Rolling Stone: Better Pill

[l0vemaiden]

Created to treat schizophrenia, Zyprexa wound up being used on misbehaving kids. How the pharmaceutical industry turned a flawed and dangerous drug into a $16 billion bonanza.

Original Url: http://www.rollingstone.com/politics/story/25569107/bitter_pill



BEN WALLACE-WELLS

Posted Jan 28, 2009 3:10 PM

In June 1992, not long after the place closed down, a Harvard-trained psychologist named Sergio Pirrotta walked out of Danvers State Hospital for the last time. The psychiatric facility, at this late date, was a baggy old thing, rectangled into a field just north of Boston; whole wings were barely occupied, and vandals had already begun to rip out the mantelpieces and furniture. The hospital had been slowly, incrementally shutting down for a decade, and the patients that remained were the hardest cases, mostly schizophrenics and those with disorders too dense and weird to classify. But now, as Pirrotta took a walk around the campus, even those patients were gone: released into the larger world to fend for themselves or bused to hospitals where the staffs had little psychiatric training.

Pirrotta had come to Danvers in the mid-1970s to rehabilitate children whom the courts had declared insane. Back then the place was overpopulated, the halls packed with madmen who would wander around smoking cigarettes, leering and lunging at the kids. In those days, the drugs used to treat mental illness were crude and ugly things. Thorazine was the best, and it made you into a ghouled and lifeless ogre - your face seized up involuntarily, you kept shuffling around, you were an emotional drone. But gradually the medications got a little bit better, the pharmacology more precise. First there was haloperidol, similar to Thorazine but with less-vivid side effects. Then clozapine, which had at first seemed a wonder drug, before it turned out to trigger a potentially fatal immune deficiency in two cases out of a hundred.

The patients at Danvers, their symptoms softened by the new medications, began to venture forth, almost miraculously, into the world beyond the hospital. Pirrotta took a group that included schizophrenics to a children's camp in New Hampshire, off-season, where they spent a week cleaning and grooming the grounds. "For most of them, it was the first time they'd been out of an institution in their adult lives," he recalls. But the state's budget crunchers had wanted to close places like Danvers for years - pills, after all, were far cheaper than hospitals - and the new drugs made the move clinically defensible. To the staff at Danvers, it seemed as if the state had abandoned its responsibilities to the mentally ill. "It felt like we'd been sold a bill of goods," Pirrotta says. "It felt like a betrayal."

By 1992, when Danvers closed, something even more vivid and hopeful was looming: A whole new class of drugs, called atypical antipsychotics, were being tested in clinical trials. The atypicals held the promise of a more perfect tranquilizer, one that would calm the storms of schizophrenia while eliminating the side effects that made the older drugs so despised. Psychiatrists reserved their greatest excitement for a molecule being developed by Eli Lilly, a pharmaceutical company based in Indianapolis. The new chemical mirrored the powers of clozapine but without its fatal flaw. It was called olanzapine, and the scientists working on it believed it might be the One.

Dr. William Wirshing, a UCLA psychiatrist who had a grant from Lilly to conduct clinical trials on olanzapine, was one of those enthused by the early results. He believed the hype was warranted, and Lilly was flying him around the country to brief other psychiatrists on his work and to seed excitement for the coming medication. Then one morning in 1995, as Wirshing was driving to LAX to catch a pre-dawn flight, a story came on the radio about olanzapine. Wirshing listened in astonishment as a top Lilly executive announced the company's plans for the new drug, which it was preparing to market under the name Zyprexa.

"He says it's got the potential to be a billion-dollar-a-year drug," Wirshing recalls. "I almost pulled off the road and crashed into the side rail." At the time, the entire market for atypical antipsychotics was only $170 million. "How the hell do you make $1 billion?" Wirshing thought. "I mean, who are we gonna give it to? It's not like we're making any more schizophrenic brains."

There is a well-known feature of medical science called the placebo effect, which suggests that, in a clinical trial, patients who are told they are being medicated but are in fact given only a sugar pill will see their symptoms improve, merely out of the misplaced conviction that they are being healed. During the late 1990s, and then with increasing speed during the current decade, Wirshing and other psychiatrists watched as the market for atypical antipsychotics swelled well beyond its marked territory, far exceeding the country's supply of schizophrenic brains - past $2 billion a year, $5 billion, $10 billion, all the way to $16 billion. What had begun as niche drugs are now the third-largest class of medication in the world, their sales greater than those of the antidepressants. The mechanisms used to leverage this growth were in some ways the most modern and perfect the pharmaceutical industry had developed, but they were also, according to state and federal prosecutors, illegal. Lilly has already agreed to pay $2.6 billion to settle charges that it built the market for Zyprexa first by concealing its side effects, and then by marketing it "off-label," for diseases for which it had not been approved.

"It was a very clever sort of con," says Dr. Peter Tyrer, a leading psychiatric researcher at Imperial College in London who wrote in the latest issue of the respected medical journal The Lancet about a new study that debunks the effectiveness of the atypicals. "Almost the whole scientific community was conned into thinking - as a consequence of good marketing - that this was a different and better set of drugs. The evidence, as it's all added up, has shown this to be untrue."

Eli Lilly insists that it has not marketed Zyprexa off-label and that it has accurately represented the drug's side effects. But some medical researchers who have studied the atypical antipsychotics say that, in the final tally, the drugs, which have already been linked to some deaths, may eventually be responsible for tens of thousands of cases of diabetes and other potentially fatal diseases. And despite their early promise for treating schizophrenia, the drugs have not even performed any better than the crude and imprecise earlier medications that preceded them. "We have been paying $16 billion a year instead of $2 billion a year for drugs that seem to be no better and might be worse," says Douglas Leslie, a researcher at the Medical University of South Carolina who contributed to an extensive federal study of the drugs. The story of how Zyprexa and other atypicals became a multibillion-dollar market suggests that the medical community - doctors, researchers, the institutions that back them - may be themselves prone to a placebo effect: the willed conviction that a new drug, presented as a breakthrough, must in fact be one, that a product sold as healing must in fact do good.

Advertisement

FOREVER UNQUIETED
Few diseases are as haunting - and as poorly understood - as schizophrenia. Even in the psychiatric wards of major hospitals, where every patient is severely mentally ill, the schizophrenics stand out. In the depressives, the manic-depressives, the alcoholics and the addicts, you can still detect echoes of healthier people now and then; at their worst they pass in and out of episodes of insanity. But in schizophrenics, the old, familiar personality is often obliterated. The exact nature of the disease has not yet been precisely mapped, and so schizophrenia is defined by its manifestations, by the dramatic onset of psychosis, of delusions and hallucinations. Those who suffer from it can seem forever unquieted, as if by an alarm bell constantly ringing.

