Merck's New Melancholy Baby

Early word on the latest antidepressant is creating a stir

For a long time, it looked like a blind alley. Pfizer, Eli Lilly, Warner-Lambert, and others had been trying for years to come up with painkillers that block the action of Substance P, a neurotransmitter that conveys pain messages. The hope was that by blocking the receptor on a cell's surface where Substance P attaches, they could block the message and stop the pain. But none of the compounds tested so far has delivered much relief.

It turns out the scientists may have been focusing on the wrong kind of pain. Merck & Co. is now in Phase II clinical trials of a new antidepressant that works by blocking Substance P and plans to publish data on its research in the journal Science by mid-September. Merck researchers have already said the compound is as effective as the popular class of antidepressants that includes Prozac, with fewer side effects.

GIDDY. Certainly, Merck's drug may fizzle. But it could also open up the first new approach for treating depression since Prozac arrived in the late 1980s. "If the data is as impressive as people say it is, then it's a remarkable breakthrough," says Dr. Charles B. Nemeroff, chairman of Emory University School of Medicine's department of psychiatry and behavioral sciences.

Rivals are not waiting for Merck to tell them how remarkable the new drug is. At least five companies are developing Substance P blockers for possible use against conditions such as chemotherapy-induced nausea and asthma. Meanwhile, Pfizer and Novartis are studying Substance P blockers for psychiatric disorders--where financial gain could be biggest (chart). Market researcher IMS Health Inc. estimates that antidepressants are a $5 billion market in the U.S. alone. Says Merrill Lynch analyst Steven C. Tighe: "If it truly is superior to existing antidepressants, then you could be looking at multibillion dollars in potential revenue."

Researchers at Merck are almost giddy over the possibilities. While the company declines to comment until the Science article is published, research chief Dr. Edward M. Scolnick told analysts last December that based on a six-week study involving 210 patients, the Substance P compound appears to be as effective as the widely used selective serotonin re-uptake inhibitors (SSRIs), which include Prozac. At a recent meeting in Glasgow, Merck researchers said the Substance P drug appears to have a lower incidence of some of the pesky side effects of SSRIs, such as sexual dysfunction.

Substance P has been frustrating researchers for decades. This snippet of protein was discovered in 1931 by scientists studying tissue from horse brains and intestines. It wasn't until 1971 that researchers were able to produce it in pure form. Another 20 years passed before Pfizer created an effective blocker. Why so long? Scientists found that would-be blocking compounds were broken down by enzymes in the body or couldn't get through the barrier from the blood to the brain.

Despite Pfizer's breakthrough, Substance P blockers have been ineffective in preventing pain. Allan I. Basbaum, chairman of the department of anatomy at the University of California at San Francisco, says Substance P appears to relay only certain intense pain messages; it may have little involvement in more moderate pain.

"A SHOCK." Until Merck's announcement last year, there had been little work done on Substance P and depression. While Substance P is found in parts of the brain believed to be involved in anxiety and mood regulation, there were few signs that it had a major role in causing depression. For now, Merck won't say why it started looking for a link. "I think [Merck's work] came as a shock to everyone in the field," says James E. Krause, a vice-president at competitor Neurogen Corp.

Merck's compound still faces plenty of hurdles. Unexpected side effects can often develop as proposed drugs are tested on larger numbers of patients. But the drug industry is buzzing with the hope that this latest twist in the Substance P saga won't turn out to be another dead end.

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