Donepezil, sold under the brand name Aricept among others, is a medication used to treat Alzheimer's disease. It appears to produce a small improvement in mental function and ability to function. However, use has not been shown to affect the progression of the disease. Treatment should be stopped if no benefit is seen. It is taken by mouth. Common side effects include nausea, difficulty sleeping, aggression, diarrhea, feeling tired, and muscle spasms. Serious side effects may include irregular heartbeat, urinary retention, and seizures. Donepezil acts as an acetylcholinesterase inhibitor. Donepezil was approved for medical use in the United States in 1996. In the United Kingdom, donepezil costs the NHS about £8.44 per person as of 2019. The total cost in the United States is about $1.38. In 2016, donepezil was the 98th most prescribed medication in the United States, with more than 7 million prescriptions. There is no evidence that donepezil or other similar medications alter the course or progression of Alzheimer's disease. Studies lasting 6 to 12 months have shown modest benefits in improving cognition or behavior. The National Institute for Health and Care Excellence recommends donepezil as an option for treating mild to moderate Alzheimer's disease. However, the person should be monitored frequently, and if there is no significant benefit, the drug should be discontinued. In 2006, the FDA also approved donepezil for the treatment of moderate to severe dementia in Alzheimer's disease. The most common side effects in clinical trials that led to discontinuation were nausea, diarrhea, and vomiting. Other side effects included difficulty sleeping, muscle cramps, and loss of appetite. Most side effects were seen in patients taking the 23 mg dose compared with the 10 mg or lower dose. Side effects were also less common with continued use. Donepezil should be used with caution in people with heart disease, conduction disorders, chronic obstructive pulmonary disease, asthma, cardiac arrhythmias, and sick sinus syndrome. People with peptic ulcer disease should be careful when taking NSAIDs because of the increased risk of gastrointestinal bleeding. Slow heart rate and fainting have also been seen in people with heart problems. These symptoms may occur more frequently when starting treatment or increasing the dose of donepezil. Although seizures are rare, people with a predisposition to seizures should be treated with caution. Donepezil reversibly binds and blocks the activity of cholinesterase, thereby preventing the hydrolysis of acetylcholine. This increases the concentrations of acetylcholine in acetylcholine-dependent synapses. The exact mechanism of action of donepezil in Alzheimer's disease remains incompletely understood. Alzheimer's disease is certainly caused by a significant deficiency of acetylcholine, and it is generally accepted that the symptoms of Alzheimer's disease are related to this cholinergic deficit, particularly in the cerebral cortex and other brain regions. The hippocampal formation is noted to play an important role in the control of attention, memory, and learning. The severity of acetylcholine-dependent neuronal loss in the central nervous system has been found to correlate with the severity of cognitive impairment. In addition to its role as an acetylcholine inhibitor, donepezil has been found to act as a potent σ receptor agonist, and has been shown to produce specific anticancer effects in animals primarily through this action. Research into the development of donepezil began in 1983 at Eisai, and in 1996 Eisai received FDA approval for donepezil under the brand name Aricept, which it co-marketed with Pfizer. The marketing team at Eisai was led by Hachiro Sugimoto. As of 2011, Aricept was the world's best-selling Alzheimer's disease treatment. The first generic became available in November 2010 with the USFDA approval of a formulation prepared by Ranbaxy Laboratories. In April 2011, a second generic formulation, by Wockhardt, received preliminary marketing approval from the USFDA. Donepezil has been tested in the treatment of other cognitive disorders, including dementia and vascular dementia, but has not yet been approved for these indications. Donepezil has also been found to improve sleep apnea in patients with Alzheimer's disease. It also improves movement in patients with mild Alzheimer's disease. Donepezil has also been studied in patients with mild cognitive impairment, schizophrenia, attention deficit disorder, CADASIL syndrome associated with coronary artery bypass surgery, multiple sclerosis-related disability, and Down syndrome. A three-year National Institutes of Health study in patients with mild cognitive impairment reported that donepezil was superior to placebo in delaying progression to dementia during the first 18 months of the study, but this was not sustained through 36 months. In a secondary analysis, a subgroup of individuals with the apolipoprotein E4 genotype showed sustained benefits with donepezil throughout the study. Donepezil has not been indicated for the prevention of dementia at this time.