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Basic discovery brings hope to those facing eating disorders

Woman seated on the floor with a glass of water in front of her

By Alison Palmer, Evaluation and Special Projects Lead

A fundamental research discovery from a 2012 Brain Canada MIRI grant is now bringing relief to patients living with an eating disorder, which has the highest mortality rate of any psychiatric disease after substance use.

We don’t fully understand psychiatric disorders. Why is someone schizophrenic, autistic, depressed? What’s going on? Where? What are the mechanisms? We have little knowledge about the neurobiology of these severe disorders. There’s one exception now. With our finding we really have a science-based, rational explanation for compulsive disorders.

Dr. Salah El Mestikawy

The fundamental discovery

Dr. Salah El Mestikawy, based at the Douglas Research Centre, was awarded a Brain Canada team grant in 2012 to support his research on how a region of the brain called the striatum regulates behaviours associated with compulsion. Compulsive behaviour is at the heart of many disorders including obsessive-compulsive disorder (OCD), addiction (substance use disorders), and eating disorders, as well as movement disorders like Parkinson’s disease.

The result of Dr. El Mestikawy’s project, made possible through collaboration with Dr. Marco Prado and Dr. Vania Prado at the University of Western Ontario, was a discovery that would influence the clinical trials now underway today on a knowledge-based treatment for eating disorders.

Dr. El Mestikawy and his team at the Douglas Hospital Research Centre.

What they discovered is what Dr. El Mestikawy calls the dopaminergic asymmetry in a structure of the brain called the striatum.

“When you decrease the neurotransmitter acetylcholine, for some reason, a mutation for example, then you have decreased dopamine, but only in the accumbens region (the reward center) of the striatum and in the caudate (the center that regulates action towards a specific goal) of the striatum. However, this dopamine decrease is not observed in the putamen region. The putamen region of the striatum is where you form and regulate habits and automatic behaviors. Having high levels of dopamine in the putamen results in habits becoming too strong.”

While habits are useful to us – making us more efficient and requiring less concentration – in the case of eating disorders, they become repetitive and invasive, despite severe consequences.

The researchers later found a way to restore the balance of acetylcholine in the striatum by administering a drug called donepezil, also known by the brand name Aricept®, commonly used to treat Alzheimer’s disease. The team used mice expressing a mutation found in a population of patients with addiction and eating disorders. These mutant mice exhibited anorexia-like pathology. Donepezil treatment resulted in a disappearance or deactivation of the compulsive self-starvation.

Testing the discovery in patients with eating disorders

In Canada, an estimated 2.7 million people are impacted by eating disorders; approximately 1.4 million of these are youth. After substance use, eating disorders have the highest overall mortality rate of any mental illness, between 10-15% . Dr. El Mestikawy witnessed this tragedy when one of his young students died by suicide. Eager to see whether the promising results he discovered in mice could help to avert such outcomes, he connected with Dr. Leora Pinhas, a psychiatrist based in Toronto who specializes in eating disorders. Dr. Pinhas pursued a compassionate trial of donepezil with eating disorder patients who had tried several treatments without success.

What’s the impact?

The results were remarkable; within a month, sometimes even just a few weeks, Dr. Pinhas was noticing a difference.

The twenty or so patients who took the drug are now greatly improved or in remission from their eating disorder.

The next step is a clinical trial to investigate whether the positive effect seen in the compassionate trials is due to the drug. Three trials are currently underway at Columbia University, Denver University, and the Hôpital Sainte-Anne in Paris. The trials will take years to complete, and if successful, require another several years of government approval before they can be used to treat patients.

In the meantime, Dr. El Mestikawy has turned his research focus to developing a derivative of the drug that is active exclusively in the brain, with minimal side effects. One of the downsides of drugs like donepezil is that they work on the whole body, causing side effects including muscular contractions, increased blood pressure, nausea, and cramps. So far Dr. El Mestikawy and his team have tested their novel drug derivative in mice, with positive results.

His hope is that additional clinical trials will investigate the promise of donepezil for treating other disorders.

Disorders involving compulsion affect a lot of people,” he explains. “Importantly addiction as well is fundamentally a compulsive disorder – repetition of drug intake despite very severe consequences as witnessed by the fentanyl crisis. My hope is that compassionate trials and then clinical trials with cohorts of patients suffering from addiction will start in 2025.

Dr. Salah El Mestikawy

Dementia Dialogue

The impact of Dr. El Mestikawy’s work was featured on the Radio-Canada documentary series Découverte. A patient from the compassionate trial, Madelyn Eybergen, and Dr. Leora Pinhas are also featured. To view in French, click here. An English version is available here.

“Most of the kids, young people and adults I work with are great people – they are smart, they are hardworking, they are caring. To be able to help them get back on track with their lives instead of wasting decades of time and resources, that’s why I went into medicine.” – Dr. Leora Pinhas

La Presse also published a feature on this work, available here.

Dr. Salah El Mestikawy, professor of psychiatry at McGill University and researcher at the Douglas Hospital Research Centre, and co-investigators Dr. Marco Prado and Dr. Vania Prado affiliated with BrainsCAN and the University of Western Ontario, received a $1.4 million research grant through the 2012 Brain Canada Multi-Investigator Research Initiative (MIRI) Grants competition. This project was made possible by the Canada Brain Research Fund, a unique arrangement between the Government of Canada, through Health Canada, and Brain Canada. Matching dollars for this project were contributed by Fonds de recherche du Quebec – Sante (FRQS), McGill University, and the University of Western Ontario.