Posted by Bob on October 7, 2003, at 3:03:25
Epilepsy drug may reduce obesity
By Rob Stein, The Washington Post
Soon after a new epilepsy drug hit the market in 1996, doctors noticed something unexpected: Patients using the anti-seizure medication suddenly began losing weight -- rapidly.THAT CHANCE observation has led to tantalizing new insights into the underlying reasons why some people overeat and have such a hard time shedding pounds, and the provocative question of whether food can be an "addiction."
When obesity specialists heard about the drug's side effect, some decided to try it for their patients. It seemed to work for many who had failed to lose weight by dieting, exercise or taking other drugs. And recent studies designed specifically to test the epilepsy drug as a weight-loss aid have found that it helps people, especially those prone to binge eating, to lose -- and keep off -- significant amounts of weight.Perhaps more importantly, the drug, called Topamax, has led scientists to explore what could be a new approach for controlling appetite and other cravings. The drug, along with another anti-seizure medication, an antidepressant and an experimental compound that blocks the "munchies" produced by marijuana, appears to help some people control obsessive behaviors, including overeating, smoking and alcohol abuse.
PLEASURE CENTERS
Although the drugs work in different ways, they affect the parts of the brain involved in pleasure sensations. All of them may work by tamping down uncontrolled electrical firings of nerve cells that lead to compulsive eating, drinking or smoking in the same way that blocking uncontrolled electrical firing in the brain prevents seizures."It could be that the drive to eat in the higher levels of the brain is an electrical event that keeps recurring," said Lewis J. Aronne, director of the Comprehensive Weight Loss Center at the Weill Medical College of Cornell University in New York. "You think about food and go to the refrigerator. You want it to go away, but it comes back. That persistent thinking about eating is, like alcoholism, a neurological event that won't go away -- like a seizure. Could it be that Topamax quells that and allows you to turn it off? That's one way it could work."
Addiction and obesity experts stress that both problems are extremely complex and in all likelihood have multiple environmental and biological causes. But many experts agree that they appear to have certain intriguing similarities."What characterizes addiction is the compulsion: A person may consciously not want to take it anymore, but the drive is so intense the person takes it anyway," said Nora Volkow, director of the National Institute on Drug Abuse. "That's what we see with cocaine and heroin. What's interesting is that in pathological overeating, you see the same syndrome -- a compulsion to eat an enormous amount of food."
The apparent effectiveness of these drugs to treat compulsive behavior for weight loss supports an emerging theory that becoming overweight or obese is, in many cases, a two-stage process: People start to gain weight because they live in an environment where high-calorie, high-fat food is plentiful and exercise is rare. But once they have put on an extra 20 or 30 pounds, their bodies and their brains get caught in a vicious cycle in which more weight gain becomes increasingly easy and weight loss is increasingly difficult.
'TOUGHER THAN IT LOOKS'
"People still think that weight is just a matter of behavior -- if you would only push yourself away from the table it would be okay," said Aronne, vice president of the North American Association for the Study of Obesity. "But there are messages coming from your body once you gain weight that try to keep the status quo. So when you cut back on your food intake, your body is trying to stop you. It's tougher than it looks."When his weight neared 300 pounds, Richard Davis knew he had to do something. But nothing worked: not the diets, not the exercise, not the drugs. His doctor finally referred him to Aronne, who suggested he try Topamax, known generically as topiramate.
"I started losing weight almost immediately," said Davis, 58, of Brooklyn, N.Y. He dropped 70 pounds in about eight months on the new drug and has kept the weight off for more than a year. "I used to be a binge eater who would eat enormous amounts of food even when I wasn't hungry. Now I just eat regular amounts when I'm hungry. To me, it's a miracle."
Aronne said other obesity experts caution that the search for weight loss drugs has long been marked by false hopes and shattering disappointments, and more testing is needed to fully evaluate the drug's usefulness.
Still, Aronne says, "This is the kind of drug that could be a breakthrough. I don't want to make it sound like a miracle cure, but it could turn out to be very helpful."
The new insights come as public health experts have become increasingly alarmed by the rising number of Americans who are overweight or obese. About 65 percent of U.S. adults are overweight, and about a third are obese.
The obesity epidemic has triggered a flurry of research, yielding fundamental new understanding of how the body regulates weight, hunger and appetite. That, in turn, has led to at least a half-dozen experimental compounds that show promise as long-sought safe and effective appetite suppressants.
The two epilepsy drugs and the experimental compound based on marijuana's effects, in particular, have progressed to advanced testing, and they are providing intriguing clues.
"I'm a psychiatrist, and I deal a lot with people who are obese and people who have mood and eating disorders," said Susan L. McElroy, a professor of psychiatry at the University of Cincinnati who has studied both epilepsy drugs. "I'm certainly not saying that everyone who is obese has a mental illness. But there's clearly a link between obesity, eating disregulation and mood disregulation that needs to be more fully explored."
Topamax, made by Ortho-McNeil Pharmaceutical Inc., has helped obese people lose as much as 10 percent of their body weight, according to a study published in the June 6 issue of the journal Obesity Research. Unlike other drugs, it appears to continue to work for extended periods, enabling people to keep the weight off.
The drug causes side effects in some people, including a tingling in the hands and feet, memory problems and difficulty thinking. As a result, it has earned the nickname "dopamax." But Topamax has been used for so long on so many epilepsy patients that experts consider it generally safe. Lower doses and different formulations may minimize or eliminate the side effects.
INDEFINITE USE?
Researchers say it is not clear whether patients would have to use the drug indefinitely. For epilepsy, it sells for about $1.70 for a 25-mg pill, but is it not known what it would cost if marketed for obesity.The second epilepsy drug, zonisamide, which Elan Biopharmaceuticals sells as Zonegran, produced similar weight loss in obese adults in a study published April 9 in the Journal of the American Medical Association. The only side effect appears to be relatively minor fatigue. There is also some evidence it may help people quit smoking and drinking.
Along with apparently reducing uncontrolled electrical firings in the brain, both drugs seem to affect chemical signals involved in pleasure -- serotonin and dopamine.
"Many of these neurotransmitters that regulate and modulate appetite signals and satiety signals are also involved in modulating many different things, such as depression and mood," said Kishore M. Gadde, a professor of psychiatry at the Duke University Medical Center in Durham, N.C., who led the Zonegran weight loss study.
The experimental compound, called rimonabant, is very different. It has no anti-seizure effects, but it blocks one of the signals that marijuana triggers in a part of the brain involved in increasing appetite -- producing intense hunger. Studies have shown that rimonabant significantly reduces appetite, and it is undergoing a final round of testing involving several thousand people in the United States and Europe. Like Topamax, it also shows promise in helping people quit smoking and drinking. The only side effects have been minor digestive problems.
Gadde noted that one of the new antidepressants, Wellbutrin, is also sold as Zyban to help people quit smoking, and it, too, appears to help some people lose weight.
Researchers are studying all these drugs in the hope of confirming their effectiveness and learning more about how the brain regulates food intake. Neither Topamax nor Zonegran has formally been approved as a weight-loss aid, but doctors are free to prescribe them to overweight patients frustrated by the lack of effective alternatives.
Once he started taking Topamax, Davis said, he suddenly found he could control the urge to eat.
"Before, I would sit down and eat a quart of ice cream and a pizza. I was constantly eating throughout the day. I just couldn't stop thinking about it. I was obsessed with food," said Davis, a retired teacher. "Now, I look at it entirely differently. There's no question that I still enjoy food and going out for a good meal. But now I'll look for the least fattening food when I go out to a restaurant. And I can stop eating whenever I want."
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