The Hunt For Cures: Mental Illness

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It's a long shot. Only 1 out of 5,000 potential drugs makes it from the lab to the medicine chest (a process that can take as long as 15 years). But the odds are better now than when tranquilizers came largely from inspired guesswork. Computerized brain scans, DNA probes and other technological wizardry have given drugmakers powerful new tools for understanding at a molecular level the brain's inner workings--and how chemicals affect them.

Consider schizophrenia, which strikes 1% to 2% of the world's population, including 3 million Americans, usually in their late teens or early 20s. Over the years, its harrowing symptoms--hallucinations, persistent voices, paranoia and frozen emotions--have been blamed on everything from witchcraft to the evil eye. Now scientists realize that schizophrenia is a complex syndrome resulting from the failure of various neurotransmitters--the chemical messengers that skip from one nerve cell to the next--including dopamine, serotonin and 5-hydroxytryptamine. "Certainly it's not caused by bad parenting," says Vinogradov. Knowing which neurotransmitters are implicated in the disease gives drugmakers precise targets around which to design better anti-schizophrenia compounds.

Prozac is another drug that targets a particular neurotransmitter, plugging up brain chemicals that absorb the mood elevator called serotonin. Competing ssris (selective serotonin reuptake inhibitors), as they're called, include Lilly's duloxetine and Solvay Pharmaceuticals' fluvoxamine. Both drugs affect the same biochemical pathways, only with greater precision and fewer side effects. But better ssris aren't the only new approach. Sanofi-Synthelabo is looking into the potential of a so-called mao (monoamine oxidase) inhibitor called befloxatone. Monoamine oxidase is another serotonin-disrupting enzyme, so anything that inhibits it should make more of the mood-elevating chemical available to the brain cells.

Many of the new drugs are old drugs turned to different uses. The National Institute on Drug Abuse has five compounds under review for use against cocaine dependence, all of them originally developed for treating Parkinson's disease--a good example of how different neurological disorders can have common biochemical threads. Researchers are also trying to fashion drugs that release their essential ingredients more slowly, over a period of weeks rather than hours or days, eliminating the need for daily pills or injections. That would make life easier for deinstitutionalized street people and embarrassed kids who must leave the classroom each day to get their Ritalin from the school nurse.

The biggest payoff may come from understanding the genetics of mental illness. Using gene-chip technology, a team at the University of Pittsburgh School of Medicine recently spotted the same mutation in the DNA of 10 schizophrenic patients. The flaw was in a gene on chromosome 1 called RGS4, which controls the duration of signals in a nerve cell. Intriguingly, the mutation showed up in the brain's visual, motor and cognitive centers. That could account for schizophrenics' hallucinations and attention problems, says team leader Pat Levitt.