Some schizophrenics have hallucinations that are purely auditory - a demon they are convinced loiters just behind their eyeballs; others are beset by colors and figures - religious images, or distorted body parts that disrupt their visual field. The clash of this detached and fervently received world with the actual one has unusual effects - a compulsion to lay down in traffic, a need to wear heavy jackets under the delusion that it is not really summer. Psychiatrists identify schizophrenics by clusters of symptoms, the most common being paranoid and chaotic delusions, illogical thinking and behavior, and a severe and persistent lethargy. The onset of the disease comes so suddenly and so late in life - in the teens to late 20s - that the families of schizophrenics end up watching the people they knew being rapidly submerged, like an island busily eroding. "The most disturbing part for the families is dealing with the sense of loss - the knowledge that we can't get back the way you were before," says Dr. Geoffrey Neimark, a psychiatrist who met me at Pennsylvania Hospital in Philadelphia to explain life in the mental ward.

Every medical treatment has a glimpse of mystery in it, the ghost lingering in the algorithm, but psychiatry is even closer to alchemy than most. The diseases are too complex to be fully understood, and when the drugs work it can seem as if the patient has been visited by something magical and benign. In the 1950s, French scientists looking for an alternative anesthesia discovered that a chemical compound eventually marketed as Thorazine seemed to calm schizophrenics. The drug, and those that followed (what are now referred to as the "typical antipsychotics"), were crude instruments, often derived by accident and luck rather than through the process of discovering the disease's source in the brain and then refining a drug to repair it. Besides slowing down the brains of patients, the drugs had awful effects that doctors came to call "extrapyramidal" - muscular tremors, facial twitching. Patients on Thorazine were often stunned into immobility; in extreme cases, they wound up staring at the ceiling, their eyeballs locked in place. Others drifted aimlessly, a compulsion so common that it became known as the "Thorazine Shuffle."

Psychiatrists had expected that the science of schizophrenia would improve, but the more they looked for the disease's source, the murkier it seemed to get. Then, in the early 1990s, Dr. Ezra Susser, an epidemiologist and psychiatrist at Columbia University, was scouring the historical record when he happened upon something amazing: the prevalence of schizophrenia in the children of the Dutch war famine. In the fall of 1944, as the German armies were holding tensely on to Holland, the Nazis found themselves fighting an uprising by the Dutch resistance. In retaliation, they imposed an embargo. It was a harsh winter, and the country's canals froze over; food could not reach the cities, and Holland suffered a sudden famine. People ate tulip bulbs to survive. The next spring, when the Allies conquered the country, the famine lifted as suddenly as it had begun. Researchers later tracked the babies born to mothers pregnant during the famine, hoping it would help them understand the effects of malnutrition in the womb. As Susser paged through the records, he noticed that the children had developed schizophrenia at a far higher rate than those born in Holland only a few months later. It was a hint that schizophrenia isn't determined solely by our genes.

Schizophrenia, epidemiologists noticed, was popping up in all kinds of strange places: It was associated with children born to older fathers, with those who had suffered brain injuries in the womb, with the families of Caribbean immigrants in England. But despite their best efforts, scientists had been unable to understand what united all these disparate groups, what constituted the disease's unique, underlying cause. "The complexity of schizophrenia is very great," says Dr. Pablo Gejman, director of the Center for Psychiatric Genetics at Northwestern University. "We're probably talking about hundreds of individual factors - many genetic, some the result of environmental exposures. We actually have a profound ignorance on the specific molecular mechanisms of schizophrenia."

THE MOLECULE
Before a pharmaceutical company has completed the long and labored effort of turning a biological insight into a marketable drug, the scientists who are pushing and pulling at its chemical dimensions refer to the thing, with a reverent purity, as "the Molecule." In the early 1990s, as scientists at Eli Lilly were developing the new molecule known as olanzapine, the company faced a strategic problem: Prozac, by far its best seller, would go off patent soon, and the billions it generated would largely dry up. In early reports, olanzapine looked like a promising and potentially lucrative replacement, and by 1992 company executives were searching for experts in schizophrenia willing to conduct the first clinical trials of the drug. They explained their belief in the drug, that it had replicated the successes of clozapine and excised the chemical agents that caused extrapyramidal effects. Some doctors began to wonder if they might be staring at the next Prozac, the coming revolution in mental illness. It was, Wirshing says, "exciting as hell." He signed on.

The most vivid models we have of corporate deception come from the tobacco industry, where scientists working in company labs, behind sealed walls, conducted misleading experiments out of public view and then told the wider world they had found things they hadn't. But the pharmaceutical industry is immune to this kind of conspiracy. The size of clinical trials and the federal regulations that govern them mean that a company can never develop and study a molecule in-house; it relies on a platoon of contracted researchers, specialists at academic institutions, who test the molecules and then publish their findings in academic journals. The system is not perfect; studies have found that drug trials sponsored by the industry (which, since rule changes made in the Reagan administration, has meant virtually every large drug trial) are at least four times more likely to suggest that a drug is a success than trials that are independently funded. But when the system fails, the cause is often not outright deceit, but rather a web of overbright enthusiasm, the urge that researchers have to convince themselves that a drug is a little better than it actually is, that it can save lives. Pharmaceutical companies depend, in other words, on the sincere cooperation of people like Bill Wirshing.

Like other psychiatrists who treated schizophrenia, Wirshing had long been convinced that the harsh side effects of the older drugs were so painful that patients simply stopped taking them, and he was excited by the promise of an alternative. Using experimental doses of Zyprexa provided by the company, he gave the drug to his least responsive patients, those who had stopped taking their other meds and seemed permanently adrift, "lost in the ether of space somewhere." As he watched the first patients on the drug, Wirshing was intrigued. It seemed to work better than the older medications. Patients got dizzy when they stood up; their hearts raced; they would get constipated. But in most patients, the most vivid side effects of the typical antipsychotics - the tics, the perpetual restlessness - seemed to vanish.

"Was there a magic efficacy?" Wirshing says. "The answer is no. But the thing that was really dramatic was it was devoid of the neurologic toxicity." Wirshing saw very quickly, however, that Lilly had a problem: Many of his patients taking Zyprexa were gaining a startling amount of weight. The pattern was as sudden as it was consistent. For the first few days they were on the drug, you weren't aware of any palpable difference. But by the end of the week, you could see the weight gain, almost in real time. Bellies and thighs started spreading, faces started puffing out. By the end of a year, the results were stunning. Some of his patients had gained more than 125 pounds.

