with the study, Dr. Ray said he has received research support from Pfizer Inc., manufacturer of a competing atypical antipsychotic drug called Geodon. He has also received consulting fees from plaintiffs lawyers in litigation involving other sorts of drugs. C. Michael Stein, a co-author and fellow Vanderbilt researcher, disclosed that he has received consulting fees from insurance companies regarding antipsychotic drugs.