E-drug: Antidepressants and 'miracle drug' label
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[An interesting article on how the blockbuster drug industry works: the
case of Prozac. Long message. Copied as fair use. HH]
Antidepressants Lift Clouds, but Lose 'Miracle Drug' Label
The New York Times, 29 June 2002.
By Erica Goode
Fourteen years after Eli Lilly introduced a small green and white
capsule called Prozac, antidepressants have mushroomed from a
modest market into a $12 billion industry. And Americans, little by
little, are coming to think of depression as an illness like any other, a
topic discussed on dates and at dinner parties.
But the euphoria that greeted the arrival of the generation of drugs that
Prozac heralded has faded. Millions are helped by antidepressants,
with some studies indicating that 35 to 45 percent of those who take
them experience complete relief from their symptoms. But millions
more, 55 to 65 percent, are not helped nearly enough. Some people
experience no side effects, but for others, sexual dysfunction,
emotional numbing, insomnia, weight gain, restlessness and memory
lapses make the drugs unusable � or simply not worth the trouble.
Many patients end up on a merry-go-round of medication trials,
switching repeatedly from one drug to another or combining drugs to
maximize their effects. "There is no question that the drugs work,"
said Dr. Steven Hyman, the director of the National Institute of Mental
Health before becoming the provost at Harvard, "but they leave a lot
to be desired."
At the same time, the aging of Prozac and its counterparts has sent
the pharmaceutical companies into an economic frenzy. The exclusive
patents on many of the best-selling drugs of the 1990's are nearing
expiration. Eli Lilly's patent on Prozac ran out last August, opening the
field to a crowd of generic equivalents and resulting in a drop of more
than 80 percent in sales of the brand-name drug.
The market for antidepressants, which in 1998 grew by 24 percent, is
expected to expand by only 5 percent this year, according to Richard
T. Evans, an analyst at Sanford C. Bernstein & Company. Scrambling
to regain their competitive edge, the drug manufacturers are searching
for new molecules that are more effective and have fewer side effects.
They are tweaking the chemical structures of existing drugs and
reharnessing old standbys for new uses, marketing them for everything
from social phobia to generalized anxiety and severe premenstrual
distress. Psychiatrists argue that such conditions are real illnesses that
cause unnecessary suffering. But others say the impression conveyed
by smiling faces in some television commercials for antidepressants is
clear: almost anyone could benefit from them. "The symptomatology is
so broad and vague that almost any one of us could say, yeah, that is
me," Arthur A. Levin, director of the Center for Medical Consumers,
said.
Yet even the most aggressive advertising is unlikely to be enough to
solve the industry's problems, analysts say. What is really needed is a
new class of drugs, one that will have as much impact � clinically and
economically � as Prozac did 14 years ago. "The field is waiting for
the next breakthrough in terms of new treatments, through new
mechanisms," said Dr. Alan Schatzberg, the chairman of psychiatry at
Stanford University School of Medicine. "That's what people are
hungering for." Several new drugs will reach the market soon.
Lexapro, an antidepressant from Forest Laboratories, maker of Celexa,
is expected to reach drugstores as early as next month, and Cymbalta,
a drug from Lilly, should arrive late this year or early next. But no
breakthrough product is in sight. The very complexity of depression as
an illness, experts say, makes it unlikely that the next Prozac will
arrive soon.
The Promise in a Pill
The earliest antidepressants were discovered by accident. Iproniazid, a
drug first used for depression in the 1950's, was a treatment for
tuberculosis before doctors noticed its mood-elevating effects. Prozac,
in its way, was also a product of serendipity. It arrived at a time when
scientists were first exploring in earnest the biological underpinnings of
depression, and when organizations like the National Alliance for the
Mentally Ill and the National Depressive and Manic-Depressive
Association were working to convince Americans that depression and
other serious mental disorders were illnesses like diabetes or heart
disease, not weaknesses or failures of character.
At the same time, national surveys indicated that depression was far
more common than researchers once thought. One of the most
exhaustive surveys found that in any given year, 9.5 percent of
Americans met the diagnostic criteria for some sort of mood disorder.
