Leading Antipsychotic Drugs Come Under New Scrutiny – NYT

Leading Antipsychotic Drugs Come Under New Scrutiny – NYT

Tuesday, May 20, 2003

A front page article in The New York Times reveals that the pillars of American psychiatry–including Dr. Jeffrey Lieberman, Dr. John Kane, Dr. William Carpenter–are acknowledging that evidence is lacking to support the claims that the new antipsychotic drugs are any better than the old drugs for treating psychosis. Furthermore, they acknowledge that evidence does exist showing the new drugs–that they and the drug industry have jointly been touting as “wonder drugs” for years–are not benign. The new drugs, they concede, have severe, debilitating side effectsóincluding a high risk of diabetes.

However, “It’s probably the best growth market in the business,” said Richard T. Evans, a senior research analyst at Sanford C. Bernstein. A chart shows that since May 1999, children and babies–one to ten years old–have experienced the greatest increase in use of antipsychotic drug prescriptionóan increase of 169%. What is the medical justification?

In clinical trials that compared the efficacy of these new drugs with the old, mega doses of the old drugs were prescribed, increasing the incidence of adverse drug reactionsóthereby artificially creating the illusion that the new drugs were better. But when examined independently, the new drugs did not prove better than the old. See: John Geddes, et al, Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis British Medical Journal 2000;321:1371-1376 ( 2 December ) http://www.bmj.com/cgi/content/full/321/7273/1371#related_editorials

For years, critics who questioned the effectiveness of psychotropic drugs and raised serious concerns about drug-induced side effects in a significant number of patients, were pilloried or shunned and ignoredó-among them psychiatrists such as Dr. Loren Mosher (board member of The Alliance for Human Research Protection), Dr. Nathaniel S. Lehrman, Dr. Peter Breggin. Neither psychiatry nor the media paid attention to the patients who suffered the debilitating effects of the drugs.

Indeed, as early as 1993, the Food and Drug Administration found that in clinical trials Jennsen Pharmaceuticals had failed to prove that its antipsychotic drug, Risperdal, was any better than Haldol. And the FDA found that one in every 35 patients in Risperdal clinical trials had suffered a “serious adverse event.” See: Robert Temple Risperdal approval letter, December 29, 1993 (obtained under Freedom of Information Act) Yet, the Times quoted a company official who claimed the incidence of adverse effects were “the same as placebo.”

It is fair to ask, why the NYT participated in myth making for the past 10 years, by lending its pages to promote these drugsónot just in its advertising pages but in the Science news section? “All the News That’s Fit to Print?”

Those uncritical, but influential articles that touted (unproven) benefits, and failed to report evidence-based negative features of the drugs, misled readers, clinicians, and policy makers. The Times did not even see fit to review an important fully documented book that sheds light on the promotional myth making and dubious claims about the ‘atypical’ antipsychotic drug. See: Robert Whitakerís book, Mad in America: Bad Science, Bad Medicine, and the Enduring Mistreatment of the Mentally Ill Perseus Books, 2002. http://www.madinamerica.com/

The Timesí historic failure to report the facts about severe adverse effects from antipsychotic and antidepressant drugs has been exceedingly valuable to the manufacturers of these drugs. Physicians and the public were systematically mislead into believing the drugs were safe and effective for a host of conditions. As a result, these powerful, diabetes-inducing drugs are being prescribed to millions of unsuspecting people–including thousands of helpless children.

Inappropriate prescribing has made these drugs into blockbuster sellers. Indeed, the Times reports today: ìSales of the drugs soaredÖNational sales of antipsychotics reached $6.4 billion in 2002Öî Industry figures show: ìMore than 15 million prescriptions were written last year for the two leading drugs alone, Zyprexa and Risperdal.î

The Times has yet to report critically about an unethical schizophrenia drug experiment at Yale University. Healthy adolescents–some as young as 12–are being recruited to take Zyprexa for a year. The rationale for the trial is a highly speculative hypothesis by psychiatrists who are under contract with Eli Lilly, the sponsor of the trial. They are suggestingówithout proof–that healthy siblings of patients diagnosed with schizophrenia are “at risk” of developing schizophrenia, and that Zyprexa will prevent schizophrenia. The reality is that adolescents are being exposed to evidence-based risksóincluding the high risk of diabetes. The claimed benefit is based on nothing more than hypothetical conjecture. Spearheading this rationale, no doubt, is the potential for even greater market expansion for antipsychotics.

