May 20, 2003
Leading Drugs for Psychosis Come Under New Scrutiny
http://www.nytimes.com/2003/05/20/health/20PSYC.html
The New York Times (Page A!)
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.
The Questions
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."
The Future
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.
Last Updated on
04/14/04
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