Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): enhancing serotonin release by combining serotonin (5HT) transporter inhibition with actions at 5HT receptors (5HT1A, 5HT1B, 5HT1D, 5HT7 receptors)

Abstract

Vortioxetine is an antidepressant that targets multiple pharmacologic modes of action at sites-or nodes-where serotonergic neurons connect to various brain circuits. These multimodal pharmacologic actions of vortioxetine lead to enhanced release of various neurotransmitters, including serotonin, at various nodes within neuronal networks. Take-Home Points' Most known antidepressants, including vortioxetine, inhibit the serotonin (5HT) transporter (SERT) as one of their pharmacologic actions.' Although SERT inhibition enhances 5HT release, that release is blunted at various nodes within neuronal networks when 5HT stimulates 5HT negative feedback receptors.' More robust release of 5HT can be caused by vortioxetine, even at lower degrees of SERT inhibition, when 5HT1B, 5HT1D, and 5HT7 receptors are also fully or partially blocked, and if 5HT1A receptors are also stimulated at nodes within brain circuits where serotonin neurons connect to neural networks.

Tolerability and Efficacy of Vortioxetine Versus SSRIs in Elderly With Major Depression. Study Protocol of the VESPA Study: A Pragmatic, Multicentre, Open-Label, Parallel-Group, Superiority, Randomized Trial

“…Vortioxetine is a novel antidepressant, licensed for the treatment of depression in 2013 by FDA and EMA [18 19]. Vortioxetine is an antagonist to 5-HT3, 5-HT1D and 5-HT7 receptors, a partial agonist to the 5-HT1B receptor and a 5-HT1A receptor agonist [20] [21]. Its mechanism of action is not fully understood yet, but it is likely to be related with both a direct modulation of the serotoninergic receptor activity and an inhibition of the serotonin transporter.…”

Farmakoterapia depresji u pacjentów z zaawansowanymi chorobami

“…One of the most recently registered AD widely modulates neurotransmission in the CNS directly through serotonin receptors, and indirectly through other pathways [77]. It is considered one of the fastest-acting AD with first effects that can be seen after two weeks of therapy [78].…”

“…Najnowszy spośród zarejestrowanych w Polsce leków przeciwdepresyjnych wykazuje szeroko moduluje neuroprzekaźnictwo w OUN bezpośrednio poprzez receptory serotoninowe, a pośrednio poprzez pozostałe szlaki [77]. Jest uznawany za jeden z najszybciej działających AD z pierwszymi efektami, które mogą być widoczne już po 2 tygodniach terapii [78].…”

Zinc in the Monoaminergic Theory of Depression: Its Relationship to Neural Plasticity

“…Drugs that selectively inhibit SERT, namely, SSRIs, have revolutionized clinical psychopharmacology and nowadays are among the first-line medications used for depression [4]. Although the newest drugs, such as the multimodal agent vortioxetine, combine action occurring at different 5-HT receptor subtypes, SERT inhibition remains an important element of their action [49]. The current view on the mechanism of action of SSRIs states that, following acute treatment, the 5-HT level rises in the somatodendritic area located in the raphe nuclei and stimulates the 5-HT 1A autoreceptors.…”

“…This leads to increased 5-HT release from the axon terminals [50]. As well as targeting SERT, vortioxetine targets 5-HT G-protein-coupled (5-HT 1A and 5-HT 1B partial agonism and 5-HT 7 antagonism) and 5-HT ionotropic (5-HT 3 antagonism) receptors [49]. Other medications, such as trazodone, as well as inhibiting SERT, possess 5-HT 2A and 5-HT 2C antagonistic properties [51].…”