Vilazodone, a new antidepressant introduced in the US, which combines SERT inhibition with a second property: 5HT1A partial agonism.

How is vilazodone different from other SSRIs?
A unique mechanistic approach is that of vilazodone, an agent that combines two mechanisms in a single drug, namely that of the SSRIs with 5HT1A receptor partial agonist actions, or a serotonin partial agonist reuptake inhibitor (SPARI).

1. vilazodone Presenter: Dr. Dikshya Upreti PG Resident Department of Psychiatry NMCTH,Birgunj

2. Classification of antidepressant Cyclic antidepressants Selective serotonin reuptake inhibitors (SSRIs) Serotonin partial agonist/reuptake inhibitors (SPARIs) Norepinephrine–dopamine reuptake inhibitors (NDRIs) Selective norepinephrine reuptake inhibitors(SNRIs) Norepinephrine serotonin reuptake Enhancers (NSREs) Noradrenergic and specific serotonergic antagonists ( NaSSAs ) Serotonin antagonists and reuptake inhibitors(SARIs) Noradrenergic reuptake inhibitors(NARIs) Mono-amine oxidase inhibitors(MAOIs) Melatonin receptor agonist and 5-HT2c antagonist Stahl’s Essential Psychopharmacology, 4 th edition

3. Serotonin partial agonist/reuptake inhibitors (SPARIs) A new antidepressant introduced in the US is vilazodone, which combines SERT inhibition with a second property: 5HT1A partial agonism . The combination of serotonin reuptake inhibition with 5HT1A partial agonism has long been known by clinicians to enhance the antidepressant properties and tolerability of SSRIs/SNRIs in some patients. Although vilazodone is the only approved agent selective for just these two actions. Stahl’s Essential Psychopharmacology, 4 th edition

4. Mechanism of action of serotonin partial agonist/reuptake inhibitors (SPARIs) When a SPARI is administered, about half of serotonin transporters (SERTs) and half of serotonin 1A (5HT1A) receptors are occupied immediately. Blockade of the serotonin transporter (SERT) causes serotonin to increase initially in the somatodendritic area of the serotonin neuron.

5. The consequence of serotonin increasing in the somatodendritic area, is that the somatodendritic 5HT1A autoreceptors desensitize or downregulate. Once the somatodendritic receptors downregulate, there is no longer inhibition of impulse flow in the serotonin (5HT) neuron. Thus, neuronal impulse flow is turned on. The consequence of this is release of 5HT

6. Approved by the FDA for use in the United States to treat major depressive disorder in Adults in 2011. 5HT1A partial agonist actions plus SERT inhibition can also be attained by augmenting SSRIs/SNRIs with the 5HT1A partial agonist buspirone.

7. Vilazodone Buspirone 5HT1A partial agonists occupy more 5HT1A receptors for longer time Weaker 5HT1A partial agonists occupy fewer 5HT1A receptors for a shorter time Vilazodone binds to 5HT1A receptors with higher affinity than 5HT Buspirone and 6-hydroxybuspirone also bind to 5HT1A receptors with lower affinity than 5HT itself Vilazodone is dosed so that about 50% of both SERTS and 5HT1A receptors are occupied. Buspirone augments an SSRI, the buspirone is generally dosed so that about 10–20% of 5HT1A receptors are occupied and the SSRI is dosed so that about 80% of SERTS are blocked. It could account for the apparent lesser incidence of sexual dysfunction. It could account for the apparent more incidence of sexual dysfunction. Stahl’s Essential Psychopharmacology, 4 th edition

8. Pharmacodynamics and pharmacokinetics Onset of action : Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvements through 4 to 6 weeks. Protein binding : ~96% to 99% Metabolism : Extensively hepatic, via CYP3A4 (major pathway) and 2C19 and 2D6 (minor pathways) Bioavailability : 72% (with food); blood concentrations (AUC) may be decreased ~50% in the fasted state Half-life elimination : Terminal: ~25 hours Time to peak serum : 4 to 5 hours Excretion : Urine (1% as unchanged drug) F eces (2% as unchanged drug)

9. Indication Major depressive disorder, unipolar (alternative agent) Oral:   Initial: 10 mg once daily for 7 days, then increase to 20 mg once daily; may increase up to 40 mg once daily after an additional ≥7 days based on response and tolerability (maximum dose: 40 mg/day).

10. Discontinuation of therapy:   The half-life of vilazodone is approximately 24 hours, decreasing the likelihood of withdrawal symptoms compared to drugs with half-lives significantly less than 24 hours

11. Dose adjustment: Dosing: Renal Impairment: Adult: No dosage adjustment necessary. Dosing: Hepatic Impairment: Adult: No dosage adjustment necessary. Dosing: Geriatric Refer to adult dosing. Geriatric patients: High-risk medication: Beers Criteria: Selective Serotonin Reuptake Inhibitors (SSRIs) are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older due to the potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults. American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults.  Journal of the American Geriatrics Society ,  67 (4), 674–694.

12. Drug Interactions Acalabrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet properties. Alcohol Agents with blood glucose lowering effects: selective serotonin reuptake inhibitors may enhance the hypoglycemic effect of agents with blood glucose lowering effects .  Amphetamines Anticoagulants Antiemetics (5HT3 antagonists) Aspirin Buspirone

13. Adverse Reactions >10%: Central nervous system: Headache Gastrointestinal: Diarrhea, nausea 1% to 10%: Cardiovascular: Palpitations Central nervous system: Dizziness , insomnia , drowsiness, fatigue, abnormal dreams, restlessness, paresthesia, delayed ejaculation, migraine, sedation, panic attack, ventricular premature contractions Dermatologic: Hyperhidrosis. night sweats Endocrine & metabolic: Decreased libido, weight gain Gastrointestinal: Xerostomia , abdominal pain, vomiting, dyspepsia, flatulence, increased appetite, abdominal distension, gastroenteritis Genitourinary: Erectile dysfunction, orgasm disturbance Neuromuscular & skeletal: arthralgia , tremor Ophthalmic: Blurred vision, xerophthalmia Hyperhidrosis

14. Contraindications Use of MAO inhibitors (concurrently or within 14 days of discontinuing either vilazodone or the MAO inhibitor), including MAO inhibitors such as linezolid or intravenous