Cholinesterase Inhibitors and Memantine

Several lines of evidence suggest that acetylcholine (ACh) neurotransmission is important to the normal functioning of memory, and loss of ACh-producing cells in the basal forebrain (nucleus basalis) is a consistent finding in patients with Alzheimer’s disease and other dementias. The most successful approach to increasing ACh in vivo has been to develop drugs that reduce its degradation by the synaptic enzyme acetylcholinesterase (AChE). Four cholinesterase inhibitors are available to treat memory and other cognitive symptoms in dementia patients. They may also stabilize or prevent the onset of milder non-cognitive neuropsychiatric or behavioral symptoms, although their use as exclusive agents for the more severe forms of the latter is not recommended. A recent Consensus Panel has articulated sound clinical principles regarding the use of these drugs in the context of the broader treatment of Alzheimer’s dementia (Lyketsos et al., 2006). Tacrine, donepezil, rivastigmine, and galantamine have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease. Tacrine should not ordinarily be used in light of the associated high risk of hepatotoxicity, its complex titration, and the availability of bettertolerated alternatives. The other three cholinesterase inhibitors seem similar in efficacy. All appear to modestly improve cognitive symptoms in 15% to 20% of patients, sometimes quite notably. In addition, they may either improve patient function and delay the emergence of behavioral symptoms or reduce the severity of the latter. The evidence does not support their use as single agents to treat more severe neuropsychiatric symptoms such as depression or delusions, although patients with apathy and visual hallucinations may respond. Any benefit of cholinesterase inhibitors to the long-term progression of dementia has not been shown conclusively. Some studies suggest that they may attenuate the long-term slope of cognitive or functional decline, but those studies have been flawed due to high levels of dropout and the use of historical untreated comparison groups. One brain imaging study, part of a clinical trial, has suggested that they may affect the size of the hippocampus or the integrity of hippocampal neurons. In the absence of replication or a better understanding of the imaging measures involved, these data are not conclusive.