A new approach combining an antidepressant, nicotine replacement and counseling is sharply     increasing the chance of success among people who are trying to quit. Typically, according to scientists at Centers for Disease Control and Prevention and other experts on smoking, fewer than 5 percent of smokers who seek to quit without outside help are successful. But when the new approach was tried with 4,000 smokers at centers across the country, 40 percent to 60 percent remained smoke-free a year after completing the program.

Dr. Linda Ferry, chief of preventive medicine at the Veterans Affairs Medical Center in Loma Linda, Calif., who first proposed the combination treatment, said it involved bupropion, a drug originally developed as atreatment for depression; varying dosages of nicotine replacement delivered through patches, gum nasal spray or inhalers, and counseling individually tailored to the patient.

 Dr. John Slade of the American Society of Addictive Medicine, an organization of doctors and others who treat alcoholism, drug abuse and nicotine addiction, called the new results "very exciting."  

Dr. C. Everett Koop, the former Surgeon General, said the results so far were "highly encouraging for 45 million Americans who smoke but now have a much better chance of quitting." Worldwide, health experts estimate, three million people, including more than 440,000 in the United States, die prematurely each year from strokes, cancer, heart disease and other illnesses brought on by smoking. Experts in tobacco dependence caution that the findings on the new approach must be regarded as preliminary. Nicotine addiction is notoriously tenacious, and smokers can relapse even after going 5 to 10 years without smoking.

 Dr. Richard Hurt, director of the Nicotine Dependence Center at the Mayo Clinic in Rochester, Minn., said much more needed to be learned about the addiction. Still, he said, the addition of bupropion to programs for ending the smoking habit represents the biggest development in the field since nicotine-replacement therapy was introduced in 1991.

 Bupropion, made by Glaxo Wellcome, was first marketed in 1989 as an antidepressant under the name Wellbutrin. A slow-release form of bupropion, approved by the Food and Drug Administration in 1997 for treatment of nicotine addiction, is marketed under the name Zyban.

 The new combination approach is being widely used in clinics around the country, including the center in Loma Linda; the University of Wisconsin in Madison; the Army base at Fort Knox, Ky., and the Mayo Clinic's Nicotine Dependence Center, as well as private clinics. The success rates of 40 percent to 60 percent that were achieved compare with 10 percent to 26 percent success rates among smokers who try to quit by using  nicotine replacement alone.

One small, aggressive treatment program at Loma Linda involved six women who were lifelong smokers who had tried many times to quit. All six stopped smoking and have not smoked for a year. (Their treatment involved 12 months of outpatient counseling sessions, lectures, films, exercise and a buddy system in which one person helps persuade the other not to smoke.)

Matthew P. Bars, a clinical psychologist who runs clinics at the Pavonia Medical Associates, a group practice in Hudson County, N.J., said the new approach even worked for an airline pilot who had smoked seven packs of cigarettes a day. The pilot was so addicted to nicotine, Bars said, that "he could not sleep more than two hours at a time, when the urge for more tobacco woke him up and he'd have to have a puff or two before he could sleep again." The pilot remained free of cigarettes for a year, and then, Bars said, he lost touch with him.

The combination treatment has evolved out of initially unexpected findings in the 1980s of a high correlation between nicotine addiction, depression and other mood disorders. At the same time, scientists were learning of the trickery by which nicotine is able to work itself into the cells of the brain, influencing the production of powerful chemicals that act on the brain, dopamine and norepinephrine. Among other things, dopamine contributes to feelings of joy and pleasure, and norepinephrine increases energy and concentration. But nicotine causes rapid surges and then rapid depletions of these chemicals, leaving the smoker yearning for another cigarette.

 Meanwhile, scientists discovered a class of drugs that slow the depletion of brain chemicals that affect mood. Bupropion worked specifically on dopamine and norepinephrine, bringing them back to their more natural and longer-lasting levels -- and without being addictive.

 In 1989, Dr. Ferry proposed putting these two findings together, and treating nicotine addiction with the bupropion. The maker of the drug, Burroughs Wellcome, which later merged with Glaxo, declined to take part on the ground that there was no clinical evidence that the approach would work.

So Dr. Ferry went ahead on her own, financing a small pilot study with $5,000 from Loma Linda University, where she teaches at the medical school, and from the Loma Linda center. She enlisted her mother, a retired nurse, and a group of medical students to help.  Dr. Ferry had been treating a group of veterans who were seriously ill with smoking-related disorders but were nevertheless still unable to stop smoking. She selected 44 of these men, put half on bupropion and half on a dummy pill: all 22 on the placebo failed to quit but 12 on the medication succeeded in stopping within three weeks, and after three years only one of them had resumed smoking.  With that, the manufacturer provided $175,000 for a larger pilot study of 190 people, which achieved success rates of 43 percent after 12 weeks and 28 percent one year after completion of the trial. Those rates were then regarded as high for a group of the hardest-core nicotine addicts.

Dr. David P.L. Sachs, director of the Palo Alto Center for Pulmonary Disease Prevention in California, and an expert on smoking-related lung disorders and the neurological effects of nicotine, was among those who reviewed the Loma Linda studies and recommended the larger trials.  "It was clear from Dr. Ferry's trials that bupropion worked," Sachs said.  "We know it blocks the re-uptake of dopamine and norepinephrine molecules and helps restore the more healthy chemical balances of the brain. But we still do not know precisely how."

The manufacturer then organized what eventually became the first of two large scale placebo-controlled, double-blind trials of 1,500 nondepressed people who smoked at least 15 cigarettes a day, comparing bupropion with a placebo, and then to both a placebo and nicotine patches, and to the combination of nicotine patches and bupropion used together. In both studies brief counseling was also given. The findings of first project were reported in The New England Journal of Medicine in 1997: of smokers treated at three centers across the country, 44 percent of those who took 300 milligrams of bupropion a day stopped smoking by the end of a six-week trial period, as against 19 percent in the group taking the placebo. After a year, 23 percent were still not smoking, as compared with 12 percent in the placebo group.

 The second study, which included results of smokers treated with the combination, found that 23 percent of participants on a placebo had quit by the end of six weeks, 36 percent of those on the patch, 49 percent on bupropion alone and 58 percent on the combination of patch, medication and counseling. It was on the basis of this trial that the drug agency approved the marketing of Zyban.

The results a year later, as reported in a follow-up study awaiting publication, are expected to be lower, but still significantly higher than for any treatments previously used.  Though Glaxo Wellcome and others credit Dr. Ferry with conceiving the new approach, she cites other researchers as contributing to it, including Dr.Neal L. Benowitz at the University of California at San Francisco, who studied nicotine's influence on smoking patterns; Dr. Torgny Svensson ofthe Karolinska Institute in Stockholm, who traced, in rat studies, the pathways nicotine takes to the command centers of the brain; Dr. Alex H. Glassman, a professor of psychiatry at Columbia University, who found strong correlations between depression and the likelihood of becoming addicted to smoking; and Dr. David E. Comings of the City of Hope Medical Center in Duarte, Calif., and Dr. Caryn Lerman of the Georgetown University Medical Center in Washington, who have found a genetic link to vulnerability to nicotine addiction. Comings and Lerman have identified genetic variations that appear to leave people vulnerable to the effects of nicotine, especially at an early age.

 Despite the good news so far about the new approach, Dr. Ferry says it illustrates a serious problem with a medical system that relies on private industry to support research. "The trouble is," she said, "drug companies naturally get involved initially only if they see a potential profit, but then once they get government approval for selling their drugs, they drop the subject, when there is still much to learn about its dosages and how and under what conditions it works best."