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CATIE study results Contradict Current Clinical Practice & Treatment Guidelines Print E-mail
Tuesday, 04 April 2006
Newly published results (phase II) from the CATIE schizophrenia treatment efficacy study sponsored by the National Institute of Mental Health comparing the most commonly used second generation drug treatments for schizophrenia and depression, is highly disturbing.

The results contradict psychiatry’s current clinical practice and treatment guidelines.

It is instructive to learn flat out that psychiatry’s biological treatment paradigm—which relies solely on drugs—no longer mentions recovery nor even pretends to improve patients’ ability to engage in normal daily life functions—i.e., work, study, interact, marry. Psychiatry’s endpoint criteria for measuring treatment effectiveness for patients with schizophrenia, is "how long patients stayed with the new drug!!!"   Is this because patients can no long tolerate taking them, or the severity of the adverse effects forces the physician to withdraw patient?

Most significant, the findings provide evidence-based validation that these drugs cause severe, life-threatening side effects for a significant number of patients.

The evidence confirms that doctors who follow TMAP (Texas Medication Algorithm Project) guidelines when dispensing antipsychotic drugs are dead wrong. The treatments prescribed are not effective—and they are harmful for patients.
 
The evidence shows that Clozaril, the first of the so-called atypical (second generation) neuroleptics (now off patent), outstripped all other drugs of this class—i.e, Risperdal, Zyprexa, Seroquel, Geodon—in terms of efficacy, which is defined as time to discontinuation: 
“Clozapine showed nearly a three-fold increase in time until drug discontinuation compared with the three new antipsychotics olanzapine, risperidone, and quetiapine (10.5 months for clozapine, compared with an average of 2.9 months for the others). Efficacy outcomes are consistent with the time-to-discontinuation measure.” [1]

But Clozaril has a “significantly greater side effect burden”: weight gain, increased metabolic measures, sialorrhea, sedation, and the agranulocytosis—reduction in disease-fighting white blood cells and a potentially fatal inflammation of heart muscle.

Clozaril and its closest comparator, Zyprexa, have the worst toxic side effect profile: patients taking these drugs are at highest risk of early death.  Dr. Carol Tamminga, a leading schizophrenia researcher who wrote the editorial accompanying the two CATIE trial reports in the American Journal of Psychiatry, acknowledges that psychiatrists will now have to assume far greater medical monitoring responsibilities for patients being treated with these proven toxic drugs:

“The metabolic and other somatic effects of olanzapine and clozapine also have implications for psychiatric practice. As long as psychotropic medications were considered relatively free of side effects, psychiatrists could practice in settings appropriate to other mental health counselors. However, medication treatments with high side effect burden demand clinical settings that are capable of detecting and managing serious side effects. This knowledge means that the clinician’s office needs to be equipped to efficiently monitor antipsychotic drug side effects. Blood pressure cuffs, scales, body tape measures, a process for plasma chemistry monitoring and electrocardiograms, and qualified consultants for medical questions become important components of practice. Dynamic information of drug side effects needs to take a prominent place in a patient’s psychiatric chart. Medical consequences of psychiatric drugs are real, preventable, and require focused monitoring. Clinicians will need to have systems for the effective monitoring of drug side effects to maintain and promote physical health among patients as well as psychiatric health.”  [2]

The evidence from this major comparison study validates patients’ assessment of and dissatisfaction with the prescribed treatments they are offered: 

“the side effect outcomes are staggering in their magnitude and extent and demonstrate the significant medication burden for persons with schizophrenia.… Sky-high drug discontinuation rates were seen, suggesting rampant drug dissatisfaction and inefficacy.”  [2]

The evidence also confirms the validity of our continued criticism of psychiatry’s current treatment guidelines which are influenced by industry, not scientific evidence: TMAP guidelines were formulated by a consensus panel of academic psychiatrists. The project was funded by the makers of the drugs recommended in those guidelines—Johnson & Johnson, Eli Lilly, Pfizer, et al. Those industry-influenced, TMAP guidelines were then recommended by the President’s New Freedom Commission report which initiated new mental health policy initiatives. The confirmatory evidence from the NIMH $140 million studies raise serious doubt about the integrity of that Commission’s entire report.  

Given these drugs’ inefficacy and admittedly “staggering side effect outcomes,” the profession’s continued avoidance of a scientific comparison between the effectiveness of drug treatments for schizophrenia patients with non-drug treatment, borders on, if not constitutes, outright professional negligence. 

