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  • Vortioxetine is a multimodal antidepressant that acts as

    2024-02-22

    Vortioxetine is a multimodal antidepressant that acts as an inhibitor at the serotonin (5-HT) transporter (SERT), an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors, and an antagonist at 5-HT1D, 5-HT3 and 5-HT7 receptors (Bang-Andersen et al., 2011, Sanchez et al., 2015). Based on human binding affinities, vortioxetine is predicted to preferentially engage SERT and 5-HT3 receptors at the low end of the clinical dose range (5, 10 mg/day) and engage all targets at the high end of the range (20 mg/day) (Sanchez et al., 2015). The outcome of clinical studies indicates that vortioxetine, in addition to its antidepressant efficacy, has beneficial effects on aspects of cognitive dysfunction in MDD patients across the entire dose range of 5–20 mg/day (Katona et al., 2012, McIntyre et al., 2014, Mahableshwarkar et al., 2015). A recent fMRI study undertaken in remitted MDD patients during performance of the N-Back working memory task showed a reduced blood oxygenation level dependent (BOLD) signal in the right dorsolateral prefrontal cortex and the left hippocampus in patients treated with vortioxetine compared to placebo, indicating that vortioxetine’s pharmacological actions may counteract the over activation in these Exendin-4 structures associated with the depressive state (Smith et al., 2017). Preclinical studies in rodents have supported the notion that vortioxetine has positive effects on cognitive function across a range of cognitive domains, e.g. preclinical models of execute function (attentional set shifting, reversal learning), and memory (episodic, visual spatial, and fear memory), but not attention (visual signal detection task) (review by Sanchez et al., 2015, Pehrson et al., 2016a). Importantly, preclinical studies have demonstrated that vortioxetine is mechanistically differentiated from selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) in several of these models. We have previously hypothesized that vortioxetine’s antagonism of 5-HT3 receptors may play an important role in improving cognitive function by indirectly increasing the activity of cortical and hippocampal pyramidal neurons, which are thought to be important key integrators of cognitive processing, via inhibition of a subset of GABAergic interneurons (Pehrson and Sanchez, 2014, Dale et al., 2016, Pehrson et al., 2016a, Pehrson et al., 2016b). Vortioxetine has high (nanomolar range) affinity for 5-HT3A receptors, which are the predominant subtype of 5-HT3 receptors expressed in the brain, and are the only known serotonergic ligand-gated ion channel receptors. Thus, vortioxetine’s functional interaction with 5-HT3A receptors can be addressed via electrophysiology since 5-HT3A receptors are capable of conducting monovalent cations that can be recorded as current. Previously reported preclinical studies of vortioxetine’s effects on neurotransmission support the hypothesis that vortioxetine enhances glutamatergic pyramidal cell signaling in brain regions important for cognitive and emotional processing (medial prefrontal cortex and hippocampus) through a 5-HT3 receptor antagonism-dependent mechanism (Dale et al., 2014). Thus, single unit recordings from pyramidal cells in the prefrontal cortex of anaesthetized rats showed that clinically equivalent vortioxetine doses (corresponding to 5–20 mg/day) increased pyramidal cell firing significantly and that co-administration of a 5-HT3 receptor agonist SR 57227A abolished the effect of vortioxetine (Riga et al., 2016). The SSRI, escitalopram, had no effect on pyramidal cell firing in these assays. In line with the in vivo recordings from cortical pyramidal cells, in vitro recordings from pyramidal cells in the CA1 of rat hippocampus slices showed that vortioxetine reversed 5-HT-induced Inhibitory Post Synaptic Currents (IPSCs) and the effect was ascribed to vortioxetine’s 5-HT3 receptor antagonistic properties (Dale et al., 2014). Vortioxetine has also been shown to enhance other cognition- relevant transmission systems such as the noradrenergic, dopaminergic, cholinergic, and histaminergic, but only at doses that correspond to the high end of the clinically relevant range (Sanchez et al., 2015). These mechanisms are therefore not thought to be the main mediators of vortioxetine’s pro-cognitive effects, at least not in rodents.