Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice

Abstract

Vortioxetine (Lu AA21004) is an investigational novel antidepressant with multimodal activity that functions as a 5-HT3, 5-HT7 and 5-HT(1D) receptor antagonist, 5-HT(1B) receptor partial agonist, 5-HT(1A) receptor agonist and inhibitor of the 5-HT transporter in vitro. Here we explore its anxiolytic and antidepressant potential in adult mice. Vortioxetine was assessed in BalB/cJ@RJ mice using the open-field and forced-swim tests (acute: p.o. 1 h, repeated: daily p.o. 21 days), and in 129S6/SvEvTac mice using the novelty suppressed feeding paradigm (acute: p.o. 1 h, sustained: daily p.o. 14 or 21 days). Fluoxetine and diazepam were controls. Acute and repeated dosing of vortioxetine produced more pronounced anxiolytic- and antidepressant-like activities than fluoxetine. Vortioxetine significantly increased cell proliferation and cell survival and stimulated maturation of immature granule cells in the subgranular zone of the dentate gyrus of the hippocampus after 21 days of treatment. After 14 days, a high dose of vortioxetine increased dendritic length and the number of dendrite intersections, suggesting that vortioxetine accelerates the maturation of immature neurons. Vortioxetine displays an antidepressant and anxiolytic profile following repeated administration associated with increased neurogenesis at several stages. Vortioxetine effects were observed at low levels of 5-HT transporter occupancy, suggesting an alternative mechanism of action to 5-HT reuptake inhibition.

Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs

“…Similarly, after chronic dosing, vortioxetine activates neuronal plasticity related genes, improves visual spatial memory deficits, and shows antidepressant-like activity in 12 months old mice, whereas fluoxetine has no effects on any of these measures in old mice [76]. Vortioxetine also increases cell proliferation in the hippocampal dentate gyrus faster than fluoxetine (3 days for vortioxetine compared to 10 days for fluoxetine) [77] in rats, and produces a larger degree of dendritic branching than fluoxetine after two weeks of dosing in mice [78].…”

Forkhead box O transcription factors as possible mediators in the development of major depression

“…Preclinical evidence showed that adult hippocampal neurogenesis may contribute to the mechanism of antidepressant drug action and BDNF is probably involved in this effect (Malberg et al, 2000;Guilloux et al, 2013;Sairanen et al, 2005). In fact BDNF has been implicated in regulating adult neurogenesis in the subgranular zone of the DG and is important for the regulation of the basal level of neurogenesis in adult mice (Lee et al, 2002;Waterhouse et al, 2012).…”

“…Administration of antidepressants will produce an increase in the number of new-borne neurons within the hippocampus (Malberg et al, 2000;Guilloux et al, 2013;Sairanen et al, 2005). The observation that current antidepressant drugs promote adult hippocampal neurogenesis provides a much stronger evidence on this link (Mahar et al, 2014;Zunszain et al, 2013).…”

Neuroadaptations of the 5-HT System Induced by Antidepressant Treatments: Old and New Strategies

“…One of the most reproducible findings in antidepressant research is that different classes of antidepressants including TCAs, MAOIs and SSRIs increase hippocampal cell proliferation and neurogenesis [83,139,[144][145][146] after chronic, but not acute, treatment consistent with the time course for their onset of therapeutic action. Similar positive effects have been reported using novel therapeutic strategies.…”

“…Putative fast-acting antidepressants, including 5-HT7 receptor antagonist SB-269970 [53] and 5-HT4 receptor agonists RS67333 and prucalopride [83,85] induced an enhancement of hippocampal neurogenesis in a time course concordant with their onset of action. Very recently, a preclinical study using the multimodal antidepressant vortioxetine showed that a 21-day treatment with this drug was able to increase cell proliferation and survival and to stimulate the maturation of immature granule cells in the SGZ of the DG of the hippocampus [146] while a preliminary study revealed that such DG cell proliferation increase occurred after one day of treatment only [148]. Taken together, these data indicate that up regulation of hippocampal neurogenesis may be a common dominator of the mechanism of action of antidepressants.…”