New Mental Illness Drug Creates Its Own Dilemmas : Health: Clozapine offers hope to schizophrenics. But states are forced to ration it because of its high cost.

A new drug for schizophrenia--both more effective and more dangerous than anything else on the market--has created a tangle of ethical, scientific and public policy dilemmas across the country.

The drug, clozapine, offers hope to several hundred thousand schizophrenics for whom traditional treatments have failed, many of whom have been driven by their illness from families and jobs into psychiatric wards, board-and-care homes and the streets.

In a few remarkable cases, the drug has enabled people once debilitated by delusions and hallucinations to resume productive lives--awakening, like Rip van Winkle, after a decade or more of disease to resume life where they left off.

But clozapine has also killed, triggering a life-threatening blood disorder in a fraction of those who take it. A patient’s white blood cell count may suddenly and unpredictably plunge, leaving the person vulnerable to potentially fatal infections.

It is also expensive. A year on clozapine can cost as much as a year in private school. So public mental health systems, which end up caring for most schizophrenics, find themselves forced to ration the drug, unable to provide it to many thousands who might benefit.

For all these reasons, fewer than 20,000 patients have had the chance to try the drug since it became available in early 1990.

“All the states have really been in a crisis over how to handle this,” said Dr. Mona Bennett, a former Massachusetts state mental health official. “Because of the financial issues and the training issues, this was really an extraordinary drug to introduce.”

For some, the country’s unfolding experience with clozapine will be a test of whether it is possible to avoid pitfalls encountered by other wonder drugs--high hopes followed by dashed expectations, or, as one expert put it, our tendency to worship drugs and then kill them.

For others, the clozapine quandary draws attention once again to the limitations of the public mental health system in a period of public and political neglect. Clozapine, they say, is simply a glaring example of the inability to help more than a fraction of those in need.

“It dramatizes the fact that the whole public mental health system is a highly rationed operation,” said William A. Hargreaves, a professor of medical psychology at UC San Francisco. “. . . There is a social message, indirectly, from this kind of drug.”

Schizophrenia affects between 1.5 million and 2.5 million Americans. It is the most common form of psychotic illness, characterized by severe disturbances in thinking, behavior and emotional reactions. Its causes, believed to include brain damage, are not well understood.

The disease usually sets in between the ages of 15 and 25, blighting the lives of promising adolescents and young adults. Young men and women find themselves forced to drop out of schools and early careers before they get off the ground.

In many cases, a person becomes increasingly introverted and withdrawn. Drive and motivation dwindle. More advanced symptoms include delusions, hallucinations, jumbled thinking, emotional detachment and self-neglect.

About a third of all patients respond well to traditional antipsychotic drugs, such as thorazine. Many return to relatively normal lives. Another third respond somewhat, but remain noticeably ill and disabled. A final third--those who stand to benefit most from clozapine--fail to respond at all.

“They sit in the back rooms of board-and-care homes and smoke cigarettes and stand on street corners,” said Dr. William H. Reid, medical director of the Texas Mental Health and Retardation System. “They’re very often homeless.”

“It’s such (an awful) illness,” said Dr. David Pickar of the government’s National Institute of Mental Health. “. . . I think most people do not appreciate the tragedy of this disorder. There hasn’t been a major advance (before clozapine) in over a quarter of a century.”

Clozapine was developed in Switzerland in 1961 and first used in Europe in the 1970s. It differs from other antipsychotic drugs in several ways. Most strikingly, it does not cause many of the traditional side effects, including tremor and spasms of the face, neck and body.

It does, however, have two serious side effects of its own. People who take clozapine face a relatively high risk of seizures. It can also cause agranulocytosis, a severe drop in white blood cells called granulocytes, in 1% to 2% of those who take it.

Although agranulocytosis can be reversed if caught in time, 43 people died of it in Europe in the 1970s and 1980s. Even so, interest in clozapine in the United States increased in the late 1980s when new research showed it helped schizophrenics for whom other drugs had failed.

In one recent study, for example, 38% of patients with treatment-resistant schizophrenia did significantly better on clozapine than on other drugs, according to Pickar, who is chief of the experimental therapeutics branch at the mental health institute.

“That’s pretty terrific,” he said recently. “On the other hand, that’s over 60% who don’t benefit better. So, keeping in mind it’s not quite the miracle drug for everybody, 38% is a meaningful amount.”

The U.S. Food and Drug Administration approved clozapine, which is marketed under the name clozaril, for sale in the United States in late 1989. Its use was limited to treatment of schizophrenia in people for whom at least two other antipsychotic drugs have failed.

But the FDA and the manufacturer agreed to require that all clozapine patients have their white blood cell count monitored weekly.

