IPS: Life Out On The Pharm

In Antipsychotics, Newer Isn't Better

Drug Find Shocks Researchers

By Shankar Vedantam
Washington Post Staff Writer
Tuesday, October 3, 2006

Schizophrenia patients do as well, or perhaps even better, on older psychiatric drugs compared with newer and far costlier medications, according to a study published yesterday that overturns conventional wisdom about antipsychotic drugs, which cost the United States $10 billion a year.

The results are causing consternation. The researchers who conducted the trial were so certain they would find exactly the opposite that they went back to make sure the research data had not been recorded backward.

The study, funded by the British government, is the first to compare treatment results from a broad range of older antipsychotic drugs against results from newer ones. The study was requested by Britain's National Health Service to determine whether the newer drugs -- which can cost 10 times as much as the older ones -- are worth the difference in price.

There has been a surge in prescriptions of the newer antipsychotic drugs in recent years, including among children.

The study, published in the Archives of General Psychiatry, is likely to add to a growing debate about prescribing patterns of antipsychotic drugs. A U.S. government study last year found that one of the older drugs did as well as newer ones, but at the time, many American psychiatrists warned against concluding that all the older drugs were as good.

Yesterday, in an editorial accompanying the British study, the lead researcher in the U.S. trial asked how an entire medical field could have been misled into thinking that the expensive drugs, such as Zyprexa, Risperdal and Seroquel, were much better.

"The claims of superiority for the [newer drugs] were greatly exaggerated," wrote Columbia University psychiatrist Jeffrey Lieberman. "This may have been encouraged by an overly expectant community of clinicians and patients eager to believe in the power of new medications. At the same time, the aggressive marketing of these drugs may have contributed to this enhanced perception of their effectiveness in the absence of empirical information."

Peter Jones, a psychiatrist at the University of Cambridge in England who led the study, searched yesterday for the right word to describe what had happened to his colleagues.

" 'Duped' is not right," he said. "We were beguiled."

One drugmaker immediately questioned the findings. Carole Puls, a spokeswoman for Eli Lilly and Co., which makes Zyprexa, said it was problematic to compare large groups of medications because there are differences between the drugs in each class. Individual patients need different medication options, she said.

Janssen Pharmaceutica, which makes Risperdal, and AstraZeneca, which makes Seroquel, did not respond to requests for comment.

Schizophrenia is a serious mental disorder that is believed to affect about one in 100 adults. It is characterized by psychotic symptoms such as hallucinations and delusions and negative symptoms such as social withdrawal.

Especially over the past decade, older antipsychotics such as Haldol have been widely criticized for triggering uncontrolled body movements, even as the new "atypical" antipsychotics were hailed for causing fewer side effects. Recently, however, concern has grown that antipsychotics in general, and some of the newer drugs in particular, may be causing metabolic side effects.

The new study randomly assigned 227 schizophrenia patients to two groups -- one received a newer antipsychotic, the other an older drug. The patients were evaluated for more than a year by experts who did not know which drug was being taken.

While the researchers had expected a difference of five points on a quality-of-life scale -- showing the newer drugs were better -- the study found that patients' quality of life was slightly better when they took the older drugs. Jones said a conservative interpretation of the data suggested that there is no difference, "so the notion you would pay 10 times as much would be difficult to justify."

"Why were we so convinced?" he asked, referring to the widespread opinion among psychiatrists that the new drugs were worth the great difference in cost. "I think pharmaceutical companies did a great job in selling their products. That is certainly one issue.

"It became almost a moral issue on whether you would prescribe these dirty old drugs," he added. "It became the 'my son' phenomenon. What would you prescribe for your son?"

In retrospect, Jones and others said, there were hints going back many years. In 2003, Robert Rosenheck, a psychiatrist at the Department of Veterans Affairs, found there was no difference between Haldol and Zyprexa -- after patients taking Haldol were treated to prevent the movement side effects.

Last year, the U.S. government trial found that an older drug called perphenazine did about as well as the newer medications. Still, the belief in the newer drugs was so ingrained that many psychiatrists insisted that the results could not be extrapolated to other old drugs, said Rosenheck, who helped conduct that study.

Darrel Regier, who directs research at the American Psychiatric Association, cautioned against drawing broad conclusions after the new study and said that "a thoughtful and prolonged process " is needed before treatment guidelines are changed. Not all the drugs used in the British study were available in the United States, he said, and with many of the newer medications reaching the end of their patent lives, he predicted that questions of cost would fade away.

Jones and Rosenheck said the problem with many drug company studies that seemed to show that new drugs are better is that they focused on short-term results -- a symptom or side effect -- rather than the big picture: how patients fare long-term.

"The story of these newer antipsychotic drugs is a story that reveals an institutional gap," Rosenheck said. "It should not have needed 10 years to get three government studies."

Jones said the studies also illustrate the importance of trusting data, rather than judgment. He drew an analogy with his hobby of walking.

