Eating disorders such as anorexia and bulimia affect up to 10% of the population and are very difficult to treat. Anorexia carries the highest mortality rate of all mental-health disorders, but unlike depression and other mental illnesses, there are currently no medications to treat eating disorders.
New research from McGill professor Salah El Mestikawy at The Douglas Research Centre may change all that.
Anorexia, bulimia, addiction and obsessive-compulsive disorder (OCD) all have something in common: those affected repeat an action over and over, despite negative consequences—almost like their brains are stuck on “autopilot.” This facet of the disease drew El Mestikawy’s attention, and he began investigating the source of these behaviours in genetically modified mice. The animals express a human gene mutation identified in patients with addiction or eating disorders, and his team discovered that these mutant mice were more susceptible to developing anorexia when used in a rodent model of the disorder.
To learn more about the mechanism behind this behaviour, El Mestikawy focused on an area of the brain called the striatum. More specifically, his team investigated activity in three interconnected sub-regions of the striatum: the nucleus accumbens (part of the reward system), the caudate nucleus (control of goal-oriented behaviour) and the putamen (involved in habit formation).
The nucleus accumbens (NA) and caudate nucleus (CN) allow us to learn new tasks, and the putamen goes on to transform that new action into an automatic behaviour. Consider it in terms of learning to ride a bicycle or drive a car; once you’ve learned to do it, you don’t need think about how to do it anymore.
These types of brain networks are important, and normally they work together to make us more efficient. Each of these three brain regions has molecular brakes and accelerators that modify their function, and dopamine controls this mechanism—acting to effectively hit the gas and cut the brakes. Repetitive automatic behaviours develop when there’s too much dopamine in the putamen relative to the other two regions.
El Mestikawy found that the neurotransmitter acetylcholine (ACh) increases dopamine in the NA and CN but not in the putamen. He hypothesized that by increasing levels of ACh in the NA and CN, the three brain regions could be brought back into equilibrium and harmful automatic behaviours reduced.
Donepezil, a medication used to treat Alzheimer’s disease, blocks the enzyme that breaks down ACh and thus increases the concentration of active compound in the brain.
So, El Mestikawy’s team administered donepezil to their anorexic mice, and sure enough, the animals resumed eating normally. When patients suffering from anorexia were treated with the drug, they saw dramatic improvement. Donepezil acted quickly to change their level of behavioural flexibility and compulsivity—at much lower dosages than those used to treat Alzheimer’s. Patients noticed changes in behaviour within just a few weeks of beginning treatment.
This success came with one drawback, however. Because donepezil increases the levels of ACh throughout the body, it comes with significant side effects. Most notably, the drug increases blood pressure considerably and can be dangerous for patients already in poor health.
Using virtual drug screening and pharmacochemistry, El Mestikawy and his chemist collaborator Nicolas Pietrancosta developed an analog of donepezil that's less likely to cause systemic side effects.
Support from NeuroSphere’s Ignite grant allowed El Mestikawy to further develop the project and investigate this new drug’s effects on the brain at the cellular level. It also allowed him to evaluate whether it could alleviate anorexia in the mutant mouse model and to gain insight into the range of drug concentrations that would provide a therapeutic response with minimal adverse affects. So far, the results have been extremely promising and show that it works very well for the treatment of anorexic behaviour in mice.
The project has always had personal significance for El Mestikawy, as he lost someone close to him to anorexia. While these recent breakthroughs are just the beginning, they represent a revolutionary step in the treatment of eating disorders and a cause for hope among patients and their families. Check out this episode of Radio-Canada’s popular-science series Découverte (video available in French only) to learn more about how this research is already changing lives.
