Earlier this week on Twitter (do you follow ED Bites on Twitter? You know you want to...), I ran across an interesting article about why some antidepressants don't work in some patients. The article was published last week in the research journal Neuron and is titled "5-HT1A Autoreceptor Levels Determine Vulnerability to Stress and Response to Antidepressants." (Clicking the link will take you to the free full-text of the article.) I'll let the opening of the article's Science Daily press release explain the research for me:

An excess of one type of serotonin receptor in the center of the brain may explain why antidepressants fail to relieve symptoms of depression for 50 percent of patients, a new study from researchers at Columbia University Medical Center shows.

...Most antidepressants -- including the popular SSRIs -- work by increasing the amount of serotonin made by cells -- called raphe neurons -- deep in the middle of the brain. Serotonin relieves symptoms of depression when it is shipped to other brain regions.

But too many serotonin receptors of the 1A type on the raphe neurons sets up a negative feedback loop that reduces the production of serotonin, Dr. Hen and his colleagues discovered. "The more antidepressants try to increase serotonin production, the less serotonin the neurons actually produce, and behavior in mice does not change," Dr. Hen says.

Seeing as anti-depressant therapy hasn't shown much promise in the treatment of anorexia nervosa (although it does appear to help treat co-morbid conditions like depression and anxiety), this research could help with the development of new treatments for AN. It also seemed like a good a time as any to discuss the links between serotonin levels and eating disorders. In a 2005 review article, titled "Serotonin alterations in anorexia and bulimia nervosa," Walter Kaye wrote that people with either anorexia and/or bulimia showed alterations of brain functioning in specific neural areas:

Importantly, such disturbances are present when subjects are ill and persist after recovery, suggesting that these may be traits that are independent of the state of the illness. Emerging data point to a dysregulation of serotonin pathways in cortical and limbic structures that may be related to anxiety, behavioral inhibition, and body image distortions...Alterations of these circuits may affect mood and impulse control as well as the motivating and hedonic aspects of feeding behavior. Such imaging studies may offer insights into new pharmacology and psychotherapy approaches.

The serotonin/anorexia connection has been researched over the years (searching PubMed for "serotonin anorexia" gives you over 700 results), and the most recent thinking goes something like this. People with anorexia are generally thought to have unusually high levels of serotonin in their brains, and high levels of brain serotonin have been linked to anxiety and obsessionality. An old BBC article titled "Genetic clues to eating disorders" has a quote from Janet Treasure that explains some of the link:

People with high levels of serotonin are prone to anxiety. Dr Janet Treasure, director of the eating disorders unit at the Maudsley, believes this could be behind anorexic patients' ability to suppress appetite. She said: "In anorexia nervosa the drive to eat can be inhibited, but we know that in normal people who are starved they will kill each other and do all sorts of morally repugnant things, and eat all sorts of foodstuffs that you wouldn't normally touch.

"Yet that doesn't happen in anorexia nervosa, so there's some aspect of the appetite system that isn't working."

The unit looked at the biology of stress mechanisms, in particular the fight or flight response. This is where the body prepares itself for action when confronted by a stressful situation. Heart rate and blood pressure rise and two of what are usually humans' highest priorities, eating and reproducing, are put on hold. It is possible that anorexic people are chronically in an acute state of stress reaction - they are constantly in a fight or flight state of mind.

And by restricting food intake, people with anorexia can lower the amount of serotonin their bodies can make (serotonin is ultimately derived from the essential amino acid tryptophan). This actually makes people with anorexia feel better. However, the brain begins to sense the decreased serotonin production and tries to maintain homeostasis by increasing the number of serotonin receptors. Thus the brain is back at Square One, as it is producing less serotonin but is using the decreased amount much more efficiently. So restricting doesn't feel as good, and the (obvious!) solution is to eat even less. And thus that negative cycle is born and the anorexic becomes trapped by their own brain chemistry.

Refeeding would then increase the amount of serotonin in the brain before the brain has a chance to decrease the number of serotonin receptors. This could be the neurological equivalent of All Hell Breaking Loose and could very well explain why refeeding is so distressing, although I don't think there has been any formal research done on the subject.

