T H EP & SJ O U R N A L

Serotonin: Is There Anything It Can’t Do? By Elzy Kolb Serotonin has been linked to an exhausting list of conditions, including depression, autism, eating disorders, schizophrenia, obsessive/compulsive disorder, premenstrual syndrome, anxiety, panic disorder, seasonal affective disorder, extreme violence, hostility and aggression, suicide, migraine, manic depression, addiction, and more. After perusing a small mountain of articles on the topic, one is tempted to paraphrase Homer Simpson extolling the virtues of doughnuts, “Hmmm, serotonin, is there anything it can’t do?” In a “science topic of the moment” sweepstakes, serotonin would take home the big prizes. Check out the mainstream media, including daily newspapers, women’s magazines, health-related consumer web sites, radio and TV news programs, and you’re sure to come across abundant information on this neurotransmitter, and the drugs that regulate its activity — selective serotonin reuptake inhibitors (SSRIs). The focus of the mainstream media articles range from the sublime to the ridiculous, and it’s not always easy to pinpoint which is which. In Allure magazine (April 1997), a nutritionist refers to carbohydrates as “dietary Prozac,” saying carbohydrates stimulate production of serotonin, “a calming neurotransmitter in the brain that regulates nerve function.” In a Sept. 29, 1998, article headlined “Brain Boom?” the New York Daily News refers to the “still mysterious” serotonin’s link to depression, migraine, weight gain, insomnia, and chronic pain. During 1998, National Public Radio’s weekend self-described “fun” science program, “Sounds Like Science,” included a “Fun Factoid” about a research project at Gettysburg (Pa.) College. According to the report, scientists give Prozac and other antidepressants to clams, which “jump starts their reproductive behavior, a technique clam farmers may find useful.” The item now is posted on NPR’s web site. The Jan. 1-3, 1999, edition of USA Weekend magazine, distributed nationally in many Sunday newspapers, contained an article headlined “5 Good-mood Foods.” Three of the five categories—fats, chocolates, and foods high in vitamin D—were credited with boosting levels of serotonin, which was described as “a feel-good chemical in the brain.” Bright areas in the PET scan show that serotonin receptors are found throughout the brain. Too numerous to detail are reports about Fen/Phen. The serotonin-affecting weight-loss drug combination was widely prescribed before being pulled off the market in September 1997, after studies turned up evidence of heart valve abnormalities in users, mostly among women. The scientific and medical press have been just as busy exploring the topic. Serotonin is involved in regular day-to-day behaviors like eating, sleeping, energy levels, and moods, and it can be the culprit when something goes wrong. SSRIs, including antidepressants such as Prozac, Paxil, Zoloft, and Celexa, offer relief from some of these conditions but can exacerbate others, like migraine. They have been found to have fewer side effects and to be safer than older, tricyclic medications for a large segment of the population, including depressed patients who are pregnant, have heart disease, or are prone to falls. Also, they don’t interact negatively with many medications, including those often prescribed for HIV-positive patients. Researchers are linking serotonin and SSRIs to an ever-growing list of health and quality of life issues. The regular coverage in the mainstream media indicates that the public is avidly following the studies and hopes to benefit from the results. How can serotonin be responsible for such a variety of conditions? Dr. John J. Mann, professor of psychiatry and chief of the division of neuroscience, explains: “[Serotonin] is a compound that does a bunch of things, completely different, depending on where it is. In the brain, it’s very complicated, because there are 15 different types of serotonin receptors, and serotonin neurons project all over the brain, so they influence many, many different functions. Hence, it can be involved in a variety of different disorders.” The number of receptors has made the research more complicated. Dr. Mann’s colleague, Dr. Donald F. Klein, professor of psychiatry, says: “The drugs that affect serotonin reuptake have been effective for a whole wide range of illnesses that we didn’t have any reason to think were the same illness, or that they had much common pathophysiology. And with the 15 different serotonin receptors, there seems to be good evidence that there’s a lot of interaction among these receptors, so that sometimes if you turn on two receptors, you get less than if you turn on one.” Dr. Michael D. Gershon In addition to its presence in the brain, serotonin exists in the gut. Dr. Michael D. Gershon, chairman of anatomy and cell biology, has written a book on the topic. In “The Second Brain” (HarperCollins, 1998), Dr. Gershon reports on his serotonin research, how the neurotransmitter functions in the gut, and its effect on gastrointestinal conditions. To Dr. Gershon, it’s easy to understand the widespread interest in learning more about serotonin. “As a neurotransmitter, it affects many critical things in people’s lives. It affects their moods, so that if it’s abnormal, they get depressed. It affects how much they eat, it affects how much sex they have, among other things. It affects how the bowel works. It has to work right for the gut to function. So, for both the brain in the head and the brain in the gut, it’s critical.” The American public’s interest in reading about serotonin is just part of a larger picture, according to Dr. Mann. People are “fascinated by biomedical research, cancer, heart, blood pressure. Americans read a lot about vitamins, diets. People are much more sophisticated now, they’re much more into preventive medicine. Have a look at the rest of the world—look at the rate of smokers, of smoking, and the amount of cholesterol served in meals, and look at the United States. There’s a dramatic difference.” Dr. Klein says: “The public confuses depression and unhappiness, and there’s a lot of unhappiness around. So