Untangling Eating Disorders

When Carrie Arnold looks back on her years grappling with anorexia nervosa, she doesn’t think that her drive to eat little and to exercise a lot was triggered by social pressure to be thin.

Peer pressure is certainly a risk factor for some people with eating disorders, she says. “But I never read fashion magazines, and I couldn’t tell you who the big models are,” she says.

So when she was diagnosed with anorexia in 2001, Arnold had a tough time accepting the popular theory that young girls and boys acquired eating disorders simply because of the “thin is in” ideal. She also didn’t think the theory of bad parenting—something her therapists explored as a factor in her illness—quite fit.

It wasn’t until Arnold, a freelance science writer and author of the book “Decoding Anorexia: How Breakthroughs in Science Offer Hope for Eating Disorders,” learned about research exploring the genetics and neurochemistry of eating disorders that something clicked. The studies suggested that her illness also had a biological basis, not just a social or psychological one, and she believes this idea helped her truly begin to recover.

“For me, learning about the biology of my eating disorder was a huge turning point because I could stop blaming myself and my parents for making me ill,” she says. Knowing that “I just got a bad genetic hand of cards” meant that “I could work on moving forward and accept that I’m always going to be vulnerable to eating too little under stress.”

Today, most researchers in the field of eating disorders agree on a “biopsychosocial model” for describing this group of mental illnesses. The model points to causes within brain chemistry, as well as cultural pressures to diet and psychological traits such as perfectionism.

Yet researchers trying to pinpoint the nerve circuits, neurotransmitters, and receptors involved have run into a chicken-and-egg problem. Eating disorders throw the body out of whack in a number of ways, experts say. Anorexia nervosa, for instance, leads to muscle loss and irregular heart rhythms—changes that send distress signals to the brain and wreak havoc on molecular workings there. So it’s difficult for scientists to determine whether an abnormal level of a particular brain chemical may have triggered the onset of a disorder or whether it’s the other way around—that the disorder triggered the abnormal level.

To figure out what comes first, researchers have been looking at the aberrant genetics and brain chemistry of patients who have recovered from their conditions, rather than investigating only those who are ill. They’re also analyzing the behaviors of twins who have varying levels of suspect genes and studying lab animals that display out-of-control eating behaviors to get a better understanding of the molecular factors involved.

Given that eating disorders are among the deadliest of psychiatric disorders, the research takes on an urgency. According to a 2009 analysis, approximately 4 to 5% of people who suffer from an eating disorder die prematurely because of suicide and other factors (Am. J. Psychiatry 2009, DOI: 10.1176/appi.ajp.2009.09020247).

And the number of people with eating disorders isn’t insignificant. A national survey indicates that almost 14 million Americans today suffer from one of the “big three”—anorexia nervosa, bulimia nervosa, or binge eating disorder—at some point during their lives (Biol. Psychiatry 2007, DOI: 10.1016/j.biopsych.2006.03.040).

Treatment options are limited for some of the disorders. Nutritional counseling and psychotherapy can help, but results are variable, and some patients—nearly a third of them—struggle to recover indefinitely. There aren’t a lot of pharmaceutical options either: In fact, only one medication has been approved by the Food & Drug Administration for the treatment of an eating disorder (bulimia nervosa), and that’s the anti­depressant fluoxetine, says Erin VandenLangenberg, a postdoctoral fellow at the Emily Program, an eating disorder treatment center in St. Paul. Other compounds are in clinical trials.

But even fluoxetine, commonly known as Prozac, works only modestly for people with bulimia, studies have shown. And when given off-label to patients with anorexia, its efficacy has been questionable. A study in 2006 demonstrated that anorexia patients who reestablished a normal weight and then took the drug for a year relapsed at the same rate as those on a placebo (J. Am. Med. Assoc. 2006, DOI: 10.1001/jama.295.22.2605).

Arnold has gotten therapeutic benefit from Prozac, she says, but thinks the drug likely stifles obsessive-compulsive tendencies she exhibits rather than targeting her anorexia specifically. “I’ve found it helpful,” she says, “but I don’t know if it’s a make-or-break factor” for recovery.

So researchers have been digging deeper into neurochemistry. Although some of the first investigations began during the 1980s, back then the focus in the mental health community was still on the psychological and social aspects of the illnesses.

These pieces do play a part in eating disorders—the majority of people who end up with anorexia or bulimia exhibit anxiety, obsessive-compulsive tendencies, or perfectionism during childhood—but they don’t complete the picture. “If those were the only risk factors, we should have a lot more eating disorders in this world,” says Kelly L. Klump, a clinical psychologist and professor at Michigan State University.

After the gene-sequencing revolution of the 1990s, researchers began studying the influence of the biological makeup of twins and families on disordered eating. They now know that 50 to 80% of the reason some individuals develop eating disorders and others don’t is because of their genes.

Despite this knowledge, research into eating disorders lags behind other mental illnesses in terms of pinpointing the genes and molecules that contribute to the illnesses. The main reason for the lag is that malnutrition caused by eating disorders confounds studies, Klump says.

To figure out whether particular brain circuits and molecules trigger an eating disorder or simply help perpetuate it, scientists ideally would monitor the brains of a large group of people from childhood into adulthood and see who develops an illness, says Cara Bohon, a child and adolescent clinical psychologist at Stanford University School of Medicine. But to have statistical meaning, these studies would need to follow thousands of people, she says, and that’s the type of study that is hard to fund and carry out.