Clinical trials are not cheap to conduct or lightly undertaken. According to Wirshing, Lilly spent $200 million to test Zyprexa at 175 sites around the world. "They thought they had a drug that was superior," he says. "You don't spend that much money just for the hell of it. They really believed this." But when he brought his concerns about Zyprexa to executives at the company, Wirshing says, they tried to dismiss the evidence. First they told him that it was just the skinny schizophrenics who were getting fat. Wirshing re-examined his data; it wasn't true. Then they told him that it was the schizophrenia itself that was causing the weight gain, rather than the drug. Wirshing was apoplectic: "If schizophrenia causes that much weight gain, how come I've been working with schizophrenics for 20 years and didn't know that?"

Advertisement

At one meeting of researchers who were studying the drug, Wirshing recalls, a scientist from Lilly presented the results of a trial he had conducted at Indiana University, in which a group of healthy male students were given 10 milligrams of Zyprexa a day to test the side effects. Within two weeks, the students gained five pounds more than those in a control group, who didn't take the drug. Wirshing worked out the implications: Taking 10 milligrams of Zyprexa, the study suggested, was the equivalent of eating 1,500 additional calories every day. Some of the students gained as many as 15 pounds in two weeks. "It is just un-stinkin'-believable," Wirshing says. "It is the best drug for gaining weight I've ever seen. If you and I could just put a negative in front of those weight-gain numbers, we'd make billions."

In 1995, as the company was preparing to submit Zyprexa for approval to the Food and Drug Administration, Lilly convened a panel of experts to review the results of its largest study. The specialists concluded that Zyprexa produced an average weight gain of 24 pounds in a single year. One in six patients, clinical trials later revealed, gained more than 66 pounds. Such a staggering side effect, doctors knew, could elevate a patient's blood-sugar levels - an indication that the drug could cause diabetes. The government, if aware of these risks, might have slapped a strong warning label on Zyprexa, suppressing sales. But the data Lilly submitted in its application to the FDA that same year led the agency to draw a far less alarming picture of the drug. Relying on a database of 51 separate and conflicting studies provided by the company, the FDA concluded that patients taking Zyprexa for one year would have an average weight gain of only 11 pounds. "It's akin to the guys from the cigarette companies going, 'Well, it doesn't cause cancer,'Ê" Wirshing says. "It's just plain not true."

Fifteen years after the Reagan administration made it a policy to gut the FDA, however, the agency lacked the staffing and clout to safeguard the public. As the process stood, the government essentially entrusted drug research to the pharmaceutical industry and, given certain protocols on the collection of data, trusted that the results were accurate. Simply put, the FDA was no longer in a position to independently evaluate the effectiveness - and risks - of a drug like Zyprexa.

"What's that parable about the king who goes down to the ocean and asks the waves to stop coming in?" says Paul Leber, who directed the agency's division of neuropharmacological drug products at the time Lilly sought approval for Zyprexa. "That's what we're dealing with here. Congress creates laws that nominally protect the interests of the society and then gives insufficient funds and support to the regulatory agencies to do anything about it. This is what happens."

On September 30th, 1996, the FDA approved Zyprexa for the treatment of schizophrenia. Lilly was so confident of the go-ahead that it had already hired a sales force and stockpiled the drug in warehouses. The very next day, the company filled the first prescription for Zyprexa, making it the fastest drug to market in history. The label did little to warn doctors and consumers of the risk for severe weight gain or hyperglycemia, even though Lilly's own studies, internal documents would later show, raised concerns about these side effects. The FDA would eventually send a warning letter to Lilly, criticizing it for marketing Zyprexa as superior to other antipsychotics and as virtually free of side effects - claims the agency called "misleading" and "lacking in balance." But it would be nine years before a comprehensive government study would reverse many of the claims that surrounded Zyprexa and other atypical antipsychotics, and raise disturbing questions about their risks. And nine years, in the pharmaceutical industry, is a lifetime.

THE SALES PITCH
Every business has its own animating vanity, its conviction of its own social good, but in pharmaceuticals, where a good product saves lives by the thousands, the vanity is closer to the surface than in most. In 1998, a young man named Shahram Ahari, a few months out of Rutgers University, took a job as a drug detailer - a salesman who visits doctors - with Lilly's neuroscience division and was sent to headquarters in Indianapolis for "sales school." The new reps were told, from the beginning, that they were part of an elite. The neuroscience division not only required the most technical sophistication, but it had responsibility for the company's two best sellers, Prozac and Zyprexa. The sales reps had been hired, in part, because of their natural charisma - doctors would like them. Most of the reps, Ahari noticed, were really attractive - the company had recruited cheerleaders and athletes, and there were a couple of girls who plausibly claimed to have been models. But when the new hires were given technical training, it slowly dawned on Ahari that none of the other sales reps seemed to have any college-level science. "I was the only one in the room who could explain a very simple process, like how two neurons communicate," Ahari says. "That was startling."

Though Ahari had not known it when he applied, the company was on a kind of precipice. Its blockbuster drug, Prozac, the pill that provided nearly a third of Lilly's total revenues, was going to lose its patent protection in 2001, a date so significant that executives at Lilly referred to it, in memorandums and annual reports, as "Year X." As Lilly tried to figure out what to do, a consensus began to form around a new strategy. "The company is betting the farm on Zyprexa," one executive wrote in an internal memo in 2001. "The ability of Eli Lilly to remain independent and emerge as the fastest-growing pharma company of the decade depends solely on our ability to achieve world-class commercialization of Zyprexa."

The problem, from a marketing standpoint, was that there simply weren't enough schizophrenics in the world to save Lilly's bottom line. Among the company's most natural markets for Zyprexa, in the early days, were county jails and state prisons, where many schizophrenics and other mental patients - mostly locked up for public-nuisance crimes such as trespassing or creating a disturbance - had wound up after the closing of psychiatric hospitals like Danvers. "Before deinstitutionalization, to study people with severe mental illnesses, you went to hospitals," says Linda Teplin, director of the Psycho-Legal Studies Program at Northwestern Medical School. "After deinstitutionalization, you went to jails." Those in the profession now refer to Riker's Island and the L.A. County Jail as the two largest mental hospitals in the country. Feeling the great weight of inmate numbers, some jail doctors began to prescribe antipsychotics not only to treat schizophrenia but to tranquilize misbehaving prisoners. "It appeared that people were being medicated simply to keep them pacified," says Eric Balaban, senior staff counsel for the ACLU's National Prison Project.