Yet even as awareness increased, few drugs were available for
depressed patients. Only two classes of antidepressants were on the
market, tricyclics like Elavil and monamine oxidase inhibitors like
Parnate. Both had been in use for decades. Both had problems that
placed limitations on their use. Tricyclics often caused unpleasant side
effects, like constipation, weight gain and, in some cases, heart
irregularities. Worse, even a small overdose could be lethal, and
doctors had to dole them out carefully to severely depressed patients
lest they use the pills in a suicide attempt. The monoamine oxidase
inhibitors, on the other hand, required sticking to a special diet,
avoiding cheese, red wine and other foods that interacted with the
drugs and could cause severe headaches or even strokes. For
pharmaceutical companies, devoting much energy to marketing either
class of drugs, their patents long expired, seemed hardly worth the
effort.
Prozac and the other drugs in its class � selective serotonin reuptake
inhibitors, or S.S.R.I.'s � offered several advantages over their
predecessors. They had standard dosages, making them easy to
prescribe. Huge overdoses had caused not a single death. Also, their
side effects appeared minimal. Still, even Eli Lilly was surprised when
its new drug attained the status of a cultural icon, making the cover of
newsmagazines and inspiring books like "Listening to Prozac" and
"Prozac Nation." Executives at Lilly have said that during development,
they envisioned sales of $70 million a year for their new product.
Instead, at Prozac's peak, sales approached $3 billion a year. "We
underestimated the number of patients that could benefit from a drug
like Prozac," said Dr. Steven Paul, a psychiatrist and vice president of
Lilly Research Laboratories.
There were in fact a lot of customers, including many who would
never before have thought of taking a drug to alleviate emotional
distress. Talk therapies have been shown to be effective for
depression, especially when combined with antidepressants. But
getting Prozac or other such drugs did not even require seeing a
mental health professional. General practitioners wrote � and continue
to write � the majority of prescriptions. The drugs soon became an
option for patients with a wide variety of complaints, their reach
extending beyond severe depression to include the mildly depressed,
the bereaved, the stressed and the rejected. Antidepressants are now
the second-largest class of prescription drugs, their sales exceeded
only by heart medications. Last year, according to NDCHealth, a
company that tracks drug sales, 7.1 million Americans took
antidepressants, an increase of 700,000 over the year before.
The Pitfalls in a Pill
Yet even as the numbers have grown, it has become clear that the
drugs are more prone to side effects and in some cases less effective
than many people assumed. Many S.S.R.I.'s cause sexual dysfunction
� loss of libido and an inability to have orgasms � a side effect many
are unwilling to put up with for any length of time. Other patients
complain of apathy and emotional flatness. "All it did was make me
feel like I had no emotions," said Zachary Howard, 22, of Boston, who
took Zoloft for a month in high school. "I felt like a zombie." In still
other cases, the antidepressants simply quit working after months or
years. Stopped abruptly, they could cause dizziness, sensations of
electrical zapping in the brain, irritability and other unpleasant
withdrawal reactions, a problem that can be solved by tapering the
drugs very slowly. A lawsuit filed last August against GlaxoSmithKline,
the maker of Paxil, another drug in Prozac's class, claims that the
manufacturer deliberately did not warn doctors and patients about
problems that could arise if the drug was stopped too quickly. A
spokeswoman for GlaxoSmithKline said the company was "vigorously"
contesting the suit, which seeks class-action status, and noted that
drugs besides antidepressants produced withdrawal symptoms if
stopped too fast. In December, the manufacturer added a precaution
to Paxil's packaging about discontinuing the drug suddenly.
There is no question that antidepressants have saved many lives.
Recent studies have linked drops in suicide rates in Hungary and
Sweden, among other countries, to an increase in the prescription of
antidepressants over the last 15 years. But a 1999 review of studies
by the Agency for Health Care Policy and Research in the Department
of Health and Human Services found that Prozac and its cousins had
more tolerable side effects than older drugs but were no better �
though also no worse � at treating depression. Other studies have
indicated that a minority of depressed patients who take the
antidepressants experience complete relief of their symptoms; many
more improve somewhat without recovering entirely.
Susan L., 45, a graphic designer in Manhattan who spoke on condition
that her last name not be used, switched from an older drug to Prozac
when it entered the market in the late 1980's. At first she did well.
But five years later, the drug lost its potency. In the years since, she
has cycled through a series of drugs and drug combinations. "I tried
Zoloft, I tried Effexor. I was on Wellbutrin and Effexor for a while, now
I'm on Wellbutrin and Celexa," she said. "It's still not that great. I
couldn't say that I'm happy."
