“Selective serotonin (5-HT, SERT) reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression. However, they have delayed efficacy and can induce side-effects that can encourage discontinuation. Recently, agents have been developed, including vortioxetine (Trintellix), that augment SERT blockade with interactions at other targets. At therapeutic doses, vortioxetine interacts with SERT as well as 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors. (The authors) assessed the SERT-dependency of vortioxetine action using the SERT Met172 mouse model, which disrupts high-affinity interactions of many antidepressants with the transporter, (and) demonstrate that the SERT Met172 substitution induces a ∼19-fold loss in vortioxetine potency for SERT inhibition in midbrain synaptosomes. …… Despite reduced interactions with SERT, vortioxetine maintained its ability to enhance mobility in tail suspension and forced swim tests, reduce consumption latency in the novelty induced hypophagia test, and promoted proliferation and survival of subgranular zone hippocampal stem cells. (The) findings suggest that the antidepressant actions of vortioxetine may be SERT-independent, and encourage consideration of agents that mimic one or more actions of the drug in the development of improved depression treatments.”
Nackenoff AG, Simmler LD, Baganz NL, Pehrson AL, Sánchez C, Blakely RD: Serotonin Transporter-Independent Actions of the Antidepressant Vortioxetine As Revealed Using the SERT Met172 Mouse. ACS Chem Neurosci. doi: 10.1021/acschemneuro.7b00038. [March 20, 2017, Epub ahead of print].