In his new job, persuading psychiatrists to prescribe the drug, Ahari and those like him were pivotal: If Lilly hoped, one day, to break out of the circumscribed market of schizophrenia, it needed psychiatric experts to tell primary-care doctors that Zyprexa was a good drug and a safe drug. Ahari was given a $60,000 expense account and an assignment to cover Brooklyn and Long Island.

Pharmaceutical sales reps think of themselves as the intellectuals of the sales world, but they spend their days in a gauzy suburban existence, driving from hospitals to private offices in big American sedans, their detailing kits and golf clubs in the trunk. They chat up receptionists to get in to see doctors, chat up residents to find out who is on a hospital's formulary committee. What was striking to Ahari, at least at the beginning, was how easy it was. Lilly had spent hundreds of millions of dollars developing Zyprexa, as well as millions more on market research, yet its campaign was built largely around the fact that the drug was newer than rival medications. "The Novel Psychotropic," they called it. Ahari had talking points and brochures that referred to the initial studies and had been trained to stress the lower rates of extrapyramidal symptoms that Zyprexa caused. But frequently the conversations didn't even get that far. "Most doctors were inclined to think that the atypicals were better," Ahari says. "That's one of the things that made selling Zyprexa so much easier. A lot of them just wanted to play with the shiny new toy."

Advertisement

Though Zyprexa cost far more than the older drugs, which were mostly generic, neither insurance companies nor doctors seemed primarily concerned about cost, and Zyprexa was, from the beginning, a vast success. "The existing treatments were so bad that people were willing to pay a lot for the prospect of something better," says Meredith Rosenthal, an associate professor of health economics and policy at the Harvard School of Public Health who has studied the atypicals extensively.

One afternoon during Ahari's first week on the job, a psychiatrist pulled him into a small room. The doctor had put some of his patients on Zyprexa, he said, and he had noticed that they were gaining a troubling amount of weight. What could the sales rep tell him about that? Ahari was "stunned." He'd spent six weeks at sales school, and though he'd been coached extensively on the beneficial features of the drugs, the company had downplayed the risk of weight gain. Ahari passed the doctor on to Lilly's science desk and then put in a query himself. Eventually, the company's reply came back. If he heard similar complaints from doctors, he was supposed to tell them to have patients drink a glass of water before taking the pill, and a glass of water afterward. Ahari started to have doubts. "This was," he says, "a ridiculous way to cope with weight gains of 20 or 30 pounds in a month."

The more Ahari started to poke around, the more skeptical he became. Lilly had instructed its sales reps, if asked about weight gain, to explain that Zyprexa was not statistically worse than other antipsychotics. But this contradicted the company's own data. At this point the drug had 5 million users; a senior Lilly scientist did a quick calculation and estimated that Zyprexa had caused as many as 100,000 of those users to gain 90 pounds. The health risks of that kind of weight gain were profound. "One hundred thousand people putting on 90 pounds of weight," the scientist concluded glumly, "is a lot."

Internally, Lilly's own experts were criticizing the company for covering up the link between Zyprexa and diabetes. "I do believe they made a very strong point that unless we come clean on this, it could get much more serious than we might anticipate," one Lilly executive warned in an internal e-mail in October 2000. But in hospitals and doctor's offices, the company's sales force continued to push Zyprexa as a wonder drug. In a common industry practice, Lilly persuaded leading psychiatric experts to endorse the drug and then paid them to tout it to doctors, who had little expertise when it came to antipsychotics. Ahari was struck by how perfectly the strategy worked: Most doctors, pressed for time, did not "approach the education they were getting from the industry with any skepticism at all."

Nor did the experts, who were all paid to hock the drug, strike Ahari as unbiased. The first time he met a national psychiatric expert, flown in to recommend Zyprexa to local doctors, the expert pulled Ahari aside and started quizzing him about sales in his territory; he was trying to figure out, he said, when he might optimally exercise his stock options. One rep arranged to fix a doctor's swimming pool; another paid a nightclub hostess to spend time with a doctor. Some of the more attractive reps boasted about ways to "exploit sexual tension." Ahari had been taught strategies to manipulate physicians during conversations - such as providing subliminal reminders of the favors he had done for them - and he found himself using the techniques on his girlfriend.

Ahari was becoming convinced that what he had been trained to do was to make a pitch that seemed scholarly and then to let that impression stand in for a flawed product. Because federal law allowed pharmaceutical companies to purchase a doctor's prescribing records, they could measure exactly how much all of this attention was buying. "There were a few doctors where it didn't make any difference, but far more frequently you could see a direct correlation," Ahari recalls. What was particularly striking, in the case of Zyprexa, was that even as more and more studies criticized the drug's side effects, it continued to win market share. The FDA didn't require that sales reps tell a doctor about every single study that had been done on a particular drug, only that what they did say was accurate.

"It's like a magician," says Dr. Robert Rosenheck, a professor of psychiatry at Yale University. "The magician just says, 'Look at my right hand. There's a marvelous rabbit in my right hand.' And you don't pay any attention to what's going on in their left hand. When you have such a devastating illness, and so much yearning for hope, it's easy for marketing to convert that hope into conviction."

THE ALGORITHM
The pharmaceutical industry and the federal government have always had an unusually intimate relationship - the government is both the industry's watchdog and its biggest customer. The FDA regulates the development of a drug and, at least in theory, the marketing that follows its release. Because Medicaid and Medicare buy such a large portion of drugs - particularly in the case of the antipsychotics, since virtually no schizophrenics can afford private insurance - the companies lobby those agencies, and their state subsidiaries, to try to win preferences for their own medications. To make clear which drugs the government will pay for, some states issue complex medication algorithms - detailed "decision trees" that spell out precisely what a psychiatrist seeking government reimbursement should prescribe when confronted with certain symptoms. (Lilly, for its part, has lobbied extensively to keep state legislatures from favoring generics over Zyprexa.) But in 2002, an investigator in the Pennsylvania inspector general's office, a guy named Allen Jones, became convinced that another line had been crossed, and that the government itself had been enrolled in marketing the drugs.,/p>

Following up on a complaint, Jones discovered that the state's chief pharmacist, Steven Fiorello, was receiving checks from drug companies - $2,000 for a speaking fee, $1,765.75 to fly in a psychiatrist for a meeting. Jones wondered if the money was buying anything else. Digging deeper, he learned that Fiorello was heading a panel that wanted to require psychiatrists in state hospitals, prisons and other institutions to prescribe newer, brand-name medications rather than older, cheaper generics. Under the new formula, the state would pay millions more to the pharmaceutical companies for antipsychotics like Zyprexa. Fiorello had touted the newer, more expensive drugs as better than the older ones. But as Jones examined the medical literature and called up experts, he noticed that the studies that Fiorello relied on were industry-sponsored; third-party studies seemed far less convinced of the merits of the atypicals. "Independent science, minus the drug-industry money, had come to a different conclusion," Jones says. "It was a big red flag."The practice of industry-paid doctors and research is so commonplace that for most medical professionals, it barely registers - it's just part of the background noise. Virtually every clinician in the country who conducts original drug research gets money from the pharmaceutical industry, because that's who pays for research. The industry currently spends 50 percent more than the government on basic medical research, a gap that has consistently widened for the past 15 years. But to Jones there was something different happening here: Fiorello was a state employee, not a university researcher. And this looked to Jones a lot like a bribe.

