Federal Study Finds No Benefit of New Antipsychotic Drugs – WashPost/Wall StreetJ/NY Times

Federal Study Finds No Benefit of New Antipsychotic Drugs – WashPost/Wall StreetJ/NY Times

Tue, 20 Sep 2005

The findings of a $44 million government sponsored study, CATIE, published in The New England Journal of Medicine, comparing an older generic antipsychotic to four new atypical antipsychotics, undercut the legitimacy of psychiatry’s treatment and practice guidelines for schizophrenia.

The Washington Post reports: “Expensive new antipsychotic drugs that are among the most widely prescribed pills in medicine are no more effective and no safer than an older, cheaper drug that has been largely discontinued, according to the most comprehensive comparative study ever conducted.”

The New York Times reports: “A landmark government-financed study that compared drugs used to treat schizophrenia has confirmed what many psychiatrists long suspected: newer drugs that are highly promoted and widely prescribed offer few – if any – benefits over older medicines that sell for a fraction of the cost.”

“The study has vital public health implications,” said Thomas Insel, director of the National Institute of Mental Health, which funded the study. “It is the largest, longest and most comprehensive, independent trial ever done to examine existing therapies for this disease.”

The Wall Street Journal reports: “the study also exposed just how poorly current antipsychotic drugs really work: Nearly three-quarters of people treated stopped taking the medicine they had been given within 18 months, due to side effects or poor control of symptoms.”

The CATIE study findings confirm an earlier comparison by John Geddes and a team of British scientists (BMJ, 2000). The findings have exposed as untenable the rationale behind psychiatry’s current practices, and are as significant as the findings of the Women’s Health Initiative (2002) which brought to an end a generation of hormone replacement therapy for women. CATIE spells the demise of a $10 billion dollar a year US market for a class of highly toxic drugs that have dominated psychiatry. The success of the atypicals rests largely on aggressive marketing that falsely claimed “they caused fewer side effects” than the old.

Technically, the study did not measure drug effectiveness: the primary measure used to test these drugs’ effectiveness was how long patients stayed on them, which the investigators say, reflects patients’ and physicians’ judgment about “whether the benefits were worth the undesirable effects.”

The reported findings of the first phase of the study should not have surprised clinicians whose patients do not improve with these drugs. Depending on which drug they were assigned, between 64% and 82% of patients quit before completing the 18 month study: patients on olanzapine (Zyprexa) quit after 9.2 months; those on the older drug, pephenazine, quit after 5.6 months; patients on risperidone (Risperdal) quit after 4.8 month; those on quetiapine (Seroquel) quit after 4.6 months; and those on Ziprasidone (Geodon) quit after 3.5 months. How does one justify the vast cost differential? The old drug, pephenazine, costs $60 for a month’s supply; the cost of the newer atypical antipsychotics ranges from $290 for Geodon, $250 for Risperdal; $450 for Seroquel; and a whopping $520 a month for Zyprexa.

The most serious reported findings concern the metabolic changes produced by Zyprexa: “Patients in the olanzapine group gained more weight than patients in any other group, with an average weight gain of 2 lb (0.9 kg) per month. A larger proportion of patients in the olanzapine group than in the other groups gained 7 percent or more of their baseline body weight (30 percent vs. 7 to 16 percent, P<0.001). Olanzapine had effects consistent with the potential development of the metabolic syndrome and was associated with greater increases in glycosylated hemoglobin, total cholesterol, and triglycerides after randomization than the other study drugs, even after adjustment for the duration of treatment."

The study does not indicate how these serious metabolic changes manifested in adverse clinical events – such as heart attack? If longer exposure to the drug increased patients’ risk of developing diabetes, cardiac abnormalities, and other metabolic diseases, then it cannot be said that the longer time patients stayed on Zyprexa was a benefit. Indeed, in the accompanying editorial in the NEJM, psychiatrist Robert Freedman concurred stating: “the uncontrolled movements caused by the older drugs were “less troubling than potentially fatal metabolic problems associated with some of the newer drugs.”

