What is Vilazodone?
Vilazodone is a dual-mechanism antidepressant that combines selective serotonin reuptake inhibitor (SSRI) activity with partial agonist activity at serotonin 5-HT1A receptors, approved by the FDA for the treatment of major depressive disorder in adults. 1
Mechanism of Action
Vilazodone's antidepressant effect is thought to result from enhanced serotonergic activity in the central nervous system through two complementary mechanisms 1:
Selective 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), while showing minimal affinity for norepinephrine (Ki = 56 nM) or 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 acts as a partial agonist at these receptors, though the net contribution of this action to its antidepressant effect remains unknown 1
Classification and Relationship to Other Antidepressants
Vilazodone is classified as a second-generation antidepressant within the SSRI class 2. The American Academy of Child and Adolescent Psychiatry lists vilazodone among SSRIs currently marketed in the United States, which include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone 2. However, vilazodone's dual mechanism distinguishes it from traditional SSRIs that lack 5-HT1A receptor activity 3, 4.
Clinical Efficacy
Vilazodone 40 mg/day demonstrates significant efficacy in treating major depressive disorder across multiple symptom domains and severity levels 5, 6:
In pooled analysis of two 8-week randomized controlled trials, vilazodone showed statistically significant improvement compared to placebo on the Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale as early as week 1, with continued improvement throughout treatment 6
Vilazodone demonstrated significant improvement on all 10 individual MADRS symptom items at end of treatment (P<0.01) 6
Response rates (number needed to treat: 8-9) and remission rates (number needed to treat: 12-17) were significantly greater than placebo 6
A separate 10-week trial confirmed efficacy for both vilazodone 20 mg/day and 40 mg/day compared to placebo, with effect sizes comparable to the active comparator citalopram 40 mg/day 5
Dosing and Administration
Vilazodone must be taken with food to ensure adequate absorption and effectiveness 1:
- Initial dose: 10 mg once daily for 7 days 1
- Titration: Increase to 20 mg once daily for 7 days, then to target dose of 40 mg once daily 1
- Food requirement: Vilazodone bioavailability is 72% with food; without food, AUC and Cmax decrease by approximately 50% and 60%, respectively, which can result in inadequate drug concentrations and reduced effectiveness 1
Pharmacokinetic properties 1:
- Time to peak concentration (Tmax): 4-5 hours
- Terminal half-life: approximately 25 hours
- Steady-state: achieved in about 3 days
- Protein binding: 96-99%
- Metabolism: primarily via CYP3A4, with minor contributions from CYP2C19 and CYP2D6
Safety and Tolerability Profile
The most common adverse events with vilazodone are gastrointestinal symptoms, occurring at rates at least twice that of placebo 7:
- Diarrhea: 28.0% (vilazodone) vs 9.2% (placebo) 7
- Nausea: 23.4% (vilazodone) vs 5.1% (placebo) 7
- Insomnia: 6.0% (vilazodone) vs 2.1% (placebo) 7
- Most adverse events were mild to moderate, with <5% requiring concomitant treatment 7
Discontinuation rates due to adverse events 7:
- 8-week studies: 7.1% (vilazodone) vs 3.2% (placebo)
- 52-week study: 20.7%
Serious warnings and precautions 1:
Suicidal thoughts and behavior: Increased risk in patients age 24 years and younger, particularly during initial treatment months and at dosage changes; requires monitoring for clinical worsening 1
Serotonin syndrome: Can occur with vilazodone alone or in combination with other serotonergic drugs (triptans, tricyclic antidepressants, fentanyl, meperidine, methadone, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John's Wort) or MAOIs 1
Increased bleeding risk: Concomitant use with aspirin, NSAIDs, antiplatelet drugs, warfarin, or other anticoagulants may increase bleeding risk 1
Cardiovascular safety: Vilazodone does not prolong the QTc interval at doses up to 80 mg (twice the recommended dosage) 1
Sexual function: Unlike many SSRIs, vilazodone demonstrated minimal impact on sexual functioning in phase III studies, with improved sexual function scores seen across all treatment groups including placebo 5, 3
Discontinuation
Vilazodone should be tapered gradually rather than stopped abruptly 1:
- From 40 mg daily: taper to 20 mg daily for 4 days, then 10 mg daily for 3 days
- From 20 mg daily: taper to 10 mg daily for 7 days
Contraindications
Vilazodone is contraindicated in patients taking MAOIs or within 14 days of stopping MAOIs, including linezolid or intravenous methylene blue, due to increased risk of serotonin syndrome 1.
Clinical Context
While vilazodone lacks FDA approval specifically for anxiety disorders, it belongs to the SSRI class that has demonstrated efficacy for anxiety in children and adolescents 2. However, its primary indication remains major depressive disorder in adults 1. The drug's relatively high cost and lack of long-term remission data compared to established SSRIs may limit its role as a first-line agent 4.