Donepezil, sold as the trade name Aricept among others, is a medication used to treat Alzheimer's disease.[1] It appears to result in a small benefit in mental function and ability to function.[2] Use, however, has not been shown to change the progression of the disease.[3] Treatment should be stopped if no benefit is seen.[4] It is taken by mouth.[1] Common side effects include nausea, trouble sleeping, aggression, diarrhea, feeling tired, and muscle cramps.[1][4] Serious side effects may include abnormal heart rhythms, difficulty emptying urine from the bladder, and seizures.[1] Donepezil is a centrally acting reversible acetylcholinesterase inhibitor.[1] Donepezil was approved for medical use in the United States in 1996.[1] It is available as a generic medication.[4] In the United Kingdom a typical months supply costs the NHS about £8.44 as of 2019.[4] The wholesale cost of this amount in the United States is about US$1.38. [5] In 2016 it was the 98th most prescribed medication in the United States with more than 7 million prescriptions.[6] There is no evidence that donepezil or other similar agents alters the course or progression of Alzheimer's disease. 6 to 12-month controlled studies have shown modest benefits in cognition or behavior.[7] The UK National Institute for Clinical Excellence (NICE) recommends donepezil as an option in the management of mild to moderate Alzheimer's disease.[8] The person should, however, be reviewed frequently and if there is no significant benefit it should be stopped.[8] In 2006 the U.S. Food and Drug Administration also approved donepezil for treatment of mild, moderate and severe dementia in Alzheimer's disease.[9] In clinical trials the most common adverse events leading to discontinuation were nausea, diarrhea, and vomiting.[10][11] Other side effects included difficulty sleeping, muscle cramps and loss of appetite. Most side effects were observed in patients taking the 23 mg dose compared to 10 mg or lower doses. Side effects improved with continued use.[12] Donepezil should be used with caution in people with heart disease, cardiac conduction disturbances, chronic obstructive pulmonary disease, asthma, severe cardiac arrhythmias and sick sinus syndrome.[12] People with peptic ulcer disease or taking NSAIDS should use with caution because increased risk of gastrointestinal bleeding was noted.[12] Slow heart beat and fainting in people with heart problems were also seen. These symptoms may appear more frequent when initiating treatment or increasing the donepezil dose. Although occurrence of seizures is rare, people who have a predisposition to seizures should be treated with caution.[12] Donepezil binds and reversibly inactivates the cholinesterases, thus inhibiting hydrolysis of acetylcholine. This increases acetylcholine concentrations at cholinergic synapses. The precise mechanism of action of donepezil in patients with Alzheimer's disease is not fully understood. Certainly Alzheimer's disease involves a substantial loss of the elements of the cholinergic system 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 areas of the brain.[13][14] It is noted that the hippocampal formation plays an important role in the processes of control of attention, memory and learning. Just the severity of the loss of cholinergic neurons of the central nervous system (CNS) has been found to correlate with the severity of cognitive impairment. In addition to its actions as an acetylcholinesterase inhibitor, donepezil has been found to act as a potent agonist of the σ1 receptor (Ki = 14.6 nM), and has been shown to produce specific antiamnestic effects in animals mainly via this action.[15] Donepezil medications are racemates.[16] Research leading to the development of donepezil began in 1983 at Eisai, and in 1996, Eisai received approval from the United States Food and Drug Administration (USFDA) for donepezil under the brand Aricept, which it co-marketed with Pfizer.[18] The team at Eisai was led by Hachiro Sugimoto[19] As of 2011, Aricept was the world's best-selling Alzheimer's disease treatment.[20] The first generic donepezil became available in November 2010 with the USFDA approval of a formulation prepared by Ranbaxy Labs.[21] In April 2011 a second generic formulation, from Wockhardt, received tentative USFDA marketing approval.[22] Donepezil has been tested in other cognitive disorders, including Lewy body dementia,[23] and vascular dementia,[24] but it is not currently approved for these indications. Donepezil has also been found to improve sleep apnea in people with Alzheimer's.[25] It also improves gait in people with mild Alzheimer's.[26] Donepezil has also been studied in people with mild cognitive impairment, schizophrenia, attention deficit disorder, post-Coronary artery bypass surgery cognitive impairment,[27] cognitive impairment associated with multiple sclerosis, CADASIL syndrome, and Down syndrome. A three-year National Institutes of Health trial in people with mild cognitive impairment reported donepezil was superior to placebo in delaying rate of progression to dementia during the initial 18 months of the study, but this was not sustained at 36 months.[28] In a secondary analysis, a subgroup of individuals with the apolipoprotein E4 genotype showed sustained benefits with donepezil throughout the study.[29] At this time, though, donepezil is not indicated for prevention of dementia. The addition of donepezil with existing ADHD medications has shown mixed results.[30] In those with Tourette's syndrome and ADHD, donepezil may reduce tics while it had no effect on ADHD's symptoms.[30] Donepezil along with other cholinesterase inhibitors is suggested as having potential for trouble behaviors, irritability, hyperactivity, and difficulty in social communication which are typically seen in those with pervasive developmental disorder, pervasive developmental disorder not otherwise specified, or autism spectrum disorder.[30]