Press reports noted: “The findings may have significant implications for how doctors treat the 3.2 million people in this country suffering from schizophrenia.”

In fact, these drugs are also used for bipolar disorder, and for various unapproved, off-label uses – including children with behavioral problems, and elderly patients with dementia. In general, as the WSJ notes, psychiatrists have been prescribing psychotropic drugs such the antipsychotics with incomplete or false information about the benefits and risks.

The ramifications of this study seem to have eluded the American Psychiatric Association: “It would be a tremendous mistake to assume from this study that the cheaper, older drugs are, quote, ‘just as good,’ ” added Darrel Regier.

However, the new antipsychotics have documented serious risks of harm that are not offset by any unique benefit.

Thus, the findings have pulled the rug out from under a series of ill-advised, commercially motivated policies and prescription guidelines:

1. The Texas Medication Algorithm Project (TMAP) guidelines which recommend these expensive drugs as first line treatment should be declared invalid.

2. State policies that supported coercive measures to force patients to take antipsychotics must be rescinded.

3. The FDA must issue a public advisory at once warning physicians against prescribing atypicals off-label.

4. Doctors who prescribe an atypical must be required to monitor patients metabolic functions on a regular basis.

5. No child under 18 should be exposed to atypical antipsychotics – which are mainly used to control bad behavior.

6. The so-called schizophrenia prevention study conducted at Yale University, in which healthy adolescents are exposed to olanzapine for a year. The stated rationale for selecting these adolescents is that they have a sibling diagnosed with schizophrenia, and by extension the researchers speculate – without evidence – that the drug could prevent schizophrenia.

Contact: Vera Hassner Sharav
212-595-8974

www.washingtonpost.com/wp-dyn/ content/article/2005/09/19/AR2005091901867.html

WASHINGTON POST New Antipsychotic Drugs Criticized
Federal Study Finds No Benefit Over Older, Cheaper Drug
By Shankar Vedantam Tuesday, September 20, 2005; A01

Expensive new antipsychotic drugs that are among the most widely prescribed pills in medicine are no more effective and no safer than an older, cheaper drug that has been largely discontinued, according to the most comprehensive comparative study ever conducted.

The surprising result of a federally funded study released yesterday challenges widespread assumptions among psychiatrists about the best way to treat serious mental illness and underscores the extent to which physicians, patients and policymakers can be blindsided by self-interested research by drugmakers.

The study also paints a sobering picture of the state of treatment of schizophrenia, a disabling illness that afflicts about 3.2 million Americans with symptoms such as delusions, hallucinations and disordered thinking: Every drug, old and new, caused serious side effects, and the vast majority of patients stopped taking each of them.

“The study has vital public health implications,” said Thomas Insel, director of the National Institute of Mental Health, which funded the study. “It is the largest, longest and most comprehensive, independent trial ever done to examine existing therapies for this disease.”

Heavily marketed on the grounds they caused fewer side effects, the newer drugs, known as atypical antipsychotics, cornered about 90 percent of the market. All won Food and Drug Administration approval on the basis of short-term studies that showed they were better than sugar pills, and researchers emphasized yesterday that the medicines do work. But they have never before been systematically compared against each other in a long-term trial designed to guide doctors in deciding which to try first, and which would best suit particular patients.

The new study tracked patients for 18 months, which allowed researchers to compare the effectiveness of the medications as they actually are used. Patients had a variety of complicating factors, much as they do in the real world, and came from diverse backgrounds. Columbia University psychiatrist Jeffrey Lieberman, who led the new study, said 90 percent of trials in the scientific literature — which doctors rely on to guide treatment — are sponsored by drug companies. Although the industry trials serve a useful purpose, he said, they are rarely designed to answer certain crucial questions.

The industry has recently come under fire for hiding unfavorable trial data, especially in studies of antidepressant medications for children. Companies conduct trials to win FDA approval or for marketing reasons, Lieberman said.

