THE MOOD MOLECULE

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But last week it became startlingly clear that monkeying with the chemistry of the human mind can trigger problems much more serious than a dull sex life. Just 1 1/2 years after it approved Redux for treatment of obesity, the FDA issued a warning advising patients to stop taking it and its close chemical cousin fenfluramine immediately. At the same time, the drugs' manufacturers and distributors, Wyeth-Ayerst Laboratories, told physicians to stop prescribing them and took the dramatic step of pulling both medications from the market. The reason for such haste: new evidence had revealed that as many as 30% of Redux and fen/phen users could develop abnormalities in the shape of their heart valves--changes that could eventually lead to serious cardiac weakness and perhaps even death.

These were not the first lethal side effects associated with Redux and fenfluramine. When Redux was approved, both Wyeth-Ayerst and the FDA already knew that the medication could lead to a potentially fatal lung condition known as primary pulmonary hypertension. But this problem seemed to affect only a small minority of users, and morbid obesity carries significant risks of its own: heart disease, diabetes, high blood pressure and stroke. On balance, the benefits seemed to outweigh the risks.

Why did the equation suddenly seesaw the other way? Partly because clinical trials reveal only the most obvious side effects; the heart-valve changes discovered over the summer do not initially cause visible symptoms in most patients. Also, many doctors went overboard, giving Redux and fen/phen to patients who were merely overweight, not obese, a violation of the FDA and drug-company prescription criteria that couldn't help skewing the risk-benefit ratio.

The abrupt change also reflects a deeper truth about serotonin: despite years of study and impressive breakthroughs, researchers are only beginning to understand the chemical's complex role in the functioning of the body and brain--and how doctors can make adjustments when serotonin levels go out of balance. So far, the tools used to manipulate serotonin in the human brain are more like pharmacological machetes than they are like scalpels--crudely effective but capable of doing plenty of collateral damage. Says Barry Jacobs, a neuroscientist at Princeton University: "We just don't know enough about how the brain works."

Still, there is plenty that researchers do understand. At the most basic level, they have been aware for more than two decades that without serotonin, dopamine, norepinephrine and the hundreds of other known neurotransmitters, the brain could not process information or send out instructions to run the rest of the body. That is because neurons, or nerve cells, do not actually touch one another; they are separated by gaps known as synapses. When the electrical impulses that carry information through the nervous system reach the end of a neuron, they have nowhere to go. The circuit is broken.