Patents, Generics and Jingles
Apart from the drugs' mixed effectiveness, the pharmaceutical
companies have another problem on their hands. Eventually, every
new drug loses its exclusive patent, which lasts 20 years from the
date of application and wards off the encroachment of generic drugs
that other companies can sell at a much lower price. In the decade and
a half since Prozac arrived, patented antidepressants have helped
transform their makers into powerhouses. Forest Laboratories, the
maker of Celexa, was a little-known manufacturer of generic drugs.
Now it is a darling of Wall Street, with sales rising by 35 percent last
year, most of them from Celexa. But Prozac's swift sales decline in the
last year has given drug manufacturers a glimpse of a dimmer future.
Even though the market is expected to improve next year, the
fast-paced growth of the 90's is not likely to return soon, according to
Mr. Evans, the market analyst. For one thing, insurance companies,
like Wellpoint Health Systems, the large California insurer, are trying to
steer patients to fluoxetine, the low-priced generic equivalent of
Prozac, by charging them higher co-payments for brand-name drugs.
Dr. Robert C. Seidman, Wellpoint's chief pharmacy officer, said the
company was giving doctors free samples of fluoxetine. "The health
care system cannot afford to pay for a brand-name drug when a
generic works just as well for a fraction of the price," Dr. Seidman
said.
To keep sales growing, the industry is pouring more money than ever
into marketing and promotion. Last year, drug companies spent $1.5
billion to market the antidepressants to doctors, according to IMS
Health, another company that monitors drug sales. They spent $200
million more on television and print advertisements aimed at
consumers, according to CMR, a firm that tracks advertising.
The companies are also coming out with formulations that make drugs
easier to take � GlaxoSmithKline, for instance, is working on a
once-a-day form of Wellbutrin. GlaxoSmithKline has also done clinical
studies to get Paxil approved for new uses, like generalized anxiety
disorder and social phobia. Each new use has created a new
advertising angle and expanded the market of patients. "It's like I
never get a chance to relax," says a man in a recent television
advertisement for Paxil. "At work, I'm tense about stuff at home. At
home, I'm tense about stuff at work." Refining older drugs is also a
sales strategy. Forest Laboratories' new drug Lexapro is a refined
version of its other antidepressant, Celexa. Both drugs were developed
by a Danish company and licensed by Forest for sale in the United
States. Charles Triano, the company's vice president for investor
relations, said, "We believe Lexapro has better potency, fewer side
effects and may work faster." But others say the new medication's
superiority has yet to be proved. "I haven't seen any data that
suggests it's an improvement in side effects and efficacy at this
point," said Dr. Dennis S. Charney, director of the mood and anxiety
disorder research program at the National Institute of Mental Health.
"But maybe when it hits the market, that will become apparent." To
make Lexapro, scientists split their older drug, Celexa, into two
mirror-image isomers or chemical compounds, then used one isomer in
the new drug.
Other companies have done this to try to reduce or eliminate side
effects. Allegra, for example, the heavily promoted allergy drug, is a
split version, or enantiomer, of Seldane, a drug taken off the market in
1997 because it could cause heart complications. Forest must
convince doctors that half of Celexa is better than the whole. Generic
companies will be allowed to sell Celexa in early 2004, although Forest
predicts it will take another year before they get their lower-priced
versions to the pharmacies. Already Forest is paying for Lexapro
advertisements in medical journals like Psychiatric Annals. "Coming
soon, Lexapro, the isomer of Celexa," says one. Once Lexapro is
approved, Forest plans to dispatch its 2,150 sales representatives to
doctors' offices with tens of thousands of free samples.
But here again, Prozac offers a cautionary tale. Two newer versions
offered by Lilly after it lost its patent � Prozac Weekly, meant to be
taken once a week, and Sarafem, prescribed for severe premenstrual
distress � have not done much to offset declining Prozac sales.
Sarafem sales were $84 million last year but only $13 million in the
first quarter of 2002. "People know that it's Prozac, just with a
different name," said Dr. Leonard Yaffe, an analyst with Banc of
America Securities.
The Unknown Brain
The problem, in some ways, is simple: As much as scientists have
learned about depression, they still do not know enough to be able to
aim chemical treatments precisely. Older theories of depression's
cause were based on oversimplified notions about how the brain
worked. Researchers knew that antidepressants seemed to raise the
brain's levels of messenger chemicals called neurotransmitters, so they
theorized that depression must result from a deficiency of these
chemicals. Yet a multitude of studies failed to prove this precept.