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THE NEW YORK TIMES
May 20, 2003

Leading Drugs for Psychosis Come Under New Scrutiny
By ERICA GOODE

http://www.nytimes.com/2003/05/20/health/20PSYC.html?pagewanted=all&position=

EXCERPT: They were billed as near wonder drugs, much safer and more effective in treating schizophrenia than anything that had come before.

For many years, it seemed that the excitement was fully warranted.

There were remarkable stories of recovery. And the new generation of antipsychotic drugs, called atypicals, seemed to have few of the side effects commonly seen with high doses of older medications for psychosis.

The drugs appeared so successful that doctors began prescribing them for other things, not only for other psychotic illnesses, like manic depression, but also for Alzheimer’s, personality disorders and nonpsychotic depression, and for conduct disorder and severe aggression in children. Sales of the drugs soared. More than 15 million prescriptions were written last year for the two leading drugs alone, Zyprexa and Risperdal, industry figures show.

But 14 years after the first of the drugs entered the market, researchers e questioning whether they are quite as miraculous ó or benign ó as originally advertised.

The first round of antipsychotics had such unpleasant side effects, like dry mouth, stiffness and trembling, that people often just stopped using them. The atypicals are considered by many patients to be more tolerable, and many experts believe they are better than older drugs in treating some aspects of psychosis.

But studies suggest that their superiority is at best modest, specific to certain symptoms and variable from drug to drug. Also, there is increasing suspicion that they may cause serious side effects, notably diabetes, in some cases leading to death.

The issue of risks has become more pressing as the drugs are prescribed for children and for adults with milder conditions. And the states, which pay enormous sums for the atypicals in caring for the severely mentally ill, are questioning whether the benefits of the new drugs are worth their costs.

The drugs, experts say, have now reached a turning point where benefits must be balanced by side effects and cost. “Clinicians and investigators alike are taking a harder and closer look at areas in which the newer drugs are supposed to be better,” said Dr. Jeffrey A. Lieberman, a professor of psychiatry and pharmacology at the University of North Carolina.

Psychiatrists will debate the relative merits of older and newer antipsychotics in San Francisco tomorrow in a symposium at the annual meetings of the American Psychiatric Association. In other sessions, psychiatrists are presenting new data on the atypicals’ safety.

How the debate resolves will be watched not only by the nearly 5 million Americans who suffer from schizophrenia or manic depression and their families but by many millions of other people who have taken the drugs, as well as government officials.

The Questions

A New Kind of Drug For Psychosis

When a drug called Clozaril entered the market in 1989, it was hailed as a ajor breakthrough in the treatment of schizophrenia. European researchers who had stumbled upon the drug years before described it as “atypical” because even at very high doses, it did not produce the stiffness, trembling and other Parkinson’s-like symptoms commonly seen in patients taking older antipsychotics like Haldol.

Clozaril proved able to help some people with schizophrenia when all other drugs failed. In some cases, long-disabled patients shed their apathy and depression, went back to school, made friends and engaged in work for the first time since falling ill.

But in a small percentage of people (0.7 percent, according to the prescribing information provided by Novartis, which sells the drug), Clozaril caused a life-threatening blood disorder called agranulocytosis, and patients required regular blood tests to monitor for the side effect, adding to its expense.

Over the last decade, a series of other atypical drugs, free from association with the blood disorder, have entered the market.

Risperdal, the first such drug, from Janssen Pharmaceuticals, was approved y the Food and Drug Administration in 1994. Zyprexa, by Eli Lilly, won approval in 1996.

The new drugs ó which also include Seroquel, sold by AstraZeneca Pharmaceuticals, Geodon, sold by Pfizer, and most recently, Abilify, sold by Bristol-Myers Squibb ó have proved to be impressive moneymakers for the pharmaceutical industry.

“It’s probably the best growth market in the business,” said Richard T. Evans, a senior research analyst at Sanford C. Bernstein.