"Sometimes the compass tells you go straight in front of you, but you somehow know it is wrong and that north is behind you," he said. "I have learned to follow the compass."

Vaccines possible for unhealthy habits
Overeating, smoking, cocaine use targeted

From the Baltimore Sun
By Ronald Kotulak
October 1, 2006

CHICAGO -- Vaccines, the most potent medical weapon ever devised to vanquish deadly germs, are being called on to do something totally different and culturally revolutionary - to inoculate people against bad habits such as overeating, cigarette smoking and drug use.

Whether this new era of vaccine research can actually subdue many of the poor lifestyle choices that are today's biggest threats to health, causing obesity, cancer, heart disease and other problems, has yet to be proved.

But the evidence is promising enough to persuade the federal government to put millions of dollars toward finding out whether two of the vaccines can end nicotine and cocaine addiction.

The National Institute on Drug Abuse, which has spent $15 million on clinical trials for the vaccines and plans to spend more, predicts that one of the nicotine vaccines might be available for marketing in three years.

"The American Cancer Society has projected that we will have 1 billion people die from smoking in the world in this century," said Frank Vocci, director of medications development for the institute. "If you had a vaccine that helped people quit and stay quit, or prevent them from smoking, that's where you'd get the greatest public health benefit."

Meanwhile, results from a major obesity vaccine trial under way in Switzerland are expected this year, and company officials are hopeful that the vaccine could be ready for use in a few years if all goes well.

To block deleterious behavior, the new vaccines employ the body's natural immune system in an innovative way. Instead of building antibodies to destroy germs as traditional vaccines do, they construct antibodies that lock onto nicotine and cocaine molecules, preventing them from reaching the brain.

"What we're seeing is a renaissance in vaccine technology," said Dr. Gary J. Nabel, director of the National Institute of Allergy and Infectious Diseases' Vaccine Research Center. "It's only natural that when you have a technology that's this powerful, it can be applied to other medical problems."

Normally, nicotine and cocaine molecules are too small to be seen by the immune system.

So to make the vaccines, scientists attach these molecules to big target proteins, such as harmless viruses or bacteria, which the immune system can recognize and attack with specialized antibodies.

When the person later smokes a cigarette or takes cocaine, the antibodies wrap up and neutralize the molecules before they can trigger feelings of euphoria and pleasure in the brain. Smokers and cocaine users given the vaccines say their pleasure is diminished or they no longer get as high, which decreases the desire for the drug.

In the case of the obesity vaccine, antibodies attach to the hunger protein called ghrelin, preventing it from reaching the brain and stimulating appetite.

Ghrelin, which is secreted by the empty stomach, travels in the bloodstream to the brain, where it tells a person to eat. But the hormone, discovered in 1999, also has other important roles, such as signaling the body to become less active and to store food as fat instead of using it for energy production.

The reason losing weight can be hard, researchers say, is that dieting causes large amounts of ghrelin to be produced as the body seeks to stimulate eating, slow down the metabolism of fat and promote fat retention.

Ghrelin also might help explain the yo-yo experience of millions of people who try to lose weight but end up putting on more pounds.

To many researchers, the vaccines seem to be a potential answer to many of society's major ills - in the U.S., there are 50 million cigarette smokers, 5 million drug addicts, 60 million obese adults and 9 million overweight youngsters between the ages of 6 and 19.

Most have one thing in common: They would like to quit but can't. Nearly 7 out of 10 smokers, for instance, say they want to stop, but 80 percent to 90 percent of those who try to quit resume smoking within a year. The relapse problem is even worse for cocaine addicts.

"There is a great deal of promise for the nicotine vaccine not only as a smoking cessation tool but also potentially as a relapse prevention tool," said Dorothy Hatsukami, director of the Transdisciplinary Tobacco Use Research Center at the University of Minnesota Cancer Center.

"For those who have achieved abstinence and don't want to slip into relapse, being injected by the vaccine might be a good tool," said Hatsukami, whose preliminary data showed that in a small group of smokers, the nicotine vaccine enabled 38 percent to remain abstinent for 30 days, compared with 9 percent on a placebo.

The goal is getting people to give up cigarettes for a year.

"If you can get someone past 12 months with being smoke-free, there's a 70 to 75 percent chance that that person will remain smoke-free," said Nabi official Thomas Rathjen.

Unlike most older vaccines, which tend to confer permanent immunity, the new breed of vaccines is reversible, providing immunity against nicotine, cocaine or the hunger hormone ghrelin for one to three months before booster shots are needed.

None of the lifestyle vaccines have produced side effects other than some flu-like symptoms and soreness at the injection site.

"These vaccines are not going to be a panacea for treating everything," said Kim D. Janda of the Scripps Research Institute, a pioneer in developing vaccines for addiction and obesity. "I believe they can be helpful. When people are undergoing abstinence for drugs of abuse and they have weak moments, if you have a vaccine in place it can assist them so they don't spiral down to ground zero."
Ronald Kotulak writes for the Chicago Tribune.

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