Donepezil May Offer a New Treatment for Anorexia Nervosa

An animal study suggests that anorexia nervosa, a devastating eating disorder, could be associated with a ‘blunted’ release of a specific brain chemical.

Male mice genetically modified to carry a rare variant identified in some people with eating disorders, as well as substance use disorders, showed a shortage of the neurotransmitter acetylcholine. The deficit was found in the striatum, a brain region involved in learned behaviours, cravings and reward.

Although the findings need further confirmation and studies in people, the research “identifies a mechanism and a potential treatment to alleviate these severe psychiatric disorders,” write Mathieu Favier, a neuroscientist at McGill University in Montreal, and his colleagues in their published paper.

Put simply, raising acetylcholine levels with a medicine already licensed for Alzheimer’s disease could be beneficial, although other forms of treatment are likely to remain necessary.

Genetic link between anorexia nervosa and substance use disorders

Favier and colleagues first confirmed the association between the genetic mutation in question and substance use disorders in a new patient group that also included individuals with eating disorders. The p.T8I variant of the SLC17A8 gene is uncommon, appearing in just 9 of the 793 cases examined in this study. The findings may therefore not be relevant to everybody with these disorders.

Both conditions involve patterns that can be difficult to stop and compulsive behaviours. In eating disorders, these behaviours are driven by restriction; in substance use disorders, they are driven by ‘rewards’, as addictive drugs stimulate the brain’s reward system, producing a surge of dopamine and other reward chemicals.

Donepezil restored eating behaviour in mice

When the genetically engineered mice were given donepezil, an Alzheimer’s medicine that blocks the enzyme responsible for breaking down acetylcholine, clear changes were seen. Having previously displayed behaviours resembling binge eating and restrictive eating, the mice started to eat normally and fewer lost weight.

“We found that it fully reversed the anorexia-like behavior in mice, and we believe that it could potentially offer the first mechanism-based treatment of anorexia nervosa,” says McGill University neuroscientist Salah El Mestikawy, the study’s senior author.

“In fact, we are already seeing its effects on some patients with the disease.”

A Canadian pilot study has treated ten patients with low doses of donepezil. Randomised controlled trials are planned to assess whether the medicine is more effective than a placebo at easing anorexia nervosa.

Repurposing existing medicines for potentially different illnesses can be useful. Yet, until those trials have been completed, it will remain unclear how effectively the animal-study results apply to people, or whether restoring acetylcholine is a successful treatment approach.

The research used male mice, whereas eating disorders predominantly affect women, meaning that possible sex-based differences may not have been considered. Donepezil also has recognised serious side effects, which is why the clinical trials will use only low doses.

Biological and psychological factors in anorexia treatment

Nevertheless, the results provide cautious optimism that a medicine could eventually assist in treating anorexia, an illness with one of the highest mortality rates among severe psychiatric disorders.

As with many mental health conditions, research can appear to be a contest between the biological factors underlying disorders such as anorexia or mood conditions such as depression, and the psychological elements of each illness.

In 2019, researchers identified eight genetic markers linked to anorexia after examining DNA from almost 17,000 patients with anorexia nervosa and around 55,000 people without the condition. Several of these variants are connected with how the body metabolises fats and sugars.

Identifying such biological foundations may help to lessen stigma surrounding mental health conditions. Demonstrating a physiological basis makes clear that some people could have a genetic or biological predisposition to a particular disorder.

There is, however, further complexity: social, psychological and environmental influences - which people may or may not be able to control - act upon those biological foundations.

Understanding the overlapping factors that contribute to mental health conditions has implications for treatment. For instance, the long-held belief that a serotonin chemical imbalance causes depression has encouraged the use of antidepressants that fail to work for many people, while more recent research indicates that the theory may be somewhat inaccurate.

For anorexia, treating this and other obsessive-compulsive disorders with acetylcholine inhibitors could prove controversial, as Favier and colleagues acknowledge themselves, and no medicine is a universal solution.

Behavioural therapies, the present standard of care, will therefore remain among the tools used to support patients as new treatment options are investigated.

The study has been published in Nature Communications.