The manufacturer, Sandoz Pharmaceuticals Corp., insisted that all white-cell monitoring be done by its own contractor. As a result, the price of the drug and the monitoring, available only through Sandoz, was set at $8,944 a year.

While there are a few equally expensive drugs, most need not be taken over a lifetime. And in this case, the burden falls heavily on public mental health systems, since schizophrenia leaves so many of its victims indigent, unable to afford private insurance.

“We were talking about bankrupting the whole system here,” said Dr. Steven Shon of the California Department of Mental Health. “Public funds are very scarce. If all of a sudden several other companies followed suit, the costs would skyrocket.”

Mental health agencies protested immediately. Several dozen states filed an antitrust action against Sandoz. During a yearlong standoff in 1990 and 1991, just 7,200 of the several hundred thousand people who might be eligible managed to get the drug.

“It was an incredible public-policy irony,” said Fred Fedeli, director of government relations for the National Alliance for the Mentally Ill. “All the money invested in basic research had produced a product and it was not able to find any users.”

Finally this year, Sandoz agreed to “unbundle” the package. Mental health agencies and others could arrange for their own monitoring at a lower price. The wholesale price of the drug alone is down to an average of $4,160 a year, a figure many say is still too high.

State mental health systems “are kind of blinded by the price,” said Reid of Texas. “It has always struck me that if the price were lowered by 50%, the states would no longer be ticked off, that would break the logjam and prescriptions would probably go up 400%.”

Since last spring, when Sandoz changed its monitoring policy and federal officials ruled that state Medicaid programs should pay for the drug, states and counties have been wrestling to balance their concerns about fairness and finances, patient access and patient safety.

In Connecticut, surveys have suggested at least 600 state hospital patients might be eligible and might benefit from the drug, but the state has enough money to supply it for just 60 to 65, said Hargreaves, who is studying the success of the drug in that state.

In Pennsylvania, officials initially planned to give clozapine to 200 patients in the state hospital system, out of an estimated 800 who were eligible. The patients were to be selected through a system called “random choice”--condemned by critics as a mental health lottery.

Patient advocates sued, saying the policy violated the principles of equal protection. The suit was settled out of court, with the state agreeing to make the drug available to hospitalized patients without regard to numbers or cost.

Massachusetts officials opted to focus initially on hospitalized patients, believing they were in greatest need and that monitoring outpatients would be difficult. The state began treating about 130 of an estimated 500 to 600 patients who might benefit.

Dr. Mona Bennett, a former Massachusetts Department of Mental Health deputy commissioner, said more patients have improved than expected. Instead of the predicted one third, as many as 50% to 60% of patients have improved to a point where their level of care could be reduced, she said.

That is, some patients who were in locked intensive care units within hospitals have been able to move to open wards. Some who were in open wards have left the hospital.

In California, each county is developing its own policy--a trend that worries patient advocates, who fear wide differences in access to care based on the arbitrary distinction of what county a patient happens to live in.

In Sacramento County, there are no psychiatrists who treat patients on MediCal, said Thomas J. Sullivan, program chief for the county’s Department of Mental Health Services. So all MediCal patients who might be eligible for the drug become a county responsibility.

The county cannot afford to treat all those people in need, even with MediCal reimbursement, Sullivan said. So it intends to offer the drug initially only to patients in hospitals and locked psychiatric facilities, a small minority of those who could benefit.

“Those are the people I wanted to treat, rather than the ones already making it in the community,” Sullivan said. “. . . We’re looking for those in the most intense levels of care, with the most dramatic symptoms.”

Daniel Pone, a senior attorney at Protection and Advocacy Inc., a federally mandated advocacy organization for the disabled, said the biggest barrier to access to the drug in California is the lack of private physicians willing to prescribe it.

“A lot of the counties are very fearful about liability. And so are the private providers,” he said. “They don’t want to be sued because someone has a horrible effect or dies.”

Los Angeles County officials trying to decide how to make the drug available enlisted the help of well-known researchers at Harbor-UCLA Medical Center. The researchers spent months drawing up a detailed protocol under which the county hopes to be able to balance economics, equity and risk.

Under the Los Angeles system, patients attending county clinics who have failed on other drugs can be considered for clozapine.

If a clozapine patient’s white blood cell count ever drops precipitously, the clinic must increase the weekly monitoring. If the white count drops too far, the patient must be taken off the drug.

Whether clozapine will prove cost-effective remains to be seen. In theory, it might eventually save public money by enabling at least some patients to leave hospitals and perhaps resume productive lives.

On the other hand, formerly hospitalized patients will become candidates for social programs and other services they were once too sick to use. In the short run, social service costs may rise even if hospital costs decline.

“We’d like to think at least that we can break even,” Hargreaves said.