"Son of Clozapine" Sought by Researchers

The antipsychotic revolution started in the late 1980s, when clozapine, branded Clozaril by Sandoz Ltd., was brought back from the dead. Clozaril had been approved in the U.S. in 1972, but was pulled because of serious safety issues.

Today, Clozaril, reapproved in 1990 after a series of studies in patients who failed other treatments, offers the gold standard of efficacy. In tests, Clozaril has shown to be clearly superior to the previous gold standard, Haldol. Clozaril works well against both the positive and negative symptoms of schizophrenia. Hallucinations, delusions and impaired cognition fall under the positive rubric because they stem from an excess of stimuli. Symptoms that come about from deficit states, such as social withdrawal, a sense of isolation and lack of affect and motivation are termed negative. Many schizophrenics suffer from depression, which some experts categorize as a third type of symptom. ''Clozapine was an enormous breakthrough, just enormous,'' said Dr. Donald Goff, director of psychiatric disorders at Massachusetts General Hospital. ''The quest has been for the son of clozapine.''

So far, despite the promise of the new compounds, it seems none has been born. Though it is chemically more similar to Clozaril than any of the other new drugs, Zyprexa is ''not dramatically different (from Risperdal) and not like clozapine vs. Haldol,'' said the University of Maryland's Conley.

Instead, the new drugs, led by Risperdal, which was approved in 1992, seem to be a breakthrough similar to the one that the antidepressant Prozac and its ilk offer: similar efficacy to older drugs, with sharply curtailed side effects. Experts caution that none of these drugs is a cure and that more research into the causes of the disease is necessary.

With more research, it may turn out that schizophrenia is actually many different syndromes, all with different treatment regimens, experts predict. Because the new drugs have several different mechanisms of actions, that may mean doctors develop niches for each drug, depending on which syndrome a patient has, rather than treat all patients with their drug of choice. Perhaps 2.5% to 3% of the population has some form of psychosis, with about 1% of those suffering from traditional schizophrenia. Only about half of all schizophrenics receive treatment, experts estimate, mainly because of side effects, including tremors and muscular rigidity, restlessness, dry mouth, blurred vision, drowsiness, and elevation of sex hormones. In rare cases, the motor side effects can be irreversible.

Additionally, some schizophrenics don't regard themselves as sick or drop out of society, and so they don't seek treatment. Some psychiatrists wonder if these patients will comply even with the newer, more benign medications.

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