THE MOOD MOLECULE

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Their efforts failed, but Richard Wurtman, an M.I.T. neurologist and Lilly consultant, took a different approach. Instead of using Prozac as a starting point, he turned to fenfluramine, a European weight-loss drug. Because fenfluramine acts on both serotonin and dopamine, it has the unfortunate side effect of putting its users to sleep. That is why doctors came up with fen/phen; the "phen" (phentermine) is an amphetamine-like drug that wakes the patient up again and boosts the metabolism to burn calories faster. Wurtman separated fenfluramine into its two component chemicals, levofenfluramine and dexfenfluramine. The latter has revealed itself to be a powerful weight-loss medication. He patented the drug for M.I.T., founded a company called Interneuron Pharmaceuticals to manufacture it under license to Wyeth-Ayerst and began moving the drug, dubbed Redux, through the FDA-approval process.

From the start, it was clear that Redux has serious potential side effects. One is primary pulmonary hypertension, a rare form of high blood pressure that strikes the blood vessels of the lungs. Another, considered even more serious by some of Redux's critics, was the possibility of brain damage. When fed to monkeys, dexfenfluramine can destroy neurons. Says John Harvey of the Allegheny University of Health Sciences in Philadelphia, who edits the Journal of Pharmacology and Experimental Therapeutics: "Any of us who were pharmacologists knew this was a dirty drug. None of us was surprised."

Some critics claim that Interneuron steamrollered Redux through the FDA and that the agency acted irresponsibly in approving it, charges that the company and the agency vigorously deny. What nobody on either side considered, though, was the possibility that either Redux or its parent compound fenfluramine might damage heart valves.

But why would they? After all, other serotonin enhancers, such as Prozac, have never caused heart problems. There is a crucial difference, however, between Prozac and Redux-fenfluramine. The former, like the other SSRIS, keeps serotonin in circulation longer than it would otherwise be, thus helping the brain get the most out of its normal output. The latter do the same, but they also force nerve cells to boost the levels of serotonin that go into circulation. It is this unnatural bath of excess serotonin, some scientists theorize, that causes heart-valve defects and also triggers brain damage--in monkeys, at the very least--by overdosing neurons and burning them out.

But if Redux and fenfluramine are too powerful for the body to handle--a proposition not fully accepted by some doctors despite the FDA and manufacturers' action--research into serotonin-boosting drugs is hardly slowing down. If anything, the discovery of a new set of side effects will spur researchers to hone their pharmacological handiwork even more, to create medicines that will not just fine-tune the way serotonin is used in the brain but might target specific serotonin receptors as well or act on only specific parts of the brain and nervous system.