Jones continued to probe. Fiorello's algorithm for Pennsylvania was modeled on a program called TMAP that had been developed by Dr. Steven Shon, medical director of the Texas Department of Mental Health. In all, Jones discovered, Shon and a team of researchers he worked with at the University of Texas had taken more than $2Êmillion in grant money - from atypical manufacturers and their nonprofits - to develop TMAP.

Advertisement

When Shon's group finalized its work in 1997, the manufacturers got far more than they had paid for. The new algorithm made the more-expensive atypicals the preferred drug for doctors treating prisoners, students and poor patients covered by Medicaid. It set rules so stringent that if a doctor prescribed an older, cheaper drug instead of a newer one, they had to explain their decision in writing, making them vulnerable to malpractice lawsuits if the patient developed any problems. Influenced by the new algorithm, the state also reportedly treated the atypicals as the preferred drugs for certain mental illnesses in children, even though the FDA had not approved that use.,/p.

Studies would later show that under the new guidelines, prescriptions of atypical antipsychotics in Texas increased sixfold by 2004. The government of Texas, in effect, had instituted a taxpayer-subsidized marketing scheme for the drug industry, one that gave preferential treatment to the newest and least-tested medications.

The atypical makers paid Shon to fly around the country, taking more than 80 trips to talk up the merits of his new algorithm. In interviews from the period, Shon's sense of social purpose is palpable and zealous, as if he believed he were building a machine to save neglected schizophrenics. There were trips not just to Pennsylvania but to Italy and Japan. Eventually, 17 other states adopted versions of the TMAP program. It was, Jones believed, a classic bait-and-switch. "The scientific evidence didn't back the industry up," he says. "So they paid these experts like Shon and then let their opinions stand in for evidence. What's amazing is how well it worked."

As Jones made progress on the case, his supervisor at the inspector general's office tried to warn him off. "Stop trying to be a salmon," his boss said. "Stop swimming against the stream." When Jones persisted, he was fired. "I could begin to see what was going on," he says now. Jones filed a suit in federal court alleging a cover-up, and his efforts eventually convinced the state of Texas to reject its own algorithm and sue the drug manufacturers for millions in damages. Fiorello was convicted of violating felony conflict-of-interest laws. Shon, who was forced to resign, ended up moving to Las Vegas. But he refuses to admit that he did anything wrong. The studies on the atypicals, he insists, indicated that they really were better drugs. "When you really look at the investigators involved and the procedures they followed," he told reporters, "they were all within what has been defined as appropriate in every medical field."

In this, Shon is, more or less, right. The doctors who studied the atypicals were simply conducting business as usual. Jones, an outsider gazing in, thought he saw a basic quid pro quo, a corrupt transaction between two parties that stood to benefit. But it is possible that he missed a more complex and fundamental truth: that the system of developing and marketing drugs is so broken that it can coax corruption out of well-meaning doctors who think they are doing good. Every incremental permission that the atypical makers allowed themselves, and the regulators allowed them - structuring their studies in the most advantageous ways, omitting studies unhelpful to their cause, publicizing only the most supportive data - helped shift the medical perception of the atypicals. The companies didn't need to pay off doctors. They just needed to put the grant money out there and wait for the true believers, the Steven Shons, to walk through the door.

GOING OFF-LABEL
In the fall of 2000, marketing executives at Eli Lilly summoned the company's sales representatives to a meeting in Orlando, at which they planned to introduce a new strategy, one born not of nervousness but of success. Zyprexa had recently won FDA approval for treatment of bipolar disorder as well as schizophrenia, but these were limited markets. "To get beyond a certain point," says Sandra Chow, a drug-industry analyst with the research firm Decision Resources, "companies that manufactured the atypicals needed to expand into the primary-care market." The big money, in other words, lay in the offices of suburban doctors and family physicians.

At the Orlando conference, Lilly edged close to self-parody, a real-life version of The Office. Someone at the company rewrote the lyrics of "Viva Las Vegas," urging sales reps to target the primary-care market: "Thousands of patients waitin' out there/The way they're livin' just ain't fair/But now you bet they can get/Some help from primary care/Viva Zyprexa! Viva Zyprexa!"

But there was a problem: It was illegal for the company to suggest any "off-label" uses for Zyprexa to doctors, because no treatments other than schizophrenia and bipolar disorder had been approved by the FDA. And almost all schizophrenic and bipolar patients were being treated by psychiatrists, not by primary-care doctors. But that didn't deter Eli Lilly. The company's executives, internal documents would later show, had been planning a strategy shift for about a year, e-mailing suggestions about opportunities in the primary-care market. Some doctors, one executive wrote, might be willing to prescribe Zyprexa for depression, if they could be convinced that what they thought was depression was in fact one half of the mood swings of bipolar disorder. Another executive suggested marketing Zyprexa to treat the elderly. "Dementia should be first message," he wrote, noting that primary-care physicians "might prescribe outside of label."

In Orlando, the executives detailed their plan. As part of their marketing initiative, they had compiled "profiles" for three types of patients they wanted their drug reps to suggest Zyprexa would help. One was "Donna," a single mom in her 30s who came to the doctor's office in "drab clothing," complaining that she felt anxious, irritable and in need of little sleep. The second was "Mark," a middle-aged man who experienced mood swings. The third was "Martha," a widow who had grown agitated and restless since her grown children had left home.

In its marketing strategy, Lilly argued that such common, widespread symptoms actually indicated diseases for which Zyprexa was approved - bipolar disorder in the first two cases, schizophrenia in the last - though to most psychiatrists, the symptoms didn't come close to describing those disorders. The goal for sales reps, according to the Lilly's strategy document, was to "expand the market of Zyprexa by redefining how primary-care physicians help reduce mood, thought and behavioral disturbances." Other company documents, which later came to light during court proceedings, encouraged sales reps to use the term "mental disorders," which was "intentionally broad and vague, providing latitude to frame the discussion around symptoms and behaviors rather than specific indications." Other court documents accuse Lilly of pushing Zyprexa for anorexia, autism and sleep disorders, a charge the company denies.

