Cholinesterase inhibitor therapies and neuropsychiatric manifestations of Alzheimer's disease

Background: Neuropsychiatric symptoms (NPS) of Alzheimer's disease (AD) occur throughout the course of AD. Behaviors include mood alterations, psychosis, agitation, and apathy. These symptoms are a major cause of diminished quality of life for both patients and caregivers. Evidence suggests that a cholinergic deficit resulting from a loss of cholinergic neurons is the biological basis of some NPS in AD and related dementias. The basal forebrain nuclei, the primary source of cholinergic projections to the cortex, become atrophied in AD. Cholinesterase inhibitors (ChE-Is) enhance neuronal transmission by increasing the availability of acetylcholine at the receptors. This effect is believed to be beneficial in improving or stabilizing many behavioral symptoms of AD. Preliminary studies of ChE-Is have shown mixed results; however, the results of more recent studies have been favorable.

Objectives: To review major trials of ChE-Is and summarize effects on behavioral symptoms. Agents reviewed include donepezil, galantamine, rivastigmine, tacrine, and metrifonate.

Results: The review of the studies favors a benefit of the ChE-Is in reducing NPS. Of the three agents in current use, studies of all showed significant benefit in AD. Most studies showed a positive trend toward reduction of NPS on a scaled measuring tool in the treatment group even if statistical significance was not reached. In some studies, specific behavioral symptoms, particularly apathy and hallucinations, were reduced.

Conclusions: Evidence suggests that ChE-Is have psychotropic effects and may be of value in managing neuropsychiatric behavioral symptoms in AD. Further studies will be necessary to fully understand the potential of these agents.