Clozaril: Schizophrenia Drug

by Food and Drug Administration (FDA)

Thirty-year-old "Claudia" was a problem — to her parents, to the state mental institution where she had spent her last six years, and to her doctor. Prone to hallucinating and holding imaginary conversations, her thoughts tumbled around her mind in wild disarray. Disheveled, agitated and violent, on her infrequent visits home Claudia (not her real name) often tried to hit her parents.

The young woman suffered from schizophrenia, a devastating mental disorder that strikes people most often in their late teens. Doctors had tried most of the major antipsychotic drugs to give her life some normalcy, but nothing worked.

As a last resort, a psychiatrist decided to treat Claudia with a new antipsychotic drug under study at several institutions across the country. The drug seemed to work on patients who failed to improve on other drugs.

After a few weeks the change became obvious. Her hallucinations decreased, she stopped babbling, her violent outbreaks ceased, and she started combing her hair and putting on make-up. In a few months, she left the mental institution to live in a supervised apartment. Today, two years after she started taking this drug, Claudia dresses meticulously, holds a volunteer job at a local library, and has a boyfriend. No one, her doctor says, would ever know she had once led a life of such total disarray in a mental institution.

This is a story about a drug called Clozaril (clozapine), which, on one hand, has the ability to release thousands of the sickest schizophrenic patients like Claudia from mental institutions, but on the other hand is associated with a potentially fatal adverse event.

Serious Side Effects

Clozaril has at least two serious side effects: 1 out of 20 patients suffers from convulsive seizures, and 1 or 2 out of 100 suffer from agranulocytosis. Agranulocytosis is a serious blood disorder in which the number of white blood cells (the body's disease-fighting cells) are reduced, leaving the patient vulnerable to infection — so that even a common cold could be fatal.

A simple blood test can detect this dangerous decrease in white blood cell levels, and early detection of this disorder, along with the discontinuation of Clozaril, can decrease the risk of death. In clinical trials in the United States, 17 patients who developed agranulocytosis while taking Clozaril recovered from the blood disease when they stopped taking the drug. Although agranulocytosis is a side effect of other antipsychotic drugs, it is far more common with Clozaril.

The rate of seizures can also be controlled. Lowering the dose of Clozaril or adding an anticonvulsant drug usually controls the seizures.

Despite these serious side effects, Clozaril has proved to be free of certain other side effects commonly found with typical antipsychotic drugs, such as chlorpromazine or haloperidol. For example, there have been no documented cases of tardive dyskinesia, a serious side effect that consists of involuntary movements of the tongue and mouth such as chewing, sucking, or smacking the lips. This condition affects about 1 out of 6 patients on other antipsychotic drugs. Nor does Clozaril cause other side effects found with other antipsychotic drugs, such as rigidity, mask-like facial expression, or slowed movements. A significant number of schizophrenic patients may stop taking their drugs because of these side effects.

Researchers estimate that perhaps 200,000 chronic schizophrenia patients don't improve with traditional antipsychotic drugs. They hope that many may improve with Clozaril.

"We have patients from state hospitals who are now working in the competitive commercial area having obtained jobs on their own," said Dr. Herbert Meltzer, a research psychiatrist at Case Western Reserve University Medical School who has studied Clozaril for some 15 years. "Another patient who is taking the drug is maintaining a straight A average as a physics major after five years of hospitalization."

Bumpy Trip

Clozaril's journey to approval was not without mishap. The drug was first synthesized in 1960 and was marketed in several European countries by the late 1960s. But in the 1970s, as clinical trials were being started in this country, post-market reports from Finland that a number of schizophrenic patients on Clozaril had died from agranulocytosis reached American researchers. As a result, research in this country came almost completely to a halt.

Interest in the drug, however, was kept alive by occasional reports of remarkable results achieved in some desperately ill patients being treated in special situations. (For compassionate reasons, FDA gave permission to a few research physicians to continue prescribing Clozaril to schizophrenic patients who did not get well on other antipsychotic drugs.)

Other factors helped sustain interest in Clozaril. Families of schizophrenic patients pressured clinicians to make the drug more readily available to treatment-resistant patients, or those patients with tardive dyskinesia.

By the 1980s, researchers had crude estimates on the rate of agranulocytosis among patients who took Clozaril — 1 or 2 out of every 100 patients developed this disorder — a higher rate than for other drugs used to treat schizophrenia. Research by Sandoz also suggested that Clozaril was effective in typical schizophrenic patients, but the company didn't have any valid data supporting Clozaril's effectiveness in treatment-resistant patients.

Sandoz applied to FDA in 1983 for approval to market Clozaril for treatment-resistant schizophrenia, but FDA turned down Sandoz's request: The grim specter of agranulocytosis made the drug too dangerous in the agency's eyes to market in the absence of strong proof of effectiveness in treatment-resistant patients. Nonetheless, an FDA advisory committee (an independent body of outside experts) encouraged Sandoz to prove Clozaril's superior effectiveness in treating schizophrenic patients who had failed to get better on other antipsychotic drugs.

FDA and Sandoz designed a major research study testing this hypothesis. Sandoz established the multi-site study with 265 treatment-resistant schizophrenic patients in 1985. The results were impressive. After six weeks on Clozaril, 25 percent of the treatment-resistant schizophrenic patients greatly improved, compared to only 5 percent of those assigned to chlorpromazine (an approved antipsychotic drug). Further results from an uncontrolled follow-up study show that after six months, up to 50-60 percent of the schizophrenics taking Clozaril improved.

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