Some consultants for Lilly grew alarmed. "They were clearly pushing off-label use," says Dr. Lon S. Schneider, a psychiatrist at the University of Southern California who has served as a consultant for Lilly. The company, he says, pushed studies that supported its case while ignoring those that were negative. Schneider discovered ads in journals for geriatricians and nursing-home administrators that seemed to advocate off-label use of the drug to relieve the symptoms of dementia - even though he knew that Lilly's own studies of elderly patients with dementia had found the drug worked no better than a placebo. (In 2005, the FDA required Zyprexa's packaging to include a "black box" warning - the agency's most severe - emphasizing that the drug increases the risk of death for patients with dementia.)

Advertisement

Rhonda Stovall, a sales rep assigned to sell Zyprexa, had helped Lilly find alternative markets for drugs before, selling a repackaged version of Prozac as a treatment for PMS. At one point, as the company tried to break into the market for general depression, it came out with a formula for what it called "treatment-resistant depression," suggesting that doctors mix Prozac and Zyprexa. Such formulations involved a sort of pharmaceutical sleight of hand: "You focus on the symptoms, that's what we were taught," Stovall says. "You don't focus on the disease." The reps told primary-care doctors that what they thought of as depression might in fact be bipolar disorder - which, conveniently, could be treated with Zyprexa. Internal call sheets from the company's sales reps in Alaska show them visiting doctors, leaving peanut-butter cups and the Donna profile. "You may have some patients who are bipolar, and you've never really thought of the problem like that," Stovall recalls telling physicians. "Let me tell you about Zyprexa, how it can help with these mood swings."

Within three months, the Viva Zyprexa campaign generated 49,000 new prescriptions for Lilly, bringing in hundreds of millions of dollars in revenue. Today, a quarter of Zyprexa's sales are in off-label markets.

But peddling the drug to anxious mothers and mildly depressed middle-aged men meant that Lilly was inflicting the side effects of Zyprexa on tens of thousands of unwitting patients. Dr. John Gueriguian, a retired FDA investigator who has served as an expert witness in lawsuits against Lilly, believes the company was aware of the connection between the drug and diabetes by 1998 but concealed that evidence. Lilly put "profit over concern of the consumer," he said in court testimony. But the new markets only served to amplify the drug's side effects. If schizophrenics gained more weight than they were supposed to, Stovall points out, no one really complained - schizophrenics, after all, have bigger problems to worry about. "But if you've got your soccer mom who comes in, and the doctor gives her Zyprexa, and suddenly she goes from 110 pounds to 200 pounds - well, it could be a problem."

The weight gain was visible and striking. "You'd see it from one visit to the next," says Dr. John Abramson, a clinical instructor at Harvard Medical School who has studied the atypicals. "They'd come back, and they'd look like a different person. It looked like someone stuck an inflation needle in them and pumped them full of air." There were other effects, too. Patients got dizzy; they got tired; some saw their blood-sugar and cholesterol levels spike. (Lilly added strong warnings about these last two side effects in 2007, after publicity over Zyprexa's risks had mounted.) Even more worrying, as researchers examined the many studies that had been conducted on the utility of the atypicals in treating the elderly, they found that tiny, persistent differences in the rates of death between the population given the new drugs and those given a placebo began to accumulate. "There would be one death in the patients on the drug, none on placebo in one trial. Three on the drug, none on placebo in another trial," says Schneider, who conducted some of the analyses. "When we summed this up, we found there was a small but clear risk for death."

Such side effects might have been more easily tolerated if the drug actually eased conditions like depression or dementia. But there was little evidence that Zyprexa did any good for off-label uses. In schizophrenics, the drug at least served a much-needed purpose, and psychiatrists, properly informed, could weigh the benefits against the side effects. But with the new conditions for which the drug was being prescribed - depression, dementia, anxiety - no one knew exactly what the benefits were, because Zyprexa's effectiveness for them had not been studied. All that was left was the side effects. "Doctors had no way of knowing if the drug worked for those indications," Abramson says.

And yet the use of the atypicals continued to spread. To some psychiatrists, their success seemed the emblem of a disturbing new era. "Turn on the television and look at the commercials," says Neimark, the Pennsylvania Hospital psychiatrist. "We sell the magic pill. On one page it's like everything's stormy and downcast, and on the next page the guy's at the bowling alley, and he's the life of the party." The advertising, he says, has consequences. "Everyone comes to doctors expecting cures - but in some ways, they're fantasies."

THE RUNNER
By the early 2000s, the categories of off-label users were beginning to add up: soccer moms, the elderly and now, researchers were increasingly finding, children. This was unusual. Because kids responded badly to the earlier versions of the drugs - they exhibited, as adults had, the characteristic facial distortions, the lethargy and nonfunctionality - the consensus of most psychiatrists was to find other ways to treat children. "During medical school, I remember very vividly one kid we had in the psychiatric unit who we just couldn't get under control," says Dr. Mark Olfson, a professor of clinical psychiatry at Columbia University. "He was attacking other patients on the floor. Because we were at our wits' end, I asked the nurse on duty, 'What about an antipsychotic? And she said, 'Mark we don't use these drugs for behavioral control in kids.' That was exactly the attitude."

But that attitude began to change in the 1990s. The new atypicals carried with them the promise that antipsychotics would be softer and less severe, and the use of the drugs escalated dramatically. Since 1993, the number of kids on the atypicals has soared fivefold. The leap took place in categories where antipsychotics had not previously been prescribed: Children were now being given the drugs for anxiety, ADHD and a newly popular diagnosis, pediatric bipolar disorder. "If I get really mad and throw a piano bench at you, we used to call that aggressive behavior," says Dr. Gabrielle Carlson, director of child and adolescent psychiatry at the Stony Brook University School of Medicine. "Now we call that a mood swing. It's a way of labeling kids that is quite insidious."

The manufacturers of the drugs were not immune to the possibilities offered by the emerging market. In 2003, a Lilly executive named John Lechleiter, who would later become the company's CEO, sent an e-mail to some of his colleagues. "We must seize the opportunity to expand our work with Zyprexa in this same child-adolescent population," he wrote. The drugs grew so prevalent that by 2006, a study found, nearly one in five children who visited a psychiatrist left the office with a prescription for an antipsychotic. "People began to think it was almost completely unethical not to give kids the atypicals," says Dr. Linmarie Sikich, an associate professor of psychiatry at the University of North Carolina. "But we didn't have any long-term studies" of the drugs' effects.

