THE MOOD MOLECULE

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In the 1960s, a second class of antidepressants emerged. By tinkering with the chemical structure of antihistamines, a Swiss psychiatrist, Ronald Kuhn, created a drug called imipramine, first of the so-called tricyclic antidepressants. At the time no one had any idea why these medicines worked. Researchers have since learned that they keep excess serotonin and other neurotransmitters from being reabsorbed into the nerve cells they originally came from: same extended neurotransmitter bath as the MAO inhibitors, different mechanism.

Both types of antidepressant had major side effects, though, including profound drowsiness and heart palpitations. The reason, scientists generally agreed, was that they affected brain chemistry too broadly. The research seemed to point to serotonin as the most important mood-enhancing chemical, though not the only one, and so neurochemists set about looking for a drug that would boost the influence of serotonin alone. In 1974, after a decade of work, Eli Lilly came up with Prozac, first of the so-called selective serotonin reuptake inhibitors, or SSRIS, and it was finally approved by the FDA in 1987.

But the serotonin trail led scientists down a number of other interesting paths as well. One involved LSD: clinicians discovered that people on MAO inhibitors were much less sensitive to the drug than normal. The consensus is that LSD mimics serotonin in the brain and latches onto the same neuronal receptors. With MAO inhibitors keeping more serotonin in circulation, the acid cannot elbow its way in.

Another line of investigation revealed that serotonin may play a role in sleep. Destroy the raphe nuclei in cats, and they develop permanent and total insomnia. Give the wakeful cats a shot of serotonin, and they immediately go to sleep. In humans the amino acid L-tryptophan, which is converted to serotonin in the brain, is sometimes used as a sleeping pill. (A bad batch of L-tryptophan killed several people in the late 1980s and effectively killed the craze.) In another experiment, researchers discovered that when they stimulated raphe cells to release extra serotonin not in the brain but in the spinal cord, test subjects experienced pain relief.

In yet another series of studies in the 1970s, scientists discovered links between serotonin and aggressive behavior. Monkeys with high levels of serotonin by-products in their blood, it turns out, tend to be feistier, and drugs that boost serotonin activity tend to calm them down. The serotonin-violence link appears to hold for humans as well. In 1979 psychiatrist Frederick Goodwin, now at George Washington University, discovered that Navy enlisted men with low levels of serotonin byproducts often had a history of aggression. Subsequent studies discovered similar evidence in Marines discharged for excessive violence, in people who became violent after drinking alcohol and in children who tortured animals.

Finally, the development of Prozac led to a number of surprises--the discovery that it was good for obsessive-compulsive disorder, for example, as well as for panic disorder and social phobias. Clinicians also noticed that Prozac patients tended to lose weight, an intriguing finding, considering how many Americans are obese. But the weight loss was transitory, so Lilly scientists went back into the lab to see if they could reformulate Prozac as an effective obesity drug.