“These are not the same purposes that are consistent with the needs of clinicians, patients, family members, administrators and policymakers,” he said. “How do currently marketed treatments compare? If there are differences in cost, are they justified? There has not been any consistent means to get that information.”

Although the National Institutes of Health is increasingly funding such trials, Lieberman said they also ought to be funded by federal agencies that pay for drug treatment for huge numbers of patients, such as the Centers for Medicare and Medicaid Services (CMS). “CMS pays tens of billions to support medication, and there is no way they know what the appropriate value of these medications is,” he said.

The new study, which will be published in the New England Journal of Medicine, cost taxpayers $44 million. Last year, the United States spent $10 billion on the newer antipsychotic drugs, which include medications such as Zyprexa, Risperdal, Seroquel and Geodon. Lieberman and the other researchers said they were surprised to find that an older generic drug called perphenazine, which is 10 times cheaper than the newer drugs, was about as effective — and about as safe.

Older antipsychotics are known to cause involuntary muscle movements, and the newer drugs were heralded for not causing that problem. But Lieberman said comparisons with older drugs had mostly used a highly potent drug called Haldol, whereas the new study did not find the same degree of movement problems with perphenazine, a less potent drug.

In an editorial accompanying the study, Robert Freedman, a psychiatrist at the University of Colorado Health Sciences Center, said the uncontrolled movements caused by the older drugs were “less troubling than potentially fatal metabolic problems” associated with some of the newer drugs.

Yale psychiatrist Robert Rosenheck, who helped conduct the study, said it was “not a horse race” that produced a winner. Rather, he said, each drug had benefits and risks. Doctors will have to judge what works best for particular patients. “It would be a tremendous mistake to assume from this study that the cheaper, older drugs are, quote, ‘just as good,’ ” added Darrel Regier, director of the division of research for the American Psychiatric Association, who also said that doctors’ judgment is crucial.

The study is likely to stoke one of the most contentious debates in psychiatry — whether drug treatment ought to be forced on unwilling patients. The fact that three-quarters of patients discontinued treatment because of side effects or a lack of benefit showed that patients “trying to say no to forced neuroleptics [drugs] have had a better grip on reality than the medical community,” said David Oaks, a patient advocate who has himself been given five antipsychotic drugs at various times for a range of diagnoses, including schizophrenia.

Pharmaceutical companies called attention to aspects of the trial that showed their products to advantage. Geodon kept patients’ weight gain and cholesterol down, said Pfizer’s Daniel J. Watts. Zyprexa had a lower discontinuation rate, manufacturer Eli Lilly said. The dose of Risperdal used in the study was too small, which was why the drug did not work as well as it should have, said Ramy A. Mahmoud, vice president for medical affairs at Janssen Pharmaceutica Inc.

Alan Goldhammer of the Pharmaceutical Research and Manufacturers of America, said, “We have always made it clear during drug development that it is only the first stage, that it . . . never tells the whole story about safety and efficacy.” Large studies, which compare different drugs including generics, are beyond the capabilities of individual companies, he said: “They are so costly and time-consuming that it would probably bring drug development to a halt.”

Patient advocate Vera Hassner Sharav, who said her son died at 32 because of toxic side effects associated with the antipsychotic drug Clozaril, said the new study showed that the FDA is not doing its job. “We really only seriously test drug safety on the vast public,” she said. “That is not right.”

© 2005 The Washington Post Company

See also: The Wall Street Journal, Generic Fares Well in Big Psychiatry Study: Newer Costlier Drugs Have Little Advantage for Schizophrenia; Comparative Data on Side Effects by Leila Aboud, September 20, 2005 D-1

EXCERPT

In a surprising finding, a government study comparing schizophrenia treatments found that an older generic medicine was as effective as all but one of the newer and more expensive brandname drugs widely used to treat the mental illness.

The $67 million federally funded study also exposed just how poorly current antipsychotic drugs really work: Nearly three-quarters of people treated stopped taking the medicine they had been givern within 18 months, due to side effects or poor control of symptoms. The results, from the experience of 1,500 patients, are to be published in this week’s New England Journal of Meicine.

