Fighting Schizophrenia

Berenson, Alex. "Daring to Think Differently About Schizophrenia"

The trial results were a major breakthrough in neuroscience, says Dr. Thomas R. Insel, director of the National Institute of Mental Health. For 50 years, all medicines for the disease had worked the same way — until Dr. Schoepp and other scientists took a different path.

"This drug really looks like it's quite a different animal," Dr. Insel says. "This is actually pretty innovative."

Dr. Schoepp and other scientists had focused their attention on the way that glutamate, a powerful neurotransmitter, tied together the brain's most complex circuits. Every other schizophrenia drug now on the market aims at a different neurotransmitter, dopamine ....

.... Glutamate is a pivotal transmitter in the brain, the crucial link in circuits involved in memory, learning and perception. Too much glutamate leads to seizures and the death of brain cells. Excessive glutamate release is also one of the main reasons that people have brain damage after strokes. Too little glutamate can cause psychosis, coma and death.

"The main thoroughfare of communication in the brain is glutamate," says Dr. John Krystal, a psychiatry professor at Yale and a research scientist with the VA Connecticut Health Care System ....

.... Schizophrenia affects about 2.5 million Americans, about 1 percent of the adult population, and it usually develops in the late teens or early to mid-20s. It is believed to result from a mix of causes, including genetic and environmental triggers that cause the brain to develop abnormally.

The first schizophrenia medicines were developed accidentally about a half-century ago, when Henri Laborit, a French military surgeon, noticed that an antinausea drug called chlorpromazine helped to control hallucinations in psychotic patients. Chlorpromazine, sold under the brand name Thorazine, blocks the brain's dopamine receptors. That led the way in the 1960s for drug companies to introduce other medicines that worked the same way.

The medicines, called antipsychotics, gave many patients relief from the worst of their hallucinations and delusions. But they also can cause shaking, stiffness and facial tics, and did not help the cognitive problems or the so-called negative symptoms like social withdrawal associated with schizophrenia.

In the 1980s, drug companies looked for new ways to treat the disease with fewer side effects. By the mid-1990s, they had introduced several new schizophrenia medicines, including Zyprexa, from Lilly, and Risperdal, from Johnson & Johnson. At the time, the new medicines were hailed as a major advance — and the companies marketed them that way to doctors and patients.

In fact, the new medicines, called second-generation antipsychotics, had much in common with the older drugs. Both worked mainly by blocking dopamine and had little effect on negative or cognitive symptoms. The newer medicines caused fewer movement disorders, but had side effects of their own, including huge weight gain for many patients. Many doctors now complain that the companies oversold the second-generation compounds and that new treatments are badly needed.

"People say that there are drugs to treat schizophrenia," says Dr. Carol A. Tamminga, professor of psychiatry at the University of Texas Southwestern, in Dallas. "In fact, the treatment for schizophrenia is at best partial and inadequate. You have a cadre of cognitively impaired people who can't fit in."