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Psychiatric Drugs On the Couch

Psychiatric Drugs On The Couch
Matthew Herper, 04.03.06, 10:00 AM ET

New York -
A pair of giant, U.S. government-funded studies could drive changes in psychiatry that could slash sales of some of the world's biggest drug companies.

The clinical trials are part of a $140 million effort by the National Institute of Mental Health to compare the most common treatments for schizophrenia and depression. Already, both trials had shown that most patients didn't respond to big-name drugs like Zyprexa for schizophrenia or Celexa for depression. Now, results are in comparing different treatment regimens in patients who were left unhelped--and these new data will probably help Medicare, Medicaid and health insurers push for cheap generics in the coming years. The companies with the biggest risk are Eli Lilly, which makes Zyprexa and the antidepressant Cymbalta, and Wyeth, which makes the antidepressant Effexor.

Results from the schizophrenia trial, called the Clinical Antipsychotic Trials of Intervention Effectiveness or CATIE, were released Saturday in the American Journal of Psychiatry. Zyprexa had out-performed its rivals in the first stage of the trial, but also been more likely to cause severe side effects such as weight gain and high cholesterol. In the second stage, it still did better than most of its competitors, but there was an exception. Risperdal, a cheaper Johnson & Johnson drug that goes generic in a year and a half, did even better.

The main measure of a drug's effectiveness in CATIE was how long patients kept taking it. In second phase, patients stuck with Zyprexa and Risperdal for six and seven months, respectively. By contrast, they stayed on Seroquel, from AstraZeneca, for four months and Geodon, from Pfizer, for three.

But any efficacy win for Lilly is significantly diluted, because Zyprexa was given in a higher dose than the other medicines, some of which were introduced by their makers at doses that were too low. "The important data are the side effect data," says Carol Tamminga, a psychiatry professor at UT-Southwestern who wrote an editorial that accompanies the study.

And the side effect data don't bode well for Lilly. Patients taking Zyprexa gained more than a pound a month, compared to weight loss of more than a pound-and-a-half a month for those taking Geodon and no change for the other drugs. Zyprexa was also the only drug to cause substantial increases in cholesterol and triglycerides. Geodon was, in a sense, the best drug to try, says Joseph McEvoy of Duke University, one of the lead organizers of CATIE. "You just had to be lucky enough to respond to it."

Such concerns have already hurt Zyprexa. This year, Seroquel passed it as the top-selling antipsychotic, and it has fallen in two years from the fifth-best-selling drug in America to the 15th, according to consulting firm IMS Health. U.S. Zyprexa sales have slumped 24% to $2.4 billion even as the overall schizophrenia market rose 25% to $10 billion.

Weighty Shift

Rank

Drug

Maker

2003 U.S. Sales

2005 U.S. Sales

Change (%)

1.

Seroquel

AstraZeneca

$1.6 billion

$2.6 billion

65%

2.

Zyprexa

Eli Lilly

3.3 billion

2.5 billion

-23

3.

Risperdal

Johnson & Johnson

2.1 billion

2.3 billion

9

4.

Abilify

Bristol-Myers Squibb/Otsuka

400 million

1.5 billion

321

5.

Geodon

Pfizer

500 million

600 million

18

All Drugs:

8.4 billion

10.5 billion

25

Source: IMS Health

Zyprexa "is a good drug that has a fatal flaw," says Henry Nasrallah, a professor of psychiatry at the University of Cincinnati. He sees Lilly trying to position the drug as more efficacious than its rivals. "I can't disagree with that," he says. But Nasrallah says he might not use Zyprexa until after several other antipsychotics have failed.

The clear winner in efficacy was Clozaril, a now-generic Novartis drug. Clozaril is rarely used because of severe side effects, including not only weight gain, but also severely low white blood cell counts. Patients on Clozaril in a separate study stayed on the drug for 10 months compared to three for Zyprexa, Seroquel or Risperdal. Even as Risperdal will be available as the cheapest antipsychotic, more of the very sickest patients may be switched to Clozaril.

The depression study, called the Sequential Treatment Alternatives to Relieve Depression (STAR*D), was released on March 23. A previous part of the study had treated patients on Celexa, a generic drug sold by Forest Laboratories. The more recent results compared GlaxoSmithKline's Wellbutrin (generic), Pfizer's Zoloft (goes generic next year) and Effexor, which is Wyeth's bestseller.

Conventional wisdom says that drugs like Effexor and Lilly's Cymbalta should be better than old medicines like Zoloft, Prozac and Celexa because they work on a second neurotransmitter on the brain. STAR*D didn't dispel that notion entirely, but in the study, all the drugs worked basically the same. All the drugs helped about 25% of people. (Effexor was slightly better, but the difference was not statistically significant.) "If insurance companies want to, I don't think there's anything wrong with them saying, 'whenever is medically reasonable, use the cheaper one," says John Rush, the UT-Southwestern psychiatrist who headed up STAR*D.

Both CATIE and STAR*D highlight the role that could be played by the U.S. government in studying drugs. Companies tend to be reticent to compare their medicine to a competitor, and when they do they are frequently accused of stacking the deck. And generic drugs like Clozaril just don't get studied.

Unfortunately, these clinical trials are the exception. Most of the $29 billion budget at the National Institutes of Health goes to basic research in animals and Petri dishes, not people. The government also would need to operate on a private sector schedule: If the CATIE study had been funded by a drug company, the results would have been released as soon as they were available. But to be sure they were published in a medical journal, the CATIE researchers presented them twice over a period of months--first in Hawaii and then in Switzerland--without ever issuing a press release to the public.

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