In bulimia, the serotonin problem is reversed. People with BN appear to have much lower than average levels of serotonin in the brain, which may be temporarily increased by binge eating.* Purging increases levels of vasopressin, which can have a euphoric and sedating effect, thus making the binge/purge cycle addictive much in the same way that starvation becomes addictive in AN. The chronic low levels of serotonin in BN also explain why SSRIs can be effective at reducing the urges to binge and purge.

Of course, plenty of people cross over from anorexia to bulimia, and I haven't the slightest idea of how serotonin might affect that crossover. So many brain systems are thrown out of whack during an ED that I don't know an exact answer will ever be found.

*The story is, as usual, a little more complicated than this, but the basic idea is the same.

Last month, I wrote on Part One of an article from the magazine Psychiatric Times titled "The Cellular and Molecular Substrates of Anorexia Nervosa, Part One." As I promised, I am writing on Part Two now that it has appeared (the original link I found was bad, and I had to hunt down the article, so I apologize for the delay, but here it is!).

The author, John Medina, summarized the first article as follows:

A testable hypothesis was outlined: AN was described as a conflict between an un-acquired biological need to have food and an acquired negative reaction to it. Patients with AN recruit cortical executive reactions in response to appetite cues, reactions that insert a top-down “food-negative” bias into the normal drives for fuel. These executive reactions are consistently overstimulated in AN patients, leading to high anticipatory behavior and obsessive concern with future events. Derived mostly from noninvasive imaging studies, this notion of conflicting priorities (complete with a dysfunctional reward/punishment system) has surprising empirical support.

But it is hardly the complete story of AN. Besides behavioral and cellular concerns, there are also molecular interactions to consider. It is to these efforts that we turn, focusing on the “usual regulatory suspects” of dopamine and serotonin neurotransmitter biology.

Medina first begins discussing the role of malfunctions in the dopamine system in people with AN, since many anorexics report varying levels of asceticism, anhedonia (the inability to find anything pleasurable), and the difficulties in finding something consistently rewarding. This is otherwise known as the Theme of My Life. These are considered trait features because they often exist before the onset of illness and persist after recovery. Other clues pointing to the dopamine system are difficulties with visual tasks (which can often signal a malfunction in the dopamine system), lower levels of dopamine metabolites in the cerebrospinal fluid even after recovery, variances in the genes of dopamine receptors in the brain, as well as brain imaging studies.

The other major neurotransmitter being studied with respect to anorexia is serotonin. Medina included a diagram (that I've copied here) that portrays the two hypotheses related to abnormalities in the serotonin system that may contribute to anorexia. The first hypothesis is that people with AN have increased levels of serotonin in the brain, which may contribute to the common traits of harm avoidance and anxiety, as well as the general lack of effectiveness of SSRIs in treating AN. The other hypothesis has to do with an imbalance in serotonin receptors which can be altered by both hormonal changes and stress. The evidence for this has to do with the usual onset of AN during puberty/adolescence, and many times the onset coincides with a particularly stressful time in the sufferer's life.


Writes Medina:

Starvation-induced reductions in levels of extracellular 5-HT, for example, might result in reduced stimulation of postsynaptic 5-HT1a and 5-HT2a receptors, leading to behavioral alteration. The resulting dysphoria, normal in unaffected individuals, might be exaggerated in patients with AN.

There are testable questions surrounding these ideas. Forcing AN patients to eat, for example, might stimulate postsynaptic 5-HT1a and 5-HT2a receptor activity. This stimulation would lead to an elevation in dysphoric mood, transforming eating and weight gain activities into traumatic stress-inducing experiences. This might explain the no-win behaviors so common in AN patients. If the patient were allowed to continue to starve herself, anorexigenic information related to neuropeptide alterations (reduced b-endorphins, elevation in stress-related metabolism such as elevated corticotropic-releasing hormone), might exacerbate AN symptoms by driving food-restricting behaviors. Whether eating or starving, the same dysfunctional circuitry would be stimulated, all leading to the symptoms.

... Persons with AN show unique anxiety-related 5-HIAA metabolic perturbations. The weight loss in these patients results in a reduction in 5-HIAA CSF levels. But they concomitantly show dramatically elevated 5-HIAA receptor binding in specific cortical and limbic structures—something not seen in healthy controls. Food might very well be anxiogenic in these individuals.

