How does Vibryd (vilazodone) work?

How Vibryd (Vilazodone) Works

Vibryd works through a dual mechanism: it blocks serotonin reuptake at the presynaptic transporter while simultaneously acting as a partial agonist at 5-HT1A receptors, creating a combined effect that enhances serotonergic neurotransmission in the central nervous system. 1

Primary Mechanism of Action

Selective Serotonin Reuptake Inhibition:

• Vilazodone binds with extremely high affinity to the serotonin reuptake site (Ki = 0.1 nM), potently blocking the presynaptic reuptake of serotonin with an IC50 of 1.6 nM 1
• This blockade increases serotonin availability at the synaptic cleft, similar to traditional SSRIs 2
• The drug shows selectivity for serotonin over norepinephrine (Ki = 56 nM) and dopamine (Ki = 37 nM) reuptake sites 1

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 dual action distinguishes vilazodone from traditional SSRIs, which only block serotonin reuptake 3, 4
• The 5-HT1A partial agonist activity may theoretically lead to a more rapid rise in synaptic serotonin concentrations compared to SSRIs alone 5

Theoretical Advantages of Dual Mechanism

The combination of SSRI and 5-HT1A agonist properties is thought to potentially offer benefits over traditional SSRIs:

• The 5-HT1A agonism may accelerate the antidepressant response by immediately enhancing serotonergic transmission while the SSRI component works to downregulate inhibitory autoreceptors 6
• This differs from SSRIs alone, which require time for autoreceptor downregulation before achieving maximal serotonergic enhancement 2

Clinical Implications of Mechanism

Important Caveats:

• Despite the dual mechanism, the exact contribution of 5-HT1A partial agonism to vilazodone's antidepressant effect remains unknown 1
• The net result of this combined action on overall serotonergic transmission has not been fully elucidated 1
• Clinical trials have not definitively demonstrated that vilazodone produces faster onset of action or superior efficacy compared to traditional SSRIs 3, 4

Serotonin Syndrome Risk:

• The dual mechanism may increase the risk of serotonin syndrome, particularly in overdose situations or when combined with other serotonergic agents 5
• Single-substance vilazodone ingestions have caused serotonin syndrome in both adults and children, unlike typical SSRIs 5

Pharmacodynamic Properties

• Vilazodone reaches peak concentrations 4-5 hours after administration with a terminal half-life of approximately 25 hours 1
• Steady-state is achieved in approximately 3 days with daily dosing 1
• The drug must be taken with food to achieve adequate bioavailability (72% with food vs. 50% reduction in AUC when fasted) 1