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New Drug Offers Hope for Some Schizophrenics

The Hartford Courant

Frederick J. Benham Sr. had his first bout with mental illness in 1948, when he was on the cusp of adulthood and away from home in the Army. Something just snapped, and he found himself in a military hospital, undergoing hypnosis.

“At that time there was no such thing as tranquilizers,” the 58-year-old Bridgeport, Conn., man said of the array of anti-psychotic medications that later would help usher in a new era of treatment for schizophrenia.

Benham has been on and off neuroleptics, as they are called, since 1960. Like others who have taken them, he is ambivalent about the drugs, which becalm hallucinations and clarify disordered thinking.

“They gave me relief for symptoms I had,” he said. “I would get over-excited . . . and they made me more controllable.” But, “as for making me feel good, it was not as if I was on Cloud 9.”

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In recent years neuroscientists have searched for an improvement on the old anti-schizophrenic medicines. One could be on the market within months, its manufacturer says.

“Even though we welcomed” the older generation of drugs, “they’ve got limitations,” said Dr. William M. Glazer, an associate professor of psychiatry at Yale University School of Medicine in New Haven.

The problems of classical anti-schizophrenic medications such as Thorazine, Mellaril and Haldol include their awful side effects: uncontrollable--and often irreversible--tics and twitches, motor disturbances and persistent states of restlessness.

Another limitation is that they are not effective on as many patients as doctors would like, said Glazer, one of many scientists around the United States experimenting with new drugs that offer “a better profile.”

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One of those drugs, clozapine, is likely to be on the market for some schizophrenics by the end of the year, said Dr. Gilbert Honigfeld, who has led clozapine research for Sandoz Pharmaceuticals since 1973.

Clozapine is one of a new class of atypical neuroleptics that works differently in the brain and doesn’t seem to cause the usual side effects.

Also, studies show that clozapine more effectively reaches schizophrenics who for unknown reasons do not respond well to the older drugs.

In addition to its anti-delusional activity, clozapine seems able to help break through the wall of isolation and withdrawal that often surrounds patients in a way that current medicines do not, said Dr. John W. Goethe, head of clinical research at the Institute of Living in Hartford.

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Although it avoids the worst side effects of the existing anti-psychotic drugs, clozapine does have some side effects. It causes 2% of the patients taking it to suffer a severe drop in white blood cells, Honigfeld said. Those cells are key to the immune system’s ability to fight infection, and the condition can be life-threatening.

As a result, if the Food and Drug Administration approves it for other than experimental use, clozapine will be restricted to the quarter-million or so schizophrenics who do not respond to the current drugs, Honigfeld said.

One of the most debilitating and chronic, if least understood, diseases, schizophrenia exacts an enormous toll on the estimated 1 million Americans who have it, as well as on their loved ones.

Some schizophrenics’ “lack of insight,” or failure to acknowledge their illness and the need for treatment, is a common obstacle to many patients’ getting better and staying out of the hospital.

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But the effectiveness and side effects of the classical neuroleptics are issues that have plagued patients and doctors for years, Glazer said.

Only about 15% of schizophrenics on the regimen of existing drugs show a complete response to the medication, Glazer said, while three-quarters show a partial response. Ten percent show no response.

The side effect known as tardive dyskinesia strikes a third of all patients taking neuroleptics, said Glazer, who heads a Yale clinic that investigates the disorder.

Some patients are hit severely, exhibiting movement disturbances that an onlooker might mistakenly conclude result from the mental disorder itself. These include bizarre motions of the mouth and tongue, lip-smacking, chewing and tics of the fingers and toes, Glazer said. Painful side effects include rigid, immobilized features. The eyes can become fixed, the jaw thrust open.

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Other patients experience a chronic restlessness and hyperexcitability that can be “very, very debilitating,” he added. These side effects can have the paradoxical effect of stimulating the very delusions and hallucinations the drugs are meant to correct.

Today’s research aims at finding chemicals that minimize side effects, while more exquisitely fine-tuning the chemical reactions in the brain that have been linked to the onset of schizophrenia.

After two decades of study, neuroscience still has only dimly illuminated those reactions, even in the normal brain.

It took seven years after the discovery of Thorazine in 1952 for a Swedish scientist to determine that the drug worked by interfering with the passage within the brain of a chemical called dopamine.

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Dopamine is one of the neurotransmitters responsible for the way information from our senses, our memories and our conscious and unconscious thoughts is relayed back and forth. In the normal brain, these neurotransmitters work dynamically with each other, allowing us to perceive the world and act in it in ways that are varied and idiosyncratic, to be sure, but also, by consensus, normal.

In the schizophrenic brain, that delicate balance is upset by miniature deluges and droughts of dopamine, and, it is increasingly believed, other neurochemicals.

Scientists are “hot on the trail of the mechanism underlying schizophrenia,” Glazer said. Although “dopamine continues to be the leading candidate,” its relationship to other neurotransmitters is a subject of intense inquiry.

Clozapine research is focusing on the way the drug regulates the balance between dopamine and another neurotransmitter, serotonin, Glazer said.

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Research suggests that something about the drug’s effect on dopamine and serotonin enables it to work in schizophrenics who have been unresponsive to the older drugs, he said. Brain biochemistry is showing that schizophrenia is less “a unitary disease than a spectrum of diseases,” Goethe of the Institute of Living said.

The treatment of schizophrenia has come a long way since the day Fred Benham entered Walter Reed Hospital at age 17.

Before Thorazine, patients were strapped in “tranquilizer chairs,” spun around until they were dizzy, restrained much of the time and given high doses of insulin designed to plunge them into insulin shock, a procedure then thought to be therapeutic, Glazer said.

There is no question, he added, that the introduction of anti-psychotic drugs revolutionized the care of schizophrenia and paved the way for the movement that helps the mentally ill leave the hospital to start a new life back in the community.

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Nearly 40 years later, clozapine is “only tiding things over” until the next “designer drug” comes along, made safer and more effective by “bending atoms, adding a little carbon here, a hydrogen there,” Glazer said.

But, he said, he finds the prospects of a new generation of atypical neuroleptics exciting, capable of producing major changes in the delivery of mental health care.


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