What drug class does Trintellix (vortioxetine) belong to?

Trintellix Drug Class

Trintellix (vortioxetine) is classified as a multimodal antidepressant with serotonin modulator and stimulator activity, distinct from traditional SSRIs and SNRIs. 1

Primary Classification

Vortioxetine functions through dual mechanisms: it inhibits serotonin reuptake while simultaneously modulating multiple serotonin receptor subtypes, earning it the designation as a "multimodal" or "serotonin modulator and stimulator" antidepressant rather than a simple SSRI. 1, 2

Specific Pharmacologic Actions

The FDA label describes vortioxetine's mechanism as:

• Serotonin transporter (SERT) inhibition with high binding affinity (Ki=1.6 nM), blocking serotonin reuptake similar to SSRIs 1
• 5-HT3 receptor antagonism (Ki=3.7 nM) 1
• 5-HT7 receptor antagonism (Ki=19 nM) 1
• 5-HT1A receptor agonism (Ki=15 nM) 1
• 5-HT1B receptor partial agonism (Ki=33 nM) 1
• 5-HT1D receptor antagonism (Ki=54 nM) 1

Why It's Not Simply an SSRI or SNRI

Vortioxetine lacks significant norepinephrine or dopamine transporter activity (norepinephrine Ki=113 nM; dopamine Ki>1000 nM), distinguishing it from SNRIs. 1 Unlike SSRIs that work solely through indirect receptor activation via increased synaptic serotonin, vortioxetine directly modulates specific serotonin receptor subtypes while also blocking reuptake. 2, 3

Clinical Classification Context

Guideline Recognition

• The Japanese Society of Anxiety and Related Disorders classifies vortioxetine as "other antidepressants" rather than grouping it with SSRIs or SNRIs, acknowledging its distinct mechanism 4
• Clinical guidelines note that vortioxetine's multimodal profile affects not only serotonergic systems but also noradrenergic, histaminergic, cholinergic, GABAergic, and glutamatergic neurotransmission 2, 5

Downstream Effects

The multimodal receptor activity translates to modified neurotransmitter release patterns: vortioxetine increases extracellular concentrations of serotonin, dopamine, and noradrenaline through its combined SERT blockade and receptor modulation. 3 This mechanism modifies both glutamate and GABA release within brain circuits, differentiating its pharmacodynamic profile from traditional antidepressant classes. 5

Practical Implications

The unique classification matters clinically because:

• Vortioxetine demonstrates cognitive enhancement properties not typically seen with SSRIs, improving working memory, episodic memory, and cognitive flexibility 2, 6
• The 5-HT3 antagonism contributes to lower nausea rates compared to SSRIs after initial titration 3
• Sexual dysfunction rates remain low and similar to placebo, unlike typical SSRIs 3, 6
• The drug does not cause significant weight gain or metabolic syndrome 3

Receptor Occupancy Profile

At therapeutic doses, vortioxetine achieves approximately 50% serotonin transporter occupancy at 5 mg/day, 65% at 10 mg/day, and 80% at 20 mg/day in brain regions of interest, measured via PET imaging studies. 1 This occupancy pattern, combined with direct receptor modulation, creates its multimodal antidepressant effect.