A drug-induced increase in hippocampal neurogenesis in the
dentate gyrus in the adult brain has been associated with antidepressant
effects (Banasr and Duman, 2007), although its functional impact
on the etiology of depression and the mechanism through which it
may reduce depression remain to be understood (Lucassen et al.,
2010). Vortioxetine administered to rats under steady-state conditions
via an osmotic minipump produced a significant increase in cell proliferation
(measured as the number of 5-bromo-2-deoxeyurine (BrdU)
positive cells) in the dentate gyrus after only 1 day of treatment,whereas
the SSRI fluoxetine, tested under similar conditions, required N7 days
to produce a similar effect (Haddjeri et al., 2012). In mice dosed once
daily, vortioxetine significantly increased markers of cell proliferation
and 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 higher dose of vortioxetine
increased dendritic length and the number of dendrite intersections
compared to vehicle controls, suggesting that vortioxetine accelerates
the maturation of immature neurons (Guilloux et al., 2013). In the
same study, fluoxetine administered once daily for 21 days significantly
increased cell survival and stimulated maturation of immature granule
cells, whereas fluoxetine administered for 14 days had no effect on
dendritic length or number of dendritic intersections compared to
vehicle controls.
In summary, vortioxetine differs from the SSRIs fluoxetine and
escitalopram in promoting several measures of synaptic transmission
and neuroplasticity. Vortioxetine significantly enhances excitatory
synaptic transmission (measured as LTP and pyramidal neuron
stimulation), and increases neuroplasticity (measured as increased
cell proliferation andmaturation) and dendritic branching to a larger
degree than an SSRI. Thus, via its receptor activities, vortioxetine
enhanced glutamatergic neurotransmission in key brain areas
implicated in depression and cognitive function in rodents.