A Systematic Review on Drugs Acting as Nicotinic Acetylcholine Receptor Agonists in the Treatment of Dementia

Abstract

Acetylcholine signaling is attenuated in early Alzheimer's disease (AD) and other dementias. A significant reduction in the expression of nicotinic acetylcholine receptors (nAChRs) in the brain of AD patients has also been reported in several molecular biological and in situ labeling studies. The modulation of the functional deficit of the cholinergic system as a pharmacological target could therefore have a clinical benefit, which is not to be neglected. This systematic review was conducted to identify clinical trials, which evaluated the safety and efficacy of nicotinic acetylcholine receptor agonists using Clinicaltrial (CT) and EudraCT databases. Structured searches identified 39 trials, which used 15 different drugs designed to increase the function of the nAChRs. Most of the identified clinical trials were phase II trials, with some of them classified as ongoing for several years. The systematic screening of the literature led to the selection of 14 studies out of the 8261 bibliographic records retrieved. Six trials reported detailed data on adverse events associated with the intervention, while twelve trials reported data on efficacy measures, such as attention, behavior and cognition. Overall, smost of the physical side effects of cholinergic agonists were reported to be well tolerated. Some trials also reported improvements in attention. However, the efficacy of these drugs in other cognitive and behavioral outcomes remains highly controversial.

Keywords: Alzheimer’s disease; clinical trials; dementia; disease-modifying therapies; neurodegenerative disease; nicotinic acetylcholine receptor; nicotinic agonists.

Figure 1

Modified PRISMA flow diagram for clinical trial selection.

Figure 2

Risk of bias in the clinical trial studies included (n = 13). Summary of scores for each domain for each included study. The symbols “+ “, “-” and “?” indicate low, high and unclear risk of bias, respectively. References: Lenz, 2015 [42]; Florian, 2016 [43]; Gault, 2015 [45]; Gault, 2016 [46]; Potter, 1999 [39], Frolich, 2010 [47], Lynn Wilson, 1995 [48]; Newhouse, 1990 [35]; Snaedal, 1996 [36]; Sahakian, 1994 [37]; White, 1998 [38]; Kim, 2014 [41].