National sales of antipsychotics reached $6.4 billion in 2002, making them the fourth-highest-selling class of drugs, behind cholesterol-lowering drugs, ulcer drugs and antidepressants, said IMS Health, a company that tracks drug sales. According to NDCHealth, another company that tracks the industry, in 2002, more than 7.4 million prescriptions were written for Zyprexa and more than 7.6 million for Risperdal.
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“There has been what I see as a kind of myth-making,” said Dr. William Carpenter, a professor of psychiatry and pharmacology at the University of Maryland and the director of the Maryland Psychiatric Research Center. “It’s like: `The new generation of drugs is safe, patients like them and they’re more effective.’ ”

“Patients probably do like them a little bit more,” Dr. Carpenter said, and therefore might be slightly more likely to keep taking their medication. “But we still have plenty of trouble with the new-generation drugs.”

Like other experts, Dr. Carpenter believes that the atypicals have an edge over the older drugs in some areas. He and others said they seem better at easing the emotional blunting, withdrawal and depression often seen in schizophrenia.

Studies have indicated that they are better at preventing relapse and that they carry a lower risk of the most pernicious side effect of older drugs: tardive dyskinesia, a disorder that causes repetitive movements ó chewing motions, lip-smacking and contortions of the arms and legs ó that sometimes persisted even after the drugs were stopped.

The drugs may help with problems in memory, decision-making and other mental functions that can keep schizophrenia patients from working, but this is still debated.

“I think the new-generation drugs have shown advantages,” said Dr. John Kane, the chairman of psychiatry at Zucker Hillside Hospital in Queens and an expert on schizophrenia. “They may not be consistent across every study or every drug, but when you take them in their totality, they are meaningful.”

But determining how much more effective the drugs are is not easy. As in all areas of medicine, many studies, including those that appear in peer-reviewed journals, are financed by drug companies. Others are financed by government insurers.

Complicating matters further, many studies are small and they use a variety of methodologies, making comparison difficult.

Analyses that examine the findings from many studies have come up with mixed results. For example, in a presentation at a schizophrenia meeting last month, Dr. John Davis, a professor of psychiatry at the University of Illinois at Chicago, reported on an analysis of 124 studies comparing newer and older drugs. Ten atypical antipsychotics were included, some of them available only in Europe. Five of the newer drugs, including two not on the market here, were moderately more effective in treating psychotic symptoms than the conventional treatments, the analysis found. Of those sold here, Clozaril was the most effective, followed by Risperdal and Zyprexa. Four of the drugs, however, offered no advantage, and one drug, sold only in Europe, was actually worse. Dr. Davis said he received no financing from pharmaceutical companies for his research.

But a 2000 analysis, by Dr. John Geddes, a psychiatrist at the University of Oxford, created a stir by finding no difference in effectiveness between the two classes of drugs. The study, financed by the British government and published in the British Medical Journal, examined 52 studies comparing atypicals and older drugs.

Some patient-advocacy groups have criticized the study as biased toward the lower-cost, older-generation drugs.

In a telephone interview, Dr. Geddes said that, like other clinicians, he had seen patients improve remarkably on the newer medications. “But I remember over the last 20 years I had quite a lot of people who did really well on the older ones, too,” he said.

Part of what gave the older drugs a bad reputation, Dr. Geddes contends, was that in the past they were given in very high doses that may have made them less effective and increased side effects. Too, he said, many atypicals “were quite new, and it’s not good to go spraying around new drugs without knowing about the long-term effects.”

In a report this month in The Lancet, the medical journal, Dr. Stefan Leucht, a research associate at Zucker Hillside Hospital, and his colleagues found that although most atypicals produced fewer Parkinson’s-like side effects than high-potency older drugs like Haldol, when compared with older drugs of lower potency, some of the new drugs were just as likely to cause the side effects.

The analysis indicated that only Clozaril and, by a hair, Zyprexa had fewer of the side effects than the conventional antipsychotics, while the other drugs, including Risperdal, showed no fewer side effects.

Dr. Leucht cautioned that the number of studies examined in the analysis was small and that the findings needed confirmation through further research.
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