This is especially so, given a recent report by Dr. John Bola in the Schizophrenia Bulletin that raises doubt about the validity of the current drug-centered treatment paradigm which dictates that all patients who present with psychotic symptoms of schizophrenia should be immediately put on antipsychotics  and kept on them. His meta-analysis of published studies that included first or second-episode schizophrenia spectrum subjects, found that during the course of a year, between 10% and 40% of psychotic patients did better without drugs.

Below, a report in Forbes recognizes both the financial impact of the studies overturning current prescribing practice, and criticizes the NIH for (a) failing, for the most part, to conduct comparative treatment studies such as the CATIE—despite a $29 billion budget provided by taxpayers; and (b) delaying public dislcosure of the important findings:


“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.”

References:
1. McEvoy, et al. Effectiveness of Clozapine Versus Olanzapine,Quetiapine, and Risperidone in Patients With Chronic Schizophrenia Who Did Not Respond to Prior Atypical
Antipsychotic Treatment . Am J Psychiatry, April, 2006; 163:600–610.

2. Carol Tamminga, "Practical Treatment Information for Schizophrenia" Editorial, AJP, April, 2006, vol. 163:563-565.
 
3. “Medication-Free Research in Early Episode Schizophrenia: Evidence of Long-Term Harm?” Schizophrenia Bulletin, by Dr. John Bola.  See comments: http://www.ahrp.org/cms/content/view/124/28/

Contact: Vera Hassner Sharav
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FORBES
Pharmaceuticals
Psychiatric Drugs On The Couch
Matthew Herper, April 3, 2006

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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April 1, 2006
Schizophrenia Drug Gets Vote of Confidence
By THE ASSOCIATED PRESS
NEW YORK (AP) -- A schizophrenia drug as well-known for its risk of dangerous side effects as for its effectiveness gets a vote of confidence in a new federally financed study.
Researchers explored a common situation in schizophrenia treatment: If the first drug a patient tries fails to control symptoms adequately, what drug should be tried next?

When patients in that situation were randomly assigned a second drug in the new study, Clozaril emerged as more effective than Risperdal, Seroquel and Zyprexa, said lead author Dr. Joseph McEvoy of the Duke University Medical Center.
That's not a surprise, he said, because Clozaril ''was believed to be the most therapeutically effective drug out there.'' But it's under-used because of the risk of side effects that require patients to go through special monitoring, he said.
In a companion analysis of other patients who didn't want to try Clozaril or who'd abandoned their first medication because of side effects, Risperdal and Zyprexa were found to be more effective than Geodon and Seroquel.
Clozaril is sold by Novartis SA, Risperdal by Janssen Pharmaceutica and Zyprexa by Eli Lilly and Co.

Both papers appear in the April issue of the American Journal of Psychiatry. The work, funded by the National Institute of Mental Health, was the second phase of a government study to seek the most effective way to treat people with this devastating mental disorder.
Schizophrenics struggle with such symptoms as hallucinations, delusions, social withdrawal, and other mental impairments that interfere with a normal lifestyle.

Dr. Darrel Regier, director of the research division of the American Psychiatric Association, said the head-to-head drug comparisons are ''a major step forward'' that will help doctors make a choice for a second drug to try. Doctors have to consider both effectiveness and side effects of the various drugs in deciding what's best for each patient, he said.
In fact, McEvoy said if a patient had gotten inadequate response from a first drug other than Zyprexa, he'd recommend trying Zyprexa because it doesn't have Clozaril's side effects and the need for special monitoring of patients. But if Zyprexa doesn't work, he said, he'd recommend Clozaril.


Clozaril's potential side effects include a loss of disease-fighting white blood cells and a potentially fatal inflammation of heart muscle. The risks make it more complex to use because patients must be closely monitored. For example, users must take weekly blood tests at first.
In the new studies, effectiveness was measured by how long patients stayed with the new drug. In the study that included Clozaril, half the 45 patients on that drug stuck with it for nearly 11 months or more. In the other three medication groups, which contained about 15 patients apiece, the corresponding figure was about three months.

While the difference in that measure between Clozaril and Zyprexa was not significant by statistical criteria, other measures in the study found Clozaril to be superior, McEvoy said.

In the other analysis, which covered more than 300 patients, the results were seven months for Risperdal and six months for Zyprexa, longer than the four months for Seroquel or the three months for Geodon.
Copyright 2006 The Associated Press

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