The findings may have significant implications for how doctors treat the 3.2 million people in this country suffering from schizophrenia. The newer, costlier antipsychotics make up 90% of the market today. They are also used for bipolar disorder, and for severe cases of depression, kids with extreme behavior problems, and dementia.

But psychiatrists have been prescribing these drugs with incomplete information about the benefits and risks of each drug. The studies that companies do to get drugs approved aren’t designed to compare available treatments or shed light on the difference between similar drugs. When companies do compare their drugs to others, the studies have often been subject to criticism that they were designed in favor of a particular drug. So psychiatrists have had no head-to-head, impartial comparison to help them weigh treatments.

Now this trial, part of a six-year push by the National Institutes of Health to examine a range of psychiatric drugs, “provides a comprehensive set of data that were obtained independently of the pharmaceutical industry and in a scientifically rigorous way,” says Jeffrey Lieberman, head of psychiatry at Columbia University and principal investigator on the trial…..

It remains to be seen whether the finding s will lead psychiatrists to change their prescribing habits. One thing to watch is whether public programs like Medicaid or private insurers use the findings to justify trying older generic medeicines before the new ones. The researchers plan to analyze the cost-effectiveness of the various treatments, using data on the rates of hospitalizations, docto0rs’visits and drug costs……

See also: New York Times Study Finds Little Advantage in New Schizophrenia Drugs By Benedict Carey September 20, 2005 F-1

EXCERPT

…… The findings may not significantly alter the prescribing patterns of doctors in private practice, who often do not have to worry about cost, psychiatrists said. But they are likely to have an enormous effect on state Medicaid programs, many short on funds in part because of the high cost of schizophrenia drugs.

Several states, including Kentucky, West Virginia and Maine, have limited access to newer drugs, which cost 3 times to 10 times more than the older drugs. “The new study presents an opportunity but also a risk,” said John Goodman, president of the National Center for Policy Analysis, a policy research group based in Dallas, which estimates that Medicaid programs spend at least $3 billion a year on antipsychotics, more than for any other drug class. “The opportunity is to lower the cost of these drugs,” Dr. Goodman said. “The risk is that state Medicaid programs use this excuse to entirely deny some patients access to more effective and more expensive drugs which work for those patients.”

The government study set out to judge each drug by how long patients and their doctors continued the therapy, a criterion rarely used in studies by drug makers but crucial in real-world practice. People with schizophrenia struggle with delusional thoughts, private voices, blunted emotions and other symptoms, and most try multiple drugs in trying to avoid severe side effects……

The most common reasons were that the drug was not effective, the patient could not tolerate taking it, side effects like sleepiness and weight gain or neurological symptoms like stiffness or tremors. Doctors’ concerns about neurological side effects in particular have sped the switch to newer schizophrenia drugs over the last decade. Studies have shown that these medications carry a lower risk than the older drugs of tardive dyskinesia, a disorder that causes tics, lip-smacking and other involuntary movements. But the study found that at more modest doses, the older drug, perphenazine, while just as effective, was not significantly more likely to cause neurological symptoms. Dr. Lieberman said that there was no reason to believe that modest doses of other older drugs, like Haldol, would perform differently.

The patients on Zyprexa were less likely to be hospitalized because their condition worsened than those taking the other drugs, the study found. But these patients also gained the most weight, adding an average of two pounds a month while on the drug, and their lipid levels increased more than those of people on the other drugs. Weight gain and elevated lipids are risk factors for diabetes. In the doses used in the study, a month’s supply of perphenazine costs about $60, compared with $520 for Zyprexa, $450 for Seroquel, $250 for Risperdal and $290 for Geodon, according to Drugstore.com.

“Probably the biggest surprise of all was that the older medication produced about as good an effect as the newer medications, three of them anyway, and did not produce neurological side effects at greater rates than any of the other drugs,” said Dr. Lieberman in an interview.

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