it’s reasonable that people would be interested in whatever might make them feel better.” Another reason the public and the press pay attention to serotonin is the sheer number of people affected by the disorders related to it. As Dr. Mann points out, “Obsessive/compulsive disorder, suicide, PMS: Everybody must know somebody who’s got that.” Dr. Gershon agrees. “Twenty percent of the American people suffer from irritable colon or dyspepsia, or other disorders—that’s a lot of folks. Nobody has a clue as to why that occurs. The gut isn’t working and drugs that affect serotonin show promise of helping them, which is interesting. That affects the interest in serotonin.” A similar number of people are affected by mental and nervous problems. “Depression and anxiety disorders, which are illnesses that respond to SSRIs, affect about a quarter of the population at some time or other in their lives,” says Dr. Jack M. Gorman, professor of psychiatry. “Think of the people who are on the verge of committing suicide. They get a pill, Prozac, and suddenly life turns around, it seems OK, and they’re living again. They’ve come out of the black depths of total despair and they’ve survived on this pill. Might they be interested in serotonin?” asks Dr. Gershon. Dr. Donald F. Klein The amount of attention the news media pay to serotonin research is not without pitfalls. Balance often is missing in mainstream press articles, says Dr. Klein, “The mainstream press is regularly superficial and sensational. The way the media handle SSRIs, they emphasize their downside rather than listing their remarkable benefits. Every time something new comes out and they report on it, they make a point of saying ‘But we don’t know what the long-term effects are going to be.’ If anything, the American public is undertreated by medication, rather than overtreated.” Dr. Gorman, too, has seen articles that lack balance. “These articles often go to extremes, either representing the drugs as miracle cures or as toxic and clinically useless.” Some news reports “are looking to show that antidepressants don’t work and that people should utilize psychotherapy to ‘get to the bottom of their problems.’” Referring to coverage of the Fen/Phen diet drug combination, he adds: “It’s the usual thing. First they hype up a new treatment as if it is a miracle, then they overdo the downside. I agree that fenfluramine should have been withdrawn, but the press is never very restrained or scientific in this kind of thing.” “Most of the articles are not that great—there’s a tendency to exaggerate the significance of findings and to seek a headline that’s catchy and exciting,” Dr. Mann says. “A lot of people ask me if there’s a test to predict who’s at risk for suicide. I say no, but we’re working on a lot of promising leads. Statements like that have emerged in the press as ‘New blood tests for detecting suicides.’ It doesn’t say we’re testing a test. Oversimplification and exaggerations are sometimes corrected by a careful reading of the details of the article,” but not everyone does that. Dr. John Mann Claims that it’s possible to regulate serotonin levels in the body through diet have not been proved scientifically. Asked if carbohydrates stimulate serotonin production, Dr. Mann says that’s “not really true. The levels of the amino acid L-tryptophan regulate serotonin synthesis. Other amino acids compete with tryptophan for entry into the brain. Carbohydrate intake may influence the transport of amino acids in general. Small increases in brain serotonin have been produced by taking huge amounts of tryptophan. Most over-the-counter preparations [of tryptophan] were withdrawn by the FDA due to toxic impurity.” Media coverage of serotonin has an upside. Dr. Mann says the news reports on SSRIs might spur people to get help. “Most Americans don’t get adequate treatment when they get depressed. Highlighting the fact that there may be new and better antidepressants is a good thing.” Dr. Gorman concurs. “I certainly think the publicity has alerted depressed people in the general populationthat there is hope for them, and also that they need not feel so stigmatized by Dr. Jack M. Gorman having a psychiatric illness.” Additional funding for research might be a positive side effect of the public’s increased awareness of serotonin research. “Publicity spurs funding for research,” says Dr. Gershon. “I don’t think that scientists are spurred into action by what they read in the mainstream press. But the people who donate money to fund them read the mainstream press. As the press reports the results of science, it’s good for science. Science provides results and people like to know they’re getting something for their money.” Dr. Mann points out that the government is a major source of funding, rather than individuals, but “if articles in the paper attract the attention of people interested in philanthropy—and they do sometimes (we’ve had a couple of approaches by donors as a result of something they’ve read in the press)—in that sense, it has done some good.” One thing remains certain: As long as serotonin research continues to turn up links to weight, sex, and a general sense of well-being, the public will remain interested and the media will continue to focus attention on it.

Serotonin: A Columbia Thread John Mann finds it ironic, perhaps even fateful. The first chief of the neuroscience division in the Department of Psychiatry was Maurice Rapport, who came to Columbia after working as a post-doc at the Cleveland Clinic for the research team that isolated serotonin in the blood, purified it, and named it 50 years ago. Dr. Mann is only the third neuroscience division chief, and he is among the top serotonin researchers in the country. (The second chief, Michael Stanley, had a short tenure before dying unexpectedly in 1993.) “We had a 50th birthday party for serotonin during a meeting at Princeton University. The party included a sort of ‘Who’s Who’ of the serotonin world. I think it is interesting that the Columbia division of neuroscience has always had a very heavy orientation toward serotonin of the brain, all the way through.”

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