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It has been claimed that the [[serotonin transporter]] (SERT) and 5-HT<sub>3</sub> receptor may be primarily occupied at lower clinical doses of vortioxetine and that the 5-HT<sub>1B</sub>, 5-HT<sub>1A</sub>, and 5-HT<sub>7</sub> receptors may additionally be occupied at higher doses.<ref name="pmid25016186" /> [[Receptor occupancy|Occupancy]] of the [[serotonin transporter]] with vortioxetine in young men was found to be highest in the [[raphe nucleus]] with median occupancies of 25%, 53%, and 98% after 9 days of administration with 2.5, 10, and 60 mg/day vortioxetine.<ref name="pmid29189941" /><ref name="pmid23428337" /> In another study, serotonin transporter occupancy in men was 50%, 65%, and ≥80% for 5, 10, and 20 mg/day vortioxetine.<ref name="pmid29189941" /><ref name="Trintellix FDA label"/>
5mgVortioxetine at 5 mg/day vortioxetine may produce antidepressant effects and 5 mg/day result in SERT occupancy as low as 50%.<ref name="pmid29189941" /><ref name="pmid25016186" /> <ref name="pmid24871704">{{cite journal | vauthors = Fu J, Chen Y | title = The efficacy and safety of 5 mg/d Vortioxetine compared to placebo for major depressive disorder: A meta-analysis | journal = Psychopharmacology (Berl) | volume = 232 | issue = 1 | pages = 7–16 | date = January 2015 | pmid = 24871704 | doi = 10.1007/s00213-014-3633-z | s2cid = 17263858 | url = }}</ref>This is in apparent contrast to SSRIs and SNRIs, which appear to require a minimum of 70 to 80% occupancy for antidepressant efficacy.<ref name="pmid29189941" /><ref name="pmid25016186" /><ref name="pmid22261982">{{cite journal | vauthors = Preskorn SH | title = The use of biomarkers in psychiatric research: how serotonin transporter occupancy explains the dose-response curves of SSRIs | journal = Journal of Psychiatric Practice | volume = 18 | issue = 1 | pages = 38–45 | date = January 2012 | pmid = 22261982 | doi = 10.1097/01.pra.0000410986.61593.46 | s2cid = 30529325 }}</ref> These findings are suggestive that the antidepressant effects of vortioxetine may be mediated by serotonin receptor interactions in addition to serotonin reuptake inhibition.<ref name="pmid29189941" /><ref name="pmid25016186" /> A study found no significant occupancy of the 5-HT<sub>1A</sub> receptor with vortioxetine at 30 mg/day for 9 days, which suggests that at least this specific serotonin receptor may not be involved in the clinical pharmacology of vortioxetine.<ref name="pmid25016186" /><ref name="BundgaardPehrson2015" /><ref name="pmid23428337">{{cite journal | vauthors = Stenkrona P, Halldin C, Lundberg J | title = 5-HTT and 5-HT(1A) receptor occupancy of the novel substance vortioxetine (Lu AA21004). A PET study in control subjects | journal = European Neuropsychopharmacology | volume = 23 | issue = 10 | pages = 1190–8 | date = October 2013 | pmid = 23428337 | doi = 10.1016/j.euroneuro.2013.01.002 | s2cid = 44631551 }}</ref> However, methodological concerns were noted that may limit the interpretability of this result.<ref name="pmid25016186" /><ref name="pmid23428337" /><ref name="BundgaardPehrson2015" /> Occupancy of other serotonin receptors like 5-HT<sub>3</sub> and 5-HT<sub>7</sub> by vortioxetine in humans does not seem to have been studied.<ref name="pmid25562777" /><ref name="pmid25016186" /> In relation to the preceding, the contribution of serotonin receptor interactions to the antidepressant effects of vortioxetine is unknown and remains to be established.<ref name="pmid29189941" /><ref name="Trintellix FDA label"/><ref name="pmid25562777" /><ref name="pmid25907797">{{cite journal | vauthors = Keks NA, Hope J, Culhane C | title = Vortioxetine: A multimodal antidepressant or another selective serotonin reuptake inhibitor? | journal = Australas Psychiatry | volume = 23 | issue = 3 | pages = 210–3 | date = June 2015 | pmid = 25907797 | doi = 10.1177/1039856215581297 | s2cid = 21642202 | url = }}</ref> Uncertainties remain about whether vortioxetine is indeed a clinically multimodal antidepressant or whether it is effectively "[just] another selective serotonin reuptake inhibitor".<ref name="pmid25907797" /><ref name="pmid25562777">{{cite journal | vauthors = Zhang J, Mathis MV, Sellers JW, Kordzakhia G, Jackson AJ, Dow A, Yang P, Fossom L, Zhu H, Patel H, Unger EF, Temple RJ | title = The US Food and Drug Administration's perspective on the new antidepressant vortioxetine | journal = J Clin Psychiatry | volume = 76 | issue = 1 | pages = 8–14 | date = January 2015 | pmid = 25562777 | doi = 10.4088/JCP.14r09164 | url = }}</ref>
Antagonism of the 5-HT<sub>3</sub> receptor has been found to enhance the increase in brain serotonin levels produced by serotonin reuptake inhibition in animal studies.<ref name="pmid25016186" /><ref name="BundgaardPehrson2015" /> Whether or not the 5-HT<sub>3</sub> receptor antagonism of vortioxetine likewise does this in humans or contributes to its clinical antidepressant efficacy is unclear.<ref name="pmid25907797" /><ref name="pmid25562777" /> SSRIs and 5-HT<sub>1A</sub> receptor agonists often produce nausea as a side effect, whereas [[5-HT3 antagonist|5-HT<sub>3</sub> receptor antagonist]]s like [[ondansetron]] are [[antiemetic]]s and have been found to be effective in treating SSRI-induced nausea.<ref name="pmid25016186" /> It was thought that the 5-HT<sub>3</sub> receptor antagonism of vortioxetine would reduce the incidence of nausea relative to SSRIs.<ref name="pmid25016186" /> 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.<ref name="Trintellix FDA label"/><ref name="pmid25562777" />
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