Eating disorder prevalence data illustrate the difficulty: Out of 1,000 subjects, only six are likely to develop anorexia and just 10 are likely to end up with bulimia. To run brain scans on so many to come away with such a small sample of patients just isn’t feasible, Bohon explains.

Making headway in eating disorders research, therefore, has required scientists to “get really creative” and study targeted patient populations instead, Klump says.

One such group is recovered patients. The theory goes that if a neurochemical abnormality existed prior to an eating disorder, it should exist once a patient has been restored to good health. In this situation, though, it’s always possible that there could be a “scar” in a patient’s brain from the eating disorder, Bohon says. In other words, the chemistry might have been normal prior to the eating disorder, but after the illness kicks in it causes permanent molecular discombobulation. Still, research on recovered patients is a good first step, Klump says.

Using positron emission tomography to image the brains of recovered patients, Walter H. Kaye at the University of California, San Diego, and other researchers have implicated the neurotransmitter serotonin as a culprit in eating disorders. When the small molecule binds to one of its 14 or more protein receptors in the brain, it normally either excites or inhibits nerve cell firing. By doing this, serotonin regulates a person’s mood and appetite, among many other things.

In 2011, Kaye and his team injected radio­tracers targeted at a serotonin receptor called 5-HT_1A into patients who had recovered from bulimia. The tracers, designed to mimic serotonin, had a higher “binding potential” in the brains of these people than in a control group (Int. J. Eat.Disord. 2011, DOI: 10.1002/eat.20843). That means either that an ex-bulimic has a higher density of 5-HT_1A receptors in certain brain regions than healthy people or that those receptors bind serotonin more readily. Other experiments have shown that another receptor, 5-HT_2A, has a lower serotonin binding potential in recovered anorexics compared with healthy people. Kaye and his group say the results, although complicated, seem to implicate serotonin in eating disorders.

There is also evidence, based on studies of recovered patients, that people with anorexia and bulimia produce elevated levels of serotonin in their brains. And eating doesn’t help: It produces even higher levels of serotonin, a derivative of the amino acid tryptophan found in foods such as turkey and eggs. Because serotonin also regulates anxiety, one popular theory—at least in anorexia—is that patients starve themselves to quell serotonin activity in their brains and thus to reduce anxious feelings.

This theory resonates for Arnold, who also writes an eating disorder blog called Ed Bites. Symptoms of her anorexia didn’t arise until she left home for college at the age of 18. “I had this really high level of anxiety,” likely caused by an undiagnosed obsessive-compulsive disorder, she recalls. “I was unhappy, and I didn’t feel like I fit in.”

Restricting her diet, hitting the gym excessively, and dropping 50 lb over a terrifyingly short period during her junior year were the first remedies Arnold found that quieted her anxiety.

Aside from monitoring recovered patients, researchers also study twins to sort out eating disorders. Because identical twins share nearly 100% of their genes and fraternal twins share about 50%, scientists examine these groups to determine whether certain behaviors are genetically driven.

In 2010, Klump and her group studied twin girls between the ages of 10 and 15 from the Michigan State University Twin Registry. The researchers surveyed the girls for eating disorder symptoms and tracked their levels of estradiol, a member of the estrogen hormone family that increases in the bodies of females at puberty.

What the team found is that eating disorders seemed genetically influenced only after midpuberty (Psychol. Med. 2010, DOI: 10.1017/s0033291709992236). Before that, when estradiol levels were low, identical and fraternal twins displayed similar eating behaviors. After midpuberty, when estradiol levels were high, identical twins were much more correlated in their disordered eating than were fraternal twins—a clear indicator of gene involvement. Estradiol is a gene transcription factor in the brain, Klump says, and turns genes on and off. The hormone, therefore, could switch on some of the genes involved in the illnesses during puberty, she adds.

Finally, scientists are studying lab animals for clues about eating disorders. They’ve developed model animals for symptoms of the illnesses, including binge eating. For instance, a team led by Rebecca L. Corwin of Pennsylvania State University produced a binge-prone group of rats by allowing them access to a bowl of vegetable shortening only three times per week for about an hour. After a few weeks, the rats would binge when the shortening was present, scarfing down two to three times the number of calories they did before restricted access began (Physiol. Behav. 2011, DOI: 10.1016/j.physbeh.2011.04.041).

When treated with naltrexone, a small molecule that blocks opioid receptors in the brain, the binge-prone rats drank less of a sugary solution the researchers provided. Non-binge-prone rats on naltrexone didn’t reduce their intake. Taken together, the researchers think these findings point to a significant role for opioid receptors—mediators of pleasure and pain—in binge eating.

Despite progress with these types of innovative studies, research to discern the “bio” part of these biopsychosocial illnesses is still in early stages. “I don’t think we have any neurobiological circuit yet where we can say, ‘Yes, absolutely, this is a circuit for eating disorders,’ ” Klump says. “We can say we’re pretty sure serotonin, dopamine, and opioids are involved, but not how at this point.”

Millions of patients—including a recovering Arnold—are fervently hoping researchers figure it out soon.