Bitter Pill

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?"