A Lifeline With Risks : Health: A new drug may offer new hope to thousands of schizophrenics. But it has its costs: a high price and a fatal side effect.
The first major new drug for treating schizophrenia introduced in the United States in the last 20 years is about to hit the market, and it may signal a whole new generation of drugs that scientists hope will be more effective against the disorder.
The drug is clozapine, which Sandoz Pharmaceuticals is putting on the American market Monday. For perhaps half of the 200,000 schizophrenics in the United States who are not helped by conventional drugs, clozapine will be a lifeline.
But for some of them, it will be a life-and-death gamble that they may find not worth the risk.
That’s because tests indicate about 1% of the people who take clozapine will contract agranulocytosis, a blood disorder that cripples the immune system and could kill them if untreated.
In schizophrenia, though, the quality of a person’s days is often more the issue than the quantity of them. Blamed on abnormal brain chemistry, the disorder strikes without warning in the late teen-age or early adult years and robs its victims of a normal life. Schizophrenics withdraw into a hallucinatory world, unable and unwilling to deal with other people.
“The tragedy of schizophrenia is that it attacks that which makes us most human: our ability to organize our thinking, to care about other people, to actualize things we want to do, to participate in life,” said Dr. Steven Potkin, a psychiatrist at UC Irvine some of whose patients participated in the clinical trials.
One of his examples was a gregarious and popular Northern California high school student. In his late teens, he began hallucinating and hearing voices. They told him to attack people, and he did.
Conventional anti-schizophrenia drugs such as Haldol and Thorazine didn’t quiet the voices or improve his dangerous behavior over the next several years. He spent nearly two years in a mental institution before Potkin tried a new drug on him in 1987 as part of a nationwide clinical trial of the drug.
Today, the young man is well enough to live semi-independently, hold down a job and--most touching to his doctor--give a toast at his brother’s wedding. Potkin gives the credit to clozapine, which will be marketed under the trade name Clozaril.
“It’s amazing to see someone who looks like the shell of a person--who doesn’t respond emotionally, doesn’t give out, doesn’t take in--be transformed into a person who is caring and is capable of loving and able to enjoy himself,” Potkin says. “It’s remarkable.”
One woman, institutionalized for nearly a decade during her young adult years, told her doctor she felt like Rip Van Winkle when clozapine made her, at age 35, aware again of the world outside her own mind.
So, with enthusiasm and trepidation, the medical community is approaching its first full access to clozapine in this country.
Sandoz could have begun selling the drug widely last October, when the U.S. Food and Drug Administration approved its sale.
Instead, company representatives have spent the last four months showing videotapes to 12,000 doctors around the country to be sure they know how to use the drug, and fine-tuning an unprecedented distribution plan for it.
Sandoz has set up a system in which patients will receive clozapine not through a traditional pharmacy, but rather, through a system that requires weekly home health-care visits. A patient will receive a week’s supply of clozapine pills only after a nurse or technologist working for the home health-care firm Caremark Inc. draws blood to test for agranulocytosis. The patient’s doctor will be notified of results, and the drug will be stopped if there is evidence of agranulocytosis.
Of 112 cases of agranulocytosis that occurred worldwide through 1986, 35% resulted in death. During U.S. testing, 15 cases occurred. All were caught early and reversed after the drug was stopped. Clozapine was first developed by Swiss-based Sandoz Ltd. in 1961, but early enthusiasm for it faded by the mid-1970s because of European deaths. Sandoz unsuccessfully sought FDA approval of it in 1984. In China, clozapine is widely used without any apparent major problems, said Potkin, who spent 1981-83 working there.
Sandoz’s plan to protect patients from agranulocytosis (and the firm from liability suits) will make the drug more expensive than even the anti-AIDS drug AZT. AZT costs up to about $8,000 a year; clozapine will cost $9,000 a year per person, or about $175 a week.
This method of factoring the costs of lab tests and patient monitoring into the drug cost has public and private mental health insurance systems stymied on how to pay for the drug--if at all.
The price tag is so high that clozapine may not be easily available to patients for a few months as these third parties weigh clozapine’s large financial cost against its possible long-term therapeutic benefits.
Dr. Steve Shon, assistant director for clinical services in the California Department of Mental Health, said the state is moving toward trying to cover the cost of clozapine therapy for schizophrenics who are institutionalized, but no decision has been made yet.
For outpatients under public care, individual counties will have to decide whether to pay for clozapine. Medi-Cal officials decided Friday to reimburse the county for it under the federal Medicaid program, a key issue in whether counties would provide clozapine, said Leonard Terra, pharmacy consultant for Medi-Cal. Each prescription will have to be approved by the state.
With mental health budgets already tight, in some locales the drug may be judged just too expensive, Shon said.
“The issue comes down to we have a limited medication budget,” Shon said. “It’s like all the people who could use heart transplants, for example. The number who get them is very small. The resources are scarce, and that means you have to make choices.”
Private health plans seem equally perplexed by clozapine. In California, Kaiser Permanente hasn’t yet decided whether to provide the drug to its patients, said spokesman Jim McBride.
But patient advocacy groups can be expected to press state and county mental health care systems as well as private insurers to provide clozapine to schizophrenics in whom other drugs do not work.
