Nicotine and networks: Potential for enhancement of mood and cognition in late-life depression

Abstract

Late-life depression is characterized by both lower mood and poor cognitive performance, symptoms that often do not fully respond to current antidepressant medications. Nicotinic acetylcholine receptor (nAChR) agonists such as nicotine may serve as a novel therapeutic approach for this population. Both preclinical and preliminary clinical studies suggest that nAChR agonists can improve depressive behavior in animal models and improve mood in depressed individuals. Substantial literature also supports that nAChR agonists benefit cognitive performance, particularly in older populations. These potential benefits may be mediated by the effects of nAChR stimulation on neural network function and connectivity. Functional neuroimaging studies detail effects of nAChR agonists on the default mode network, central-executive network, and salience network that may oppose or reverse network changes seen in depression. We propose that, given the existent literature and the clinical presentation of late-life depression, nicotine or other nAChR agonists may have unique therapeutic benefits in this population and that clinical trials examining nicotine effects on mood, cognition, and network dynamics in late-life depression are justified.

Keywords: Acetylcholine; Aging; Antidepressant; Attention; Cognition; Cognitive control; Cognitive impairment; Default mode network; Depression; Depressive disorder; Executive control; Experimental therapeutics; Geriatrics; Intrinsic network; Memory; Nicotine; Nicotinic receptor; Review.

Published by Elsevier Ltd.

Figures

FIGURE 1

Variability in effects of nicotine on cognitive performance Nicotine’s effect on cognitive performance can be modeled as an inverted “U” shape dose-response relationship for each cognitive task. This figure illustrates two situations in which an equivalent degree of nAChR stimulation by extrinsic nicotine administration produces opposite effects depending on both the subject’s underlying nAChR activity and the level of cognitive effort required by the task itself. (1a) Illustrates an example of a Non-smoker who has healthy relatively high baseline nAChR activity and has improvement in cognitively difficult tasks, but worsening on easier tasks. (1b) Illustrates a different scenario of a smoker or individual with neuropsychiatric pathology that has relatively lower baseline nAChR activity and has improvement both in cognitively difficult and less difficult tasks. Figure adapted from Newhouse and colleagues (Newhouse et al., 2004).

FIGURE 2

Model of nicotinic acetylcholine receptor agonist effects on intrinsic network activity, cognition, and depressive behaviors The figure details how nAChR agonists appear to influence key intrinsic networks. In turn, it then builds on how such network effects may influence cognitive performance, core depressive behaviors (negativity bias, rumination), and the ability to modulate mood. In turn, these changes would be expected to result in overall reduced depression severity. Notably but not shown in the figure, it is also possible that improvement in cognition may reduce depressive symptoms or improve mood regulation abilities.