Which, really, explains both everything and nothing. As Medina says, there is no one neurological system that is both necessary and sufficient for the development of AN. And I hate to rain on anyone's parade, but I doubt it will be just one thing or just one system or just one factor. Human behavior is way too complicated. Still, we have made enormous strides in understanding the scientific basis of anorexia, and I'm looking forward to future research.

Serotonin is the brain chemical we've all come to know and love. It's sometimes called the "happy chemical." Why? People with depression tend to have low levels of serotonin in the brain. So do people with anxiety disorders. And bulimia nervosa.

Anorexia appears to be a little different. While researchers know that people with anorexia have abnormal serotonin levels both during illness and after recovery, the levels in recovered anorexics tend to be higher than usual. A review article from 1997, followed by a study from 1998, says that

Certain traits, such as negative affect, behavioral inhibition, compliance, high harm avoidance, and an obsessive concern with symmetry, exactness, and perfectionism, persist after recovery from anorexia nervosa. These persistent symptoms raise the possibility that such traits exist premorbidly and contribute to the pathogenesis of this disorder. Such traits could be associated with increased brain serotonin activity.

But an interesting study came out recently that linked low serotonin levels to impulsivity and aggression.

A press release said that the study results

"highlight why some of us may become combative or aggressive when we haven't eaten. The essential amino acid necessary for the body to create serotonin can only be obtained through diet. Therefore, our serotonin levels naturally decline when we don't eat, an effect the researchers took advantage of in their experimental technique.

The research also provides insight into clinical disorders characterised by low serotonin levels, such as depression and obsessive compulsive disorder (OCD), and may help explain some of the social difficulties associated with these disorders."

Restrictive eating causes a drop in serotonin, temporarily normalizing mood. Then, of course, the not eating continues and serotonin continues to drop. This drop in serotonin also helps to (temporarily) decrease anxiety.

The chaotic eating surrounding bulimia may also help explain the dramatic rise in impulsivity seen in people with this illness. Besides possibly having a lower-than-average level of serotonin, the periods of food restriction that often accompany bingeing and purging could further lower serotonin levels, making the impulses to binge and purge even harder to resist. Purging also lowers serotonin, compounding the situation even further.

It also, I might add, explain why dieters are so darn cranky!

If anyone can help explain why people with anorexia have higher rates of pre-illness OCD and high serotonin levels (when OCD is associated with low serotonin), I would greatly appreciate it.

Here's some research confirming what we all know: your body weight is determined by more than just the amount of food you eat.

From a press release:

"It says that the nervous system is a key regulator coordinating all energy-related processes through distinct molecular pathways," said Kaveh Ashrafi of the University of California, San Francisco. "The nervous system makes a decision about its state leading to effects on behavior, reproduction, growth and metabolism. These outputs are related, but they are not consequences of each other. It's not that feeding isn't important, but the neural control of fat is distinct from feeding."

If the results in worms can be extrapolated to humans, as Ashrafi suspects at a fundamental level they can given serotonin’s ancient evolutionary origins, then the finding may have clinical implications.

"From a clinical perspective, this may mean you could develop therapeutic strategies to manipulate fat metabolism independently of what you eat," he said. "Now, the focus is primarily on feeding behavior. As important as that is, it's only part of the story. If the logic of the system is conserved across species, a strategy that focuses solely on behavior can only go so far. It may be one reason diets fail."

Obviously, the amount of food you eat can and does affect your weight. But it's not as simple as that. The amount of serotonin in your brain can stimulate to eat more or less. Yet serotonin also regulates how this energy is used. This kind of finding helps fill in the gap as to why people who eat the same can weigh differently.

As a science reporter (an intern science reporter, but still), I get on mailing lists for all of the latest research. Most of what I report on would be of basically no interest to people on this blog (the lastest chemistry research), but I do get a variety of stuff. When this one came across my desk, I immediately searched for the results online. Just to see.

It had five results.

If this paper was about how to lose weight, there wouldn't be just five results. I would give just a little bit of slack if the title of the press release was something super esoteric. But it wasn't. The title of the press release was: Thinness vs. obesity not directly linked to eating habits, study suggests.

I think these findings are far more important and meaningful than whether Atkins raises your cholesterol levels more or less than 5 points. This has to do with the fundamental ways your weight is regulated. But this study doesn't have the potential to earn companies a lot of money. So it wasn't promoted as much. If it's not promoted, it probably won't get reported.

Which is exactly what happened here.