The National Alliance for the Mentally Ill is working with Sandoz to establish a fund that would pay for clozapine treatment for people who can’t get it any other way, said Bob Haack, a board member and the parent of a schizophrenic son.
Giving clozapine to people who could be helped by it is a case of humanity winning out over expense, suggests Dr. David Pickar, acting chief of the clinical neuroscience branch at the National Institute of Mental Health.
“If it was my brother, or my sister, or my cousin, or somebody I cared about or my patient, I would say yes, it’s worth the money,” Pickar said.
A study commissioned by Sandoz concluded that by the second year of treatment with clozapine, states would save an average of $9,000 to $14,000 a year per patient because of reduced hospitalization costs.
“Treatment resistant” is the label applied to schizophrenics whose hallucinations can be relieved by standard anti-psychotics only if the drugs are taken at levels that induce annoying and sometimes dangerous side effects.
These drugs, called neuroleptics, block the action of a chemical called dopamine within the part of the brain in which schizophrenia seems to originate.
However, neuroleptics also block dopamine action in cells that communicate with the muscle system--causing a distinctive shuffling, stiff-armed gait that medicated schizophrenics often have.
More extreme side effects are tongue thrusting, lip smacking, Parkinson’s disease-like tremors and the involuntary bodily jerking of tardive dyskinesia, which is sometimes irreversible.
About 10% of the 2 million U.S. schizophrenics cannot or will not take standard neuroleptics at therapeutic levels because of such problems.
Some of these people can end up institutionalized for years. It is estimated that one out of every four institutionalized mental patients throughout the country is there because of uncontrolled schizophrenia.
Clozapine offers hope for such people because it seems to act differently than do standard anti-psychotics, said Dr. Herbert Meltzer, a Case Western Reserve Medical School professor who acknowledges a “certain paternity” for clozapine in this country.
Meltzer, Dr. Gilbert Honigfeld at Sandoz and a few other physicians pressed the firm and the U.S. Food and Drug Administration over the last decade to allow studies of clozapine despite its known fatal side effect.
Clozapine seems to have a weaker action at dopamine receptors than previous drugs, so it does not have the motor side effects of standard antipsychotic drugs, Meltzer said. In addition, it inhibits the action of another neurotransmitter chemical, serotonin.
Consequently, clozapine has changed the traditional view of schizophrenia as a problem with dopamine, Meltzer said.
This new dopamine-serotonin model for schizophrenia also is fueling current research to find clozapine-like drugs without agranulocytosis as a side effect.
Sandoz is among the drug companies that are actively researching such compounds, said Honigfeld, now director of scientific communications for Sandoz’s Clozaril effort.
Meltzer’s research group is looking at four such drugs already, and he predicts that within two to five years at least one of them will be available as a safer alternative to clozapine.
“Sandoz knows I’m trying to put them out of business,” Meltzer said with a laugh.
In the interim, Sandoz will have five years of patent protection in which to make up its approximately $200-million cost of bringing clozapine to market--a figure that could be reached if just more than 22,000 schizophrenics were treated with the drug for a year.
Currently, under pilot programs sponsored by Sandoz, about 1,500 patients in the United States are receiving clozapine at no charge to them, Honigfeld said. After Feb. 5, those patients, their insurers or public agencies will be charged for the drug.
The study of clozapine’s effectiveness that led to FDA approval found that it resulted in significant improvements in condition for about a third of the schizophrenics who took it for six weeks.
Subsequent follow-up found that by six months, about 60% of patients are helped by it, and improvement can continue even after that, Meltzer said.
Clozapine’s listed side effects include drooling, constipation, sedation, increased heart rate, a drop in blood pressure, weight gain and a risk of seizures that rises to 5% at the highest doses. Potkin said he also has seen it make a few patients more agitated.
The strict labeling on the Clozaril package warns that the drug should be used only for patients in whom at least two other drugs have been found ineffective.
If the weekly blood tests done by the Caremark nurses and technologist find early signs of agranulocytosis, the drug must be discontinued to try to reverse the condition, the FDA-approved labeling warns.
Still, some doctors say privately that they expect at least a few fatalities to result from the drug’s use in the United States.
Whatever the economic and health policy issues that clozapine raises, say its proponents, clozapine is a drug that can free people trapped inside their own brains’ pathology.
“I have been working with schizophrenic patients since 1964, and I never thought I’d see the day that this kind of change would take place in people,” Meltzer said. “It is astonishing to see people who have been institutionalized for five or 10 years, with unremitting hallucinations and delusions, to have all those symptoms disappear and function on a quasi-normal basis. And sometimes not so quasi.
“You cannot imagine what the families feel, what the patients feel when this starts to happen. It’s just great to be part of it.”
How Patients Will Get Clozaril A physician decides Clozaril might help a patient and enrolls the patient in the Clozaril Patient Management System (CPMS) by phone or mail. Sandoz Pharmaceuticals provides Clozaril only Caremark Inc., a national home health care firm. Patients are visited weekly by nurses and technologists from Caremark Inc. They take blood specimens and provide one week of medication. Test results are sent to doctors and entered in a national records system. Many patients will begin Clozaril treatment in hospitals. If they improve sufficiently, they can move to halfway houses or home.
