Repurposing Cholinesterase Inhibitors as Antidepressants? Dose and Stress-Sensitivity May Be Critical to Opening Possibilities

Abstract

When stress becomes chronic it can trigger lasting brain and behavioral changes including Major Depressive Disorder (MDD). There is conflicting evidence regarding whether acetylcholinesterase inhibitors (AChEIs) may have antidepressant properties. In a recent publication, we demonstrated a strong dose-dependency of the effect of AChEIs on antidepressant-related behavior in the mouse forced swim test: whereas the AChEI donepezil indeed promotes depression-like behavior at a high dose, it has antidepressant-like properties at lower doses in the same experiment. Our data therefore suggest a Janus-faced dose-response curve for donepezil in depression-related behavior. In this review, we investigate the mood-related properties of AChEIs in greater detail, focusing on both human and rodent studies. In fact, while there have been many studies showing pro-depressant activity by AChEIs and this is a major concept in the field, a variety of other studies in both humans and rodents show antidepressant effects. Our study was one of the first to systematically vary dose to include very low concentrations while measuring behavioral effects, potentially explaining the apparent disparate findings in the field. The possibility of antidepressant roles for AChEIs in rodents may provide hope for new depression treatments. Importantly, MDD is a psychosocial stress-linked disorder, and in rodents, stress is a major experimental manipulation for studying depression mechanisms, so an important future direction will be to determine the extent to which these depression-related effects are stress-sensitive. In sum, gaining a greater understanding of the potentially therapeutic mood-related effects of low dose AChEIs, both in rodent models and in human subjects, should be a prioritized topic in ongoing translational research.

Latent Sex Differences in CaMKII-nNOS Signaling That Underlie Antidepressant-Like Effects of Yueju-Ganmaidazao Decoction in the Hippocampus

“…It is implied that lower doses of drugs can safely be used to treat depression such as YG and ES. Previous research showed that the therapeutic effects of a low dose of antidepressants merely disappeared, instead of becoming aversive or toxic ( Fitzgerald et al, 2020 ). However, chronic treatment with antidepressants was more popular.…”

Acetylcholinesterase Inhibitors in the Treatment of Neurodegenerative Diseases and the Role of Acetylcholinesterase in their Pathogenesis

“…Most of the commonly used AChE inhibitors show a dose-dependent response, as previously mentioned. It is suggested that their use in the treatment of depression is also associated with a dose-dependent response [328]. Researchers suggested that these inhibitors induce antidepressant efficacy only at lower doses.…”

Donepezil Beyond Alzheimer's Disease? A Narrative Review of Therapeutic Potentials of Donepezil in Different Diseases

“…Moreover, in a case report by Lim et al, the antidepressant effect of donepezil at a dose of 5 mg as adjunctive therapy was noticed in a 62-year-old woman with a history of depression without any cognitive problems whose depression was resistant to routine depression treatments and even nextline drugs (82). However, as previously stated, some studies have shown inconsistent evidence regarding donepezil's efficacy in treating depression (80,83). Reynolds et al, for example, in a clinical trial study, found that donepezil was ineffective in treating depression in 130 older adults with depression and mild cognitive impairment (38).…”

“…Donepezil and AChEIs have shown mood-modifying properties in animal and clinical trials. However, some research has refuted this efficacy, and the findings of specific studies have shown that these medicines cause depression, mania, or even exacerbation of the underlying condition (13,80). In an animal study by Papp et al, using 96 rats in both stress and control groups, the anxiolytic, antidepressant, and cognitive-improving effects of donepezil (0.3 mg/kg intraperitoneally), rivastigmine, imipramine, and memantine were investigated.…”