The risk of serotonin syndrome may also be increased when vortioxetine is combined with other serotonergic drugs, like SSRIs, SNRIs, tricyclic antidepressants (TCAs), triptans, tramadol, tryptophan, buspirone, St Johns wort, fentanyl, and lithium, among others. However, vortioxetine is not considered to be contraindicated with serotonergic medications besides MAOIs. Pharmacology
Pharmacodynamics
Vortioxetine increases serotonin concentrations in the brain by inhibiting its reuptake in the synapse, and also modulates (activates or blocks) certain serotonin receptors. This puts it in the class of serotonin modulators and stimulators, which also includes vilazodone. More specifically, vortioxetine is a serotonin reuptake inhibitor, agonist of the serotonin 5-HT1A receptor, partial agonist of the 5-HT1B receptor, and antagonist of the serotonin 5-HT1D, 5-HT3, and 5-HT7 receptors, as well as an apparent ligand of the β1-adrenergic receptor. In terms of functional activity however, vortioxetine appears to be much more potent on serotonin reuptake inhibition and 5-HT3 receptor antagonism than for its interactions with the other serotonin receptors. Whereas vortioxetine has IC50 or EC50 values of 5.4 nM for the SERT and 12 nM for the 5-HT3 receptor, its values are 120 to 450 nM for the 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT7 receptors. This translates to about 22- to 83-fold selectivity for SERT inhibition and 10- to 38-fold selectivity for 5-HT3 antagonism over activities at the other serotonin receptors.It has been claimed that the serotonin transporter (SERT) and 5-HT3 receptor may be primarily occupied at lower clinical doses of vortioxetine and that the 5-HT1B, 5-HT1A, and 5-HT7 receptors may additionally be occupied at higher doses.
Uncertainties remain about whether vortioxetine is indeed a clinically multimodal antidepressant or whether it is effectively "[just] another selective serotonin reuptake inhibitor".Antagonism of the 5-HT3 receptor has been found to enhance the increase in brain serotonin levels produced by serotonin reuptake inhibition in animal studies. Whether or not the 5-HT3 receptor antagonism of vortioxetine likewise does this in humans or contributes to its clinical antidepressant efficacy is unclear. SSRIs and 5-HT1A receptor agonists often produce nausea as a side effect, whereas 5-HT3 receptor antagonists like ondansetron are antiemetics and have been found to be effective in treating SSRI-induced nausea. It was thought that the 5-HT3 receptor antagonism of vortioxetine would reduce the incidence of nausea relative to SSRIs. However, clinical trials found significant and dose-dependent rates of nausea with vortioxetine that appeared to be comparable to those found with the SNRI duloxetine. Pharmacokinetics
Vortioxetine is well-absorbed when taken orally and has an oral bioavailability of 75%. It is systemically detectable after a single oral dose by 0.781 hours. Peak levels of vortioxetine are reached within 7 to 11 hours post-dose with single or multiple doses. Steady-state levels of vortioxetine are generally reached within 2 weeks of administration, with 90% of individuals reaching 90% of steady state after 12 days of administration. Steady-state peak levels of vortioxetine with doses of 5, 10, and 20 mg/day were 9, 18, and 33 ng/mL, respectively. The accumulation index of vortioxetine (area-under-the-curve levels after a single dose versus at steady state) is 5 to 6.