Major depressive disorder (MDD) is a disease with huge societal burden and mortality, yet many patients suffering from this disease are not helped by current treatment options. Most antidepressants modulate neurochemicals called “monoamines” such as serotonin, norepinephrine and dopamine. Recently, the anesthetic medication ketamine, which may act by affecting very different neurotransmitter systems such as glutamate, has been “repurposed” as an antidepressant, since, when used at low doses, it has strong antidepressant properties. Thus ketamine, with a unique mechanism of antidepressant action, has opened alternative treatment options for tens of thousands of MDD patients. Our team was curious whether another neurotransmitter, acetylcholine, might enable us to treat MDD. Acetylcholine is increased by the commonly-used dementia drug Aricept (donepezil) and Dr. Paul Fitzgerald, along with Dr. Brendon Watson, formed the hypothesis that similar to ketamine, low doses of Aricept might have antidepressant properties not present at the standardly-used doses.
To explore the possibility that Aricept has antidepressant properties, Dr. Watson, Assistant Professor in the U-M Psychiatry Department, and his co-workers carried out a study in which mice were administered this drug at both standard and lower doses. They found that at low doses, Aricept induced behavior similar to other conventional antidepressants such as SSRIs, as well as ketamine. Interestingly, the therapeutic effect was only present at doses of Aricept much lower than those typically used, whereas a higher dose promoted depression-like behavior. Previous rodent studies of this class of drugs had largely reported depression-promoting effects, so the current findings underscore the importance of using low doses. Further, these findings raise the possibility that Aricept could have antidepressant properties in humans suffering from MDD, which would have to be explored in clinical studies but could create another pharmacological option in a disorder that does not always respond adequately to existing therapeutics.
Dr. Watson pointed out that “a major advantage would be that based on these findings it might be possible to treat depression using Aricept doses below those already FDA-approved for other conditions, greatly smoothing the pathway to potential use of this treatment.”
This research was funded by a University of Michigan Depression Center STAR award.
Fitzgerald, P.J., Hale, P.J., Ghimire, A., Watson, B.O. The cholinesterase inhibitor donepezil has antidepressant-like properties in the mouse forced swim test. Transl Psychiatry 10, 255 (2020). https://doi.org/10.1038/s41398-020-00928-w
