What is the mechanism of action of Vilazodone (Selective Serotonin Reuptake Inhibitor - SSRI)?

Mechanism of Action of Vilazodone

Vilazodone functions through a dual mechanism combining selective serotonin reuptake inhibition (SSRI activity) with partial agonism at serotonin 5-HT1A receptors, a combination termed a Serotonin Partial Agonist and Reuptake Inhibitor (SPARI). 1

Primary Pharmacodynamic Actions

Serotonin Transporter Inhibition

• Vilazodone binds with high affinity to the serotonin reuptake site (Ki = 0.1 nM) and potently inhibits serotonin reuptake (IC50 = 1.6 nM), blocking reuptake at the synaptic cleft to increase serotonin availability 1
• This selective action shows minimal effect on norepinephrine (Ki = 56 nM) or dopamine (Ki = 37 nM) reuptake sites 1
• The serotonin transporter blockade enhances serotonergic activity throughout the CNS, similar to traditional SSRIs 1, 2

5-HT1A Receptor Partial Agonism

• Vilazodone binds selectively with high affinity to 5-HT1A receptors (IC50 = 2.1 nM) and functions as a partial agonist at these sites 1
• This partial agonist activity at 5-HT1A receptors distinguishes vilazodone from traditional SSRIs and is proposed to accelerate therapeutic onset by reducing the delay caused by somatodendritic 5-HT1A autoreceptor inhibition 3, 4
• The combined mechanism results in serotonin facilitation across the brain's serotonergic pathways through both reuptake inhibition and direct receptor modulation 2

Theoretical Advantages of Dual Mechanism

Faster Onset of Action

• Traditional SSRIs require time for downregulation of inhibitory serotonin autoreceptors before achieving full therapeutic effect 5
• The partial agonist activity at 5-HT1A receptors may bypass this delay by directly stimulating postsynaptic receptors while simultaneously blocking presynaptic autoreceptors, potentially decreasing time to efficacy 3, 4
• Pooled analysis suggests significant symptom reduction may occur after only 1 week of vilazodone therapy 3

Reduced Sexual Side Effects

• The 5-HT1A partial agonism is theorized to minimize sexual dysfunction compared to traditional SSRIs, as studies show incidence of sexual side effects with vilazodone similar to placebo 6
• This contrasts with traditional SSRIs that lack 5-HT1A agonist properties and commonly cause sexual dysfunction 7

Anxiolytic Properties

• The 5-HT1A partial agonist component provides concomitant anxiolytic activity similar to buspirone, making vilazodone potentially effective in patients with major depressive disorder and high levels of anxiety 3, 4

Clinical Pharmacology Considerations

• The net result of vilazodone's dual action on overall serotonergic transmission and its precise contribution to antidepressant efficacy remains incompletely understood 1
• Vilazodone's mechanism differs fundamentally from SSRIs alone, which may improve coexisting anxiety and depression but are unlikely to directly improve visceral pain because they lack norepinephrine reuptake inhibition 7
• The medication requires administration with food, as absorption without food decreases AUC and Cmax by approximately 50% and 60% respectively, potentially resulting in inadequate drug concentrations and reduced effectiveness 1