Over the last two decades, helped by advances in molecular science
and technologies that offered a window on the working brain,
scientists have realized that depression is more symphony than solo,
its symptoms a result of the chattering of neurons in many brain areas,
mediated by many neurotransmitters. Nor are these processes set off
by a person's inherited vulnerability alone. Far from being a static
organ, the brain, research has made clear, is enormously plastic, its
very architecture affected by environmental influences throughout life,
including learning, stress and medication.
Studies by Dr. Bruce McEwen, director of the laboratory of
endocrinology at Rockefeller University, and others have shown that
prolonged stress can permanently damage neurons in the
hippocampus, an area of the brain involved in memory. Studies by Dr.
Ronald Duman at Yale, Dr. McEwen and others show that
antidepressants actually stimulate the growth of hippocampal nerve
cells and, in animals, appear capable of reversing harm to the cells
done by stress. Yet scientists are far from knowing exactly what such
findings mean for depressed patients. They also have a long way to go
in understanding the other changes in brain functioning that
undoubtedly contribute to the illness. Nor have they come close to
untangling the interaction of genetics and experience that determines
whether a particular person will fall ill.
Making matters more complicated, a consensus is growing among
researchers that depression is not a single entity. Dr. Jerrold F.
Rosenbaum, a professor of psychiatry at Harvard Medical School, said,
"There are differences in symptoms, there are differences in course,
there are differences in the age of onset and differences in the
relationship to external precipitants, whether they be seasonal changes
or stress or menstrual cycles." This means, Dr. Rosenbaum said, that
the antidepressant that works for one group may not be the drug that
works for another.
The Next `Miracle Drug'
With increasing knowledge will come the promise of significant
breakthroughs. But what is not known poses a formidable challenge to
drug companies frantic to come up with more effective and more
widely tolerable treatments. "If you found any agent that would work
fairly quickly and in a large percentage of patients," said Dr. Stephen
M. Stahl, an adjunct professor of psychiatry at the University of
California at San Diego, "it would have a huge impact."
Cymbalta, Lilly's new drug, reflects researchers' suspicion that hitting
two neurotransmitters at once may be better than hitting only one.
Like Effexor, a drug introduced by Wyeth in 1994 and now one of the
fastest-selling antidepressants, Cymbalta belongs to a class called
selective serotonin and norepinephrine reuptake inhibitors, or
S.S.N.R.I.'s, because it specifically affects both neurotransmitters.
"Most of the data suggests that the more chemical systems one
engages, the bigger the bang for the buck," said Dr. Frederick
Jacobsen, a clinical professor of psychiatry and behavioral sciences at
George Washington University.
Other new drugs, still in the testing stage and not expected to reach
the market for a few years, are entirely novel compounds, their
potential resting on a mixture of theory and trial and error. One such
class acts on a particular brain chemical, a neuropeptide known as
Substance P. No one knows exactly what Substance P does in the
brain, but it is released by intense physical pain and has been
implicated in a variety of diseases. Because the peptide is present in
brain centers tied up with emotion and stress, scientists also suspect it
plays a role in the psychic pain of depression. Several companies are
exploring drugs that block the action of Substance P, though experts
say studies have yielded inconsistent results. At least one company,
Merck, has a Substance P drug in clinical trials.
A clearer rationale underlies the development of antidepressants that
block corticotrophin releasing factor, a hormone released in the brain
during stress. Studies show that some patients who suffer from major
depression also have elevated levels of stress hormones. By
interrupting the cascade of hormones that wear away at body and
brain, researchers hope they may also be able to relieve depression.
Several companies are exploring these drugs, but they are not yet in
clinical trials. Even RU-486, the so-called abortion drug, is showing
promise as a treatment for delusional depression, one of the most
serious forms of the illness, said Dr. Schatzberg, of Stanford, who is
studying the drug. Further in the future lie medications that could
home in on specific genes regulating neuronal growth, drugs that could
be tailored to an individual patient's genetic makeup and other
advances not yet conceived of, many of them the expected fruit of the
decoding of the human genome.
Yet like Prozac, experts say, each new "breakthrough" product is likely
to follow a predictable trajectory from "miracle drug" to just another
useful medication.
Perhaps this is not all bad. "It may be too much to think that there will
be a single treatment that fits all," Dr. Rosenbaum said. "I'd be happy
to have lots of new treatments that are only mini-blockbusters."
--
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