JANUARY 22, 2001 VOL. 157 NO. 3

The Hunt for Cures

Mental Illness
Probing the chemistry of the brain
By FREDERIC GOLDEN

ALSO
The Future of Drugs
Now that our DNA has been decoded, the search for better, faster and more effective medications begins in earnest
• Inside the Brave New Pharmacy: At a leading genomics firm, the star of the show is a robot
• DNA Microarrays: The workhorse of genomic medicine
• Bioinformatics: How to design a molecule
• The Search for Cures: The fight against aids, cancer, mental illness, obesity, Alzheimer's

Asked once what makes people happy, Sigmund Freud replied, "Work and love." A strange answer from the man who invented the psychoanalyst's couch? Perhaps, but in his day, doctors could offer little more for patients suffering from anxiety or depression. And when faced with intractable mental illnesses like schizophrenia, they had to resort to brute force: inducing seizures and comas with chemicals and electric shocks, infecting patients with malaria to provoke brain-clearing fever, or slicing away parts of the brain's prefrontal cortex. In general, desperation guided treatment of the deranged.

The accidental discovery in the 1950s of the first synthetic tranquilizer, chlorpromazine (Thorazine), ushered in a gentler age of psychopharmacology. As other feel-good pills followed—Tofranil (imipramine) for depression, Miltown and Equanil (meprobamate) for psychosis, Valium (diazepam) for severe anxiety and lithium for manias—no mental illness seemed beyond their reach. Governments began emptying mental wards on the assumption that madness could be medicated—ignoring the fact that thousands of former inmates ended up living, and suffering, in the streets.

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By the time Prozac (fluoxetine) swept onto the stage in 1988, the new drugs had wrought a revolution in psychiatry. Long-drawn-out talking cures were shortened or replaced by prescription pills, and some doctors found their offices filled with grateful patients. "All of a sudden, we were being told, 'Gee, doc, you're great,'" recalls Dr. Samuel Barondes, a psychiatrist and medical historian at the University of California, San Francisco. No one really understood how the wonder pills worked. Nor were they always free of distressing side effects—such as the "Thorazine shuffle," the stumbling, zombie-like gait that often accompanies this treatment for schizophrenia.

Still, the message out of the bottle was clear: forget the couch; there is no psychiatric ill that cannot be chemically controlled. Even hyperactive youngsters were caught up in the pharmacological whirlwind, given daily doses of Ritalin to tame their excess energies. Critics such as Dr. Thomas Szacz worried loudly about an overly medicated, drug-dependent society. But with hundreds of millions of people suffering from mental illnesses of varying degrees of severity, doctors in the clinical trenches felt they had no choice but to employ the best weapons at their disposal. Says Dr. Sophia Vinogradov, Barondes' UCSF colleague and a specialist in schizophrenia: "We now have a much more vigorous armamentarium for our patients."

Her armamentarium will soon grow. No fewer than 103 new psychoactive drugs are currently undergoing testing, including clinical trials, according to the Pharmaceutical Research and Manufacturers of America. These include 26 drugs for depression alone. Other drugs in the pipeline target schizophrenia, anxiety phobias and various forms of senile dementia, most notably Alzheimer's. All told, drug companies are betting $6 billion a year on R. and D. in hopes of creating new blockbuster drugs like Eli Lilly's Prozac, whose patent expires in 2003.

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 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 U.S. 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 kids on Ritalin.

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.

Such discoveries elate doctors like Barondes. "When you learn more about the biochemical pathways and mechanisms [controlled by these genes]," he says, "you'll be able to create drugs that can augment or block them." Furthermore, if researchers can spot individual genetic flaws, they may eventually be able to tailor regimens for individual patients while also factoring in differences based on age, sex and race.

For all these advances, however, most experts agree that future treatments won't be reduced simply to tinkering with brain chemistry. Doctors will still have to take into account personal relationships, job pressures and their patients' emotional well-being. As Dr. Keith Kramlinger of the Mayo Clinic in Rochester, U.S., notes, "Most of the time, mental illness is probably a complex interaction of nature and nurture." In other words, you'll need both pills and palaver. And even that old Freudian couch may come in handy.

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