The lack of science, however, didn't deter doctors from prescribing them to children. The attraction was the same as in adults: the calming influence the chemicals could have on kids who otherwise seemed uncontrollable, mad with rages and distraction. "Can I tell you what's going to happen to someone who was put on an atypical 20 years ago, between the ages of 10 and 11?" asks Carlson, the pediatric psychiatrist. "No. That's where it's hard to look someone in the eye and say, 'No sweat.' At the same time, if you have a son who is unmanageable at home and who's being offered residential treatment, and you have the choice of that or giving him this medication, what do you pick?"

As the use of the atypicals overran the evidence, however, disturbing reports began to emerge. Between 2000 and 2004, the deaths of 45 children were linked to the atypicals. Some were strikingly young. An eight-year-old boy died of cardiac arrest. A four-year-old boy died of complications from diabetes. Perhaps most vivid of all was the case of a 15-year-old boy in South Florida referred to by social workers as a "runner," a kid who kept fleeing his exasperated foster parents to return to his birth mother. Admitted to a psychiatric hospital by a judge, the boy was tethered to a chair and pumped full of atypical antipsychotics, presumably to calm him. When his lawyer came to visit him, she found the boy not only sedated, but suffering from another acknowledged side effect of the atypicals: His breasts had become engorged and started to leak milk. The boy was lactating.

Advertisement

The risks of prescribing the atypicals to children became clear last fall, when Sikich, the UNC professor, delivered the results of a study she conducted on behalf of the National Institutes of Health. Not only were the atypicals no more effective than the older, cheaper, antipsychotics, but they caused side effects that prompted more than half of the kids to drop out of the study within a year. (Earlier, industry-funded studies had claimed far lower drop-out rates.) Kids gained as much as 35 pounds in as little as eight weeks, saw their cholesterol and insulin levels rise, and experienced painful rigidity in their muscles - a side effect that the newer antipsychotics were supposed to have eradicated. In fact, Sikich concluded, the atypicals had more-severe side effects than the older antipsychotics that pediatricians had resisted using in children. "All the drugs," she says, "are dirty drugs. They act in different places in the brain, and they all have different effects - some that we want and some that we don't."

LAX OVERSIGHT
By 2001, as the atypicals threatened to break $4 billion in annual domestic sales, officials at the National Institutes of Health decided to undertake the largest-ever investigation of schizophrenia. Studies had continued to appear evaluating the merits of the different types of antipsychotics, but the data was all over the place. Some concluded that the new drugs were a godsend; others said they did little. Most exasperating of all, it was almost impossible for a doctor, investigating in his spare time, to weigh the potential conflicts of interest within any individual study - virtually everyone in research psychiatry was affiliated with one drug company or another, and their findings, oftentimes, seemed to mirror their affiliations. The NIH decided to commission a comprehensive set of studies of its own, free from pharmaceutical influence, to evaluate the merits of the new drugs. Though it had for two decades entrusted drug development to industry, the government was effectively acknowledging that the data this system had produced had become so perplexing to physicians that it needed to settle things itself.

As data from the studies emerged, Robert Rosenheck - the Yale psychiatrist, who helped analyze the findings for the NIH - began to see significant divergences between the government studies and those produced by the pharmaceutical companies. Again and again, the government found, the new drugs were no more effective in treating schizophrenia than the old drugs, which were far cheaper. In addition, the atypicals appeared to dramatically increase the risk for diabetes and other often fatal illnesses. The great advertisement for the new drugs - that because they didn't cause the Parkinson's-like symptoms of the older drugs, patients would stay on them for longer - turned out to be substantially exaggerated as well.

"What you have is both industry and opinion leaders claiming this is a breakthrough drug," Rosenheck says. "And then three large government-funded studies come out, and none of them finds evidence of a breakthrough."

Puzzled by the discrepancies, Rosenheck began to work back through the original studies. What he found was not one smoking gun but a number of small manipulations. Researchers in the original Lilly study, he concluded, had not only skewed the results by concealing data that contradicted their preferred outcomes, they had also failed to administer drugs commonly used to offset the side effects of the older antipsychotics - a decision that made the older drugs perform worse in the clinical study than they did in the real world.

By the time the studies were completed, however, the damage was already done: More than 20Êmillion people worldwide have now taken Zyprexa. As the problems leaked out, lawyers for consumers and states began to look carefully at the industry's atypical studies and the methods the drug companies used to promote their products. In October, Lilly agreed to pay $62 million to 32 states to settle claims that it improperly marketed Zyprexa for off-label uses. "The company's deceptive marketing practices were illegal and highly dangerous," according to Lisa Madigan, the attorney general of Illinois. Although Lilly admitted no wrongdoing, the settlement was the largest ever paid by a drug company in a state consumer-protection case. On January 15th, Lilly agreed to pay an additional $1.4 billion to settle federal charges of illegal marketing - a record settlement in a corporate whistle-blower case.

But the penalties pale in comparison to the money that Zyprexa makes for the company. In 2007, the latest year for which figures are available, the drug generated $4.78 billion in sales, accounting for 25 percent of Lilly's total revenues. As Rosenheck reviewed the marketing history of the atypicals, he concluded that misleading data told only part of the story. "How did this happen?" he wondered. "How did this product that's not very advantageous wind up being marketed as a great advance?" Part of the underlying cause, he concluded, lay in the privatization that began with the Reagan revolution. "Ultimately, the conservative turn - with its faith in deregulation and the virtual infallibility of markets - are at the root of what allowed this to happen," he says.

In January 2002, as the Bush administration's second-tier appointees were beginning to settle into their jobs, a former pharmaceutical lawyer named Daniel Troy, who had just been appointed the chief counsel at the FDA, was given striking new powers. The agency's medical evaluators would no longer have the authority to send a warning letter directly to a drug manufacturer engaged in questionable marketing practices - marketing like the kind that Lilly had used to sell Zyprexa. Now, FDA evaluators would have to get approval from the Office of the Chief Counsel - from Troy himself, effectively - before sending out such a letter. The shift had a remarkable chilling effect on government oversight of the drug industry: The length of time it took the FDA to issue a warning letter about deceptive advertising quintupled.

