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

Vilazodone Mechanism of Action

Vilazodone functions through a dual mechanism combining selective serotonin reuptake inhibition with partial agonism at 5-HT1A receptors, though the complete contribution of each component to its antidepressant effect remains incompletely understood. 1

Primary Pharmacological Actions

Serotonin Reuptake Inhibition

• Vilazodone binds with high affinity to the serotonin reuptake site (Ki = 0.1 nM) and potently inhibits serotonin reuptake (IC50 = 1.6 nM), enhancing serotonergic activity in the CNS. 1
• The drug demonstrates selectivity for serotonin over norepinephrine (Ki = 56 nM) and dopamine (Ki = 37 nM) reuptake sites. 1
• This selective inhibition increases serotonin availability in the synaptic cleft across serotonergic pathways throughout the brain. 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
• The partial agonist activity at 5-HT1A receptors is theorized to provide additional serotonergic modulation beyond simple reuptake inhibition. 3, 4
• The net result of this 5-HT1A partial agonism on serotonergic transmission and its specific role in vilazodone's antidepressant effect are unknown. 1

Theoretical Advantages of Dual Mechanism

Proposed Benefits Over Traditional SSRIs

• The 5-HT1A partial agonism may theoretically decrease time to therapeutic efficacy by bypassing the delayed downregulation of inhibitory 5-HT1A autoreceptors that occurs with traditional SSRIs. 4
• This combined mechanism has been termed a "serotonin partial agonist and reuptake inhibitor" (SPARI) to distinguish it from conventional SSRIs. 2, 5
• The dual action may potentially minimize sexual side effects compared to traditional SSRIs, though the exact mechanism for this benefit remains unclear. 4, 6

Clinical Implications

• Vilazodone's activity is due primarily to the parent drug, with dose-proportional pharmacokinetics from 5 mg to 80 mg. 1
• The terminal half-life is approximately 25 hours, with steady-state achieved in about 3 days. 1
• Administration with food is essential, as fasted-state AUC and Cmax can decrease by approximately 50% and 60% respectively, potentially resulting in inadequate drug concentrations and reduced effectiveness. 1

Important Clinical Caveats

• While vilazodone combines two well-established serotonergic mechanisms, no head-to-head studies against other antidepressants have definitively demonstrated superiority in efficacy or tolerability. 2, 5
• The theoretical advantages of faster onset and reduced sexual dysfunction require further validation in comparative trials. 6
• Gastrointestinal side effects (diarrhea, nausea) remain common, similar to traditional SSRIs and SNRIs. 6