Abstract
Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine’s effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected vortioxetine’s cognitive effects to those on GABA and glutamate neurotransmission. In this paper, we attempt to bridge this gap by evaluating vortioxetine’s effects in the subchronic PCP (subPCP) model, which induces impaired cognitive function and altered GABA and glutamate neurotransmission. We demonstrate that acute or subchronic vortioxetine treatment attenuated subPCP-induced deficits in attentional set shifting (AST) performance, and that the selective 5-HT3 receptor antagonist ondansetron or the 5-HT reuptake inhibitor escitalopram could mimic this effect. Furthermore, acute vortioxetine treatment reversed subPCP-induced object recognition (OR) deficits in rats, while subchronic vortioxetine reversed subPCP-induced Object Recognition and object placement impairments in mice. Finally, subPCP treatment reduced GABAB receptor expression in a manner that was insensitive to vortioxetine treatment, and subchronic vortioxetine treatment alone, but not in combination with subPCP, significantly increased GABA’s affinity for the GABAA receptor. These data suggest that vortioxetine reverses cognitive impairments in a model associated with altered GABA and glutamate neurotransmission, further supporting the hypothesis that vortioxetine’s GABAergic and glutamatergic effects are relevant for cognitive function.
Highlights
Dysfunction in cognitive domains such as executive function and memory are a common feature of psychiatric illness, including major depressive disorder (MDD; McIntyre et al, 2013)
Post hoc tests revealed a significant increase in trials to reach criteria in the extra-dimensional shift (ED) discrimination stages in the subchronic PCP (subPCP)/vehicle group compared to the vehicle/vehicle group (p < 0.01), indicating a subPCP-induced impairment
Within the ED discrimination (Figure 1A), this impairment was significantly reversed in the subPCP/acute vortioxetine treatment groups at the 1, 3, and 10 mg/kg 1 h s.c. doses, and in the subPCP/acute 64 mg/kg modafinil 30 min p.o. treatment group (p < 0.05 – 0.001)
Summary
Dysfunction in cognitive domains such as executive function and memory are a common feature of psychiatric illness, including major depressive disorder (MDD; McIntyre et al, 2013). Clinical studies have demonstrated that vortioxetine significantly improves memory performance in the Ray Auditory Verbal Learning test (Katona et al, 2012; McIntyre et al, 2014) These results are supported by non-clinical data (i.e., data from studies in animals) suggesting that vortioxetine can improve aspects of executive function (Wallace et al, 2014) and memory (Mork et al, 2013; du Jardin et al, 2014; Jensen et al, 2014; Pehrson et al, 2016a). It appears that vortioxetine is capable of producing modest but significant improvements in some aspects of MDD-related cognitive dysfunction
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