For a decade, the FDA had been instituting small but significant accommodations that increased the intimacy of its relationship with the drug industry. First, in 1992, it began requiring drug companies to pay application fees when submitting new drugs for review - a move that made the agency dependent on industry for more of its budget. Throughout the 1990s, with a Republican Congress demanding a new friendliness to industry, the posture of the agency continued to shift; by the time Bush took office in 2001, the FDA's approval rate for all new drugs had jumped from 60 percent to 80 percent. The agency was so industry-friendly that even the vast and powerful pharmaceutical lobby wasn't pushing particularly hard to further weaken lax regulations. "After 2000, the companies saw that the agency was going to be very lax," says a retired senior FDA official who asked not to be identified.

Advertisement

Bureaucracies, like fraternities, are idiosyncratic places, formed of personality, habit and tradition. In the FDA, Bush's political appointees were coaxing the agency's bureaucrats and scientists to go easy on the drug manufacturers. "What's different now is a lot of these higher-up career officers are much more industry-friendly than was the case two decades ago," says Dan Carpenter, Freed Professor of Government at Harvard and a leading scholar of the agency. By 2000, when the Los Angeles Times documented how the FDA had approved seven deadly drugs, it turned out that the agency had repeatedly ignored strenuous objections from its own experts.

Under Bush, experts say, the FDA has effectively become enrolled in the erosion of its own power. Instead of supporting consumers harmed by dangerous drugs, Troy's office began filing briefs on behalf of drug companies facing lawsuits from the families of people harmed by medications. In some cases, congressional investigators found, Troy operated in concert with the pharmaceutical companies. The number of warning letters issued by the FDA, a key indicator of how vigilant the agency is at tracking violations by drug manufacturers, has now fallen to half what it had been at the end of the Clinton administration. The industry is also well connected with Republican power: Former president George H.W. Bush has served on the board of directors of Eli Lilly, and Mitch Daniels, his son's former budget director, served as the company's vice president.

"With the FDA where it is, the pharmaceutical companies control far too much of the process, from the trials to the marketing," says Abramson, the Harvard instructor. A decade ago, it was a few figures on the fringe of the medical profession who sensed the trouble in this, and they had the feel of people who had been gazing into the vortex too long. Now it is professors at Yale and Harvard, and, in the case of the atypicals, by implication, the government itself.

BEYOND DRUGS
During the late 1960s, the World Health Organization assigned a psychiatrist named Norman Sartorius to study schizophrenics in different parts of the world. Years later, Dr. Sartorius and his fellow researchers followed up on his patients in the initial study, to track their recovery. The researchers expected to find that patients in the West, who have far better access to modern medications than those in the Third World, live longer and participate more fully in society. But the study found precisely the opposite: Schizophrenics in the developing world, with minimal access to medication, do better than those in the West. "It was a very surprising finding," Sartorius says. It was also controversial. But as follow-up studies confirmed Sartorius' initial findings, epidemiologists began to wonder if the evidence suggested something profound and definitive about the shortcomings of antipsychotic drugs. If Egyptians and Bangladeshis did better without the drugs than Americans did with them, the thinking went, how good could the drugs be?

One of the scientists who found himself fascinated by the discrepancy was William Eaton, a leading schizophrenia researcher who chairs the department of mental health at Johns Hopkins University. As he explored the ways in which schizophrenics live in the developing world, he began to think that the drugs were still crude enough that social factors might have a bigger effect on treating the disease. In the cluttered bazaar in Aswan, Egypt, Eaton met a schizophrenic man - his tongue flicking, his face bent by the tremors of Haldol - who was employed in his father's tiny shop; later he visited the man's home, where his wife had just given birth to the couple's first child. "The point is that this guy's family structure was such that he could get married because he was being protected by his father," Eaton says. "That's bound to be better than someone in the West who has to drop out of college and ends up on the street homeless."

Eaton began to see similar patterns elsewhere. In the surreal destitution of India, he visited the house of a schizophrenic - a dozen relatives crammed into three rooms, a portrait of John F. Kennedy tacked to the wall - where the family rotated round-the-clock care of the sick man. In such settings, Eaton believed, lay a basic illumination about the mystery of schizophrenia: Drugs might do some good, but they still weren't as effective as a supportive, caring environment. "The medications are helpful, but they don't work for everybody, and they have lots of side effects," Eaton says. We tend to think of drugs as solving discrete problems - penicillin to eliminate bacteria, insulin to modify diabetes - but the antipsychotics are shooting at an invisible target. With schizophrenia, says Eaton, "we don't know what the hell is going on."

Visiting the most celebrated mental-health centers in the United States, it is hard to conclude that, even after the innovation of the atypicals, the drugs make a decisive difference in care. In November, I spent a day with Dr. Ralph Aquila, a schizophrenia specialist at Columbia University, who works with a legendary center in New York called Fountain House. The "clubhouse model" developed there - which stresses job placement for even the most severely mentally ill, and a transition to functionality - has been widely praised and adopted; there are now 400 such centers in the United States, as well as dozens overseas. "Schizophrenia used to be synonymous with a death sentence," Aquila tells me. "I can get them paying taxes."

There are cases, Aquila says, where drugs play an important role. Unlike many other psychiatrists, he still prescribes Zyprexa - believing that social workers in the closely monitored environment of Fountain House can track unwanted side effects and make any necessary adjustments. But as he spends an afternoon treating patients, it becomes clear that the challenge for those treating schizophrenics goes far beyond tinkering with dosages and medications. One long-term patient, who had been focused earlier in the day, is suddenly skittish and distracted; Aquila suspects a crack relapse. A woman on Zyprexa has gained 80 pounds and had to have her stomach stapled; Aquila checks her weight, asks about her new apartment. A young man has a new job with a messenger service; Aquila, pleased, asks him how frequently he is making it to work.

This is incremental and shaky-footed work: Aquila expects his patients to have false starts and relapses, shifting, suddenly, from a medicated, functional state to more-florid and dysfunctional psychosis. Some elements of the medical establishment - at Harvard, even at Columbia - still view such efforts as social work rather than medicine. But to Aquila, the up-close contact with patients is what is essential. Many schizophrenics see a doctor only once a month, for a 15-minute consult, and Aquila believes that those psychiatrists have no chance to follow up on the things that matter most. "You don't know what the person's really about - you miss out on something that you could latch on to, to really develop a relationship," he says. "The meds are just a small part of the equation."

Aquila has learned a truth like those that Eaton discovered more distantly: a feel for the enormity of the problem, and a sense that the solution lies in hard and incremental work, with frequent backsliding. He has learned, in other words, that there is only so much the drugs can do. He has come to believe that there is no magic here.
[From Issue 1071 - February 5, 2009]