Source: The New York Times
Date: 30 June 2002

Antidepressants Lift Clouds,
but Lose 'Miracle Drug' Label


The following article was reported by Erica Goode, Melody Petersen and Andrew Pollack and was written by Ms. 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. People had taken huge overdoses and survived. 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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