Clozaril: Schizophrenia Drug : Part 2

by Food and Drug Administration (FDA)

(Page 2 of 3)

The schizophrenics who improved were the proverbial "hopeless" patients. The average length of their illness was 16 years; average number of hospitalizations, eight; and all had tried at least three other antipsychotic drugs that had been no help at all. Many were so sick that using a knife and fork, getting dressed, or taking a bath were skills long lost.

One long-term study from Europe on Clozaril's effectiveness seems to support this optimistic picture, though, because it was an open and uncontrolled study, it cannot be considered conclusive. This Swedish study of 96 treatment-resistant schizophrenics showed that 43 percent improved significantly while 38 percent improved moderately. More importantly, over half of the patients were discharged from mental institutions and able to live on their own.

Additional U.S. study data verified the rate of agranulocytosis to be one or two patients out of l00. Due to the careful monitoring and early detection of patients with this disorder, none of the affected patients died in these studies. More experience will be needed with the drug before it can be known with greater certainty that the risk of death can be substantially reduced by early detection of agranulocytosis. The rate of seizures was also high. One out of 20 patients may experience a grand-mal (epileptic) seizure. (Lowering the dose of Clozaril or adding anticonvulsant drugs usually controls seizures.)

Despite these side effects, FDA approved the drug in September of 1989. Why?

"The severity and hopelessness of unremitting chronic schizophrenia was an important factor in the decision to approve Clozaril, despite the fact that it is associated with some serious risks," said Paul Leber, M.D., FDA's director of the division of neuropharmacological drug products.

"Remember, the lives of chronic schizophrenics are tormented and hopeless," adds Case Western's Meltzer.

A Risk Worth Taking

Leber admits that approval of Clozaril is a gamble but says it's a risk worth taking. His opinion is shared by others.

"We think that the potential risk for death is worth the benefit Clozaril brings for people who have almost no life of their own," said Laurie Flynn, executive director of the National Alliance for the Mentally Ill, an organization made up of patients and the relatives of the severely mentally ill.

Consider the following: As many as 30 percent of schizophrenics attempt suicide, and 1 out of 10 succeeds. In addition to suicide, other causes of death are higher among schizophrenics. A Swedish study of more than 1,000 schizophrenic patients showed that fatal injuries were eight times higher, deaths from infections four times higher, and deaths from other diseases two times higher than those of the general population. The reasons for this higher death rate are varied but include neglect, because untreated schizophrenics are unable to take care of themselves and to explain their symptoms to medical personnel.

Nonetheless, Leber says there is no objective way to weigh risk versus benefit. There are no right answers, and the seriousness of the disease is balanced by the seriousness of the side effects. And while clinical trials may answer some "objective" questions, when Clozaril moves from the research institution to the real clinical world, the situation becomes less controlled.

Monitoring Patients

In some people, agranulocytosis can strike very suddenly. The white blood count can drop dramatically, so that in days the white blood cells are completely eradicated, leaving the body defenseless against infection. Once agranulocytosis is detected and Clozaril is stopped, it may take two to three weeks for the white cell count to return to normal. During the period of recovery, patients are vulnerable to infection. It is preferable to detect agranulocytosis before infections develop, since the risk of dying from the complications of agranulocytosis appears to be greater if it is detected after the onset of infection.

To help ensure the early detection of agranulocytosis and, therefore, decrease the risk of fatal complications, Sandoz has established a distribution system requiring that patients have a sample of blood drawn for a white blood count before they are given the next week's supply of Clozaril.

If the blood test shows a significant decrease in white blood cells, the physician will be notified immediately and the patient must be taken off the medication. No other drug in the United States is prescribed with such stringent controls, according to FDA officials. Once agranulocytosis develops, the patient cannot go back on Clozaril because preliminary research shows that there's a good chance the reaction will recur.

Distribution of Clozaril started last February. For many schizophrenic patients, Clozaril may be the drug that allows them to lead a life outside a mental institution.

As NAMI's Flynn points out, "while Clozaril is not a cure for schizophrenia, it's a remarkable advance."

A Psychiatric Mystery

"Is there no way to cure this?
No new device to beat this from his brain?"

— William Shakespeare
Henry the Eighth, Act III, Scene 2

Many people think of it as the disease that best defines madness. Schizophrenia can inflict suffering for decades and in 10 percent of the cases lead its victims to suicide. Long considered one of psychiatry's most baffling mysteries, it continues to stump scientists.

Most psychiatrists feel that schizophrenia is a collection of brain diseases that they haven't been able to sort out yet. Schizophrenia sufferers can range in severity from the babbling patient who remains in an institution to a responsible job holder on medication. Although much has been learned in the past 40 years, doctors still don't know what causes schizophrenia, and there is no cure.

About the Author

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