Leading Drugs for Psychosis
Come Under New Scrutiny
By ERICA GOODE
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 are questioning whether they are quite as miraculous - or benign - 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 five million Americans who suffer from schizophrenia or manic depression and their families but by many millions of other people who have taken the drugs, and government officials.
A New Kind of Drug for Psychosis
When a drug called Clozaril entered the market in 1989, it was hailed as a major 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 by the Food and Drug Administration in 1994. Zyprexa, by Eli Lilly, won approval in 1996.
The new drugs - which also include Seroquel, sold by AstraZeneca Pharmaceuticals, Geodon, sold by Pfizer, and most recently, Abilify, sold by Bristol-Myers Squibb - 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.
Many doctors and patients prefer the drugs to the older medications. Bretta M., 34, a Brooklyn woman, for example, said that the Zyprexa she takes is an improvement over Haldol, an old-generation drug that she said made her feel "like a zombie."
"I'm less stiff," Bretta M. said. "I can concentrate more. I'm more alert."
But the drugs have hardly proved to be a panacea, experts say, and some are more effective and less likely to cause the side effects of older medications than others.
"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 - chewing motions, lip-smacking and contortions of the arms and legs - 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.
At the time, some patient-advocacy groups objected to the study, saying it was biased toward the lower-cost older 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.
Joel Yates of Brooklyn, 53, who has schizo-affective disorder, said he took Haldol at low doses for 15 years and had no bad side effects. Three months ago, his doctor, concerned about the risk of tardive dyskinesia, switched him to Abilify, a new atypical.
"It's hard to notice any particular difference," Mr. Yates said.
But Regina Moran, a spokeswoman for Novartis, the maker of Clozaril, said that the atypicals had made a large difference for many patients and their families. Before the drugs, she said, "there were many, many schizophrenic patients who never left the back wards of mental institutions."
Researchers say the final verdict is not in.
Some experts hope that a large study comparing atypical and traditional antipsychotics, underwritten by the National Institute of Mental Health and directed by Dr. Lieberman, will help resolve the issue when its results come out next year.
But whatever its outcome, the trial will say nothing about the newer antipsychotics' effects in nonpsychotic disorders, for which they are increasingly being prescribed.
Even less is known about how the drugs affect children. Psychiatrists say they are helpful and necessary for children who suffer from psychosis or who demonstrate severe aggression. But there is so far little data on their effectiveness or safety, though pharmaceutical companies are now beginning to study the drugs in children and adolescents.
The Side Effects
'Thorazine Shuffle' vs. Diabetes
Old antipsychotic drugs were notorious for their side effects, not only tardive dyskinesia but the dull-eyed stare and stiff-legged walk that became known in the back wards of state hospitals as the Thorazine shuffle.
Such problems are less frequent in the newer generation of drugs, but they are not unheard of. If researchers agree on anything, it is that the new medications have side effects of their own, some serious.
Most disturbing are cases of diabetes, Type II and Type I, and hyperglycemia that have been reported in adults and some children taking atypical antipsychotics. A study presented yesterday at the psychiatric meetings by Dr. P. Murali Doraiswamy, chief of the division of biological psychiatry at Duke University, and his colleagues raises the possibility that some newer drugs may also be linked to pancreatitis.
Excessive weight gain is common on some atypicals, and may be linked to cases of diabetes: Some patients have reported gaining up to 65 pounds. Some developed diabetes or glucose abnormalities after gaining weight. Others already had the disease and grew worse while taking the drugs. Still others fell ill quickly after starting an atypical and got better once the drug was stopped. For some, the illness was fatal.
Many experts suspect that the drugs are somehow causing or bringing out diabetes and that some drugs may do so more than others. But they are not yet certain that this is the case. Nor do they know how big the problem is. The number of reported cases so far is relatively small, given the many millions of people who have taken the drugs. More than 12 million people have taken Zyprexa alone, according to Eli Lilly.
Complicating matters further, diabetes is common and increasing in the general population. And some studies of patients in the 1940's suggest that diabetes may be higher in people with schizophrenia even without antipsychotic medication.
But the cases are worrisome because it took many years for psychiatrists to recognize that the older drugs were causing tardive dyskinesia.
"The emergence of tardive dyskinesia was gradual," said Dr. Joseph Deveaugh-Geiss, a consulting professor of psychiatry at Duke University. "There were probably a lot of cases that simply weren't recognized and then, over time, people realized that there was an association." The diabetes link, Dr. Deveaugh-Geiss said, "is looking a lot like what we saw 25 years ago with T.D."
In three studies, researchers led by Dr. Elizabeth A. Koller examined cases of diabetes in patients taking Clozaril, Zyprexa or Risperdal in an eight-year period. The drugs had 384 reported cases, 289 cases and 132 cases, respectively. On Clozaril, 25 patients died; on Zyprexa, 28; and on Risperdal, 5. The patients who developed diabetes tended to be young and male. The data were gathered from reports filed with the F.D.A. and from medical journals.
