Rolling Stone

May 29, 2011

https://www.readability.com/mobile/articles/v7avrxoj

Bitter Pill

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

BEN WALLACE-WELLS

Posted Jan 28, 2009 3:10 PM

- Behind the Story: Q & A With Writer Ben Wallace-Wells

In June 1992, not long after the place closed down, a Harvard-trained

psychologist named 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. 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. 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 , 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.

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... More at

link.

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May 29, 2011