The researchers cautioned that reporting of adverse drug reactions to the F.D.A. is voluntary on the part of doctors, making it hard to know whether the higher numbers for some drugs truly reflect differences in relative risk. The agency says the reports it receives represent perhaps 10 percent of the actual number of adverse reactions.
Another study found higher rates of diabetes for patients on Clozaril, Zyprexa and Seroquel but not Risperdal; patients under 40 had elevated rates with all the drugs.
In their study of Zyprexa, published last year in the journal Pharmacotherapy, Dr. Koller, an endocrinologist then working at the F.D.A., and Dr. Doraiswamy concluded that the number of cases, the timing of the illnesses and the relatively young ages of the patients who fell ill "suggest a causal relationship" between the drug and the development or worsening of diabetes. Also suggestive, they wrote, was that many patients improved when the drug was stopped.
Marni Lemons, a spokeswoman for Eli Lilly, which has been served with five lawsuits involving patients who developed diabetes while on Zyprexa, said the company did not believe its product was causing diabetes. "This is not an issue for a specific drug, but for this patient population," she said.
Ms. Moran, the Novartis spokeswoman, said, "At this time, there is no evidence suggesting" that diabetes is more common or more serious in patients on Clozaril than "outside the context of Clozaril treatment."
The issue is far from settled, and more than 20 papers on the topic will are being presented at the psychiatric meetings.
The F.D.A. is also looking closely at the diabetes issues. A spokeswoman said the agency is waiting for the findings of a large analysis by the Veterans Administration, to be completed this year, before deciding whether to require warning labels on some or all of the atypicals. Some drugs already carry such labels in Japan or Europe, including Zyprexa and Seroquel.
However, psychiatrists say patients taking antipsychotic drugs should be monitored on a regular basis for glucose abnormalities.
Eventually, Dr. Geddes said, the two classes of antipsychotic medication may come down to a tradeoff of side effects: The risk of tardive dyskinesia posed by the older drugs versus the risk of diabetes.
"It's not up to me to say, is it?" Dr. Geddes asked. "It's up to the patient to say."
Cost, Consequences and Patients in Need
Of the billions of dollars spent each year on antipsychotic drugs, a large part comes from government insurance programs.
Dr. Joseph Parks, the medical director of Missouri's Department of Mental Health, said that his state spent $104 million, or 11.6 percent of the total Medicaid payout, on three atypical antipsychotics, Zyprexa, Risperdal and Seroquel, between April 2002 and March 2003. The three drugs topped the list in dollar volume of all drugs covered by the state Medicaid program, including cancer, H.I.V. and heart medications.
"They are good medications," said Dr. Parks, who is also the president of the National Association of State Mental Health Directors' medical directors' council, "and they seriously help a lot of people. I would not want to give up any of them."
But for the price of treating one person with Zyprexa at $303 for a month's prescription, he said, or two on Risperdal, at $159 per month, the state could treat 8 or 10 people with Haldol at $35 per month.
Ohio, a larger state, spent $174 million on antipsychotic medications in 2002, close to $145 million of that on the atypical drugs, said Dennis Evans, a spokesman for the state's Medicaid program.
Yesterday, researchers at the psychiatric meetings presented a study of the cost effectiveness of Zyprexa in treating patients at 17 Veterans Affairs medical centers. The study, led by Dr. Robert Rosenheck, a professor of psychiatry and public health at Yale and the director of the Department of Veterans Affairs Northeast Program Evaluation Center, found that Zyprexa cost the V.A. $3,000 to $9,000 more per patient, with no benefit to symptoms, Parkinson's-like side effects or overall quality of life.
Zyprexa was less likely to produce the physical restlessness called akisthesia, the study found, and was associated with slightly better memory and motor skills. The study was financed by Eli Lilly.
Advocacy groups like the National Mental Health Association worry that the price difference in the drug classes might cause some states, pressed by shrinking budgets, to include only some atypicals in their formularies or even to eliminate them altogether.
Because different drugs work for different people, said Jennifer Bright, the association's senior policy director for health care reform, forcing people to choose from two or three medications increases the chances that none will work, and increases the risk of hospitalization or other, higher cost care.
"We believe there ought to be open access to all medications," she said.
Whatever the final verdict on the atypicals, many experts believe what is really needed is new and better drugs.
"Many patients are taking multiple drugs, and that suggests that clinicians are not finding it as easy as they'd like to control all the signs and symptoms with one antipsychotic," said Dr. Kane. He and other experts said that no drug, however effective, would make up for larger deficiencies in services for people with severe mental illness.
Meanwhile, few psychiatrists - and perhaps even fewer patients - would want to lose any of the newer generation of antipsychotics now on the market. But how they are used and how much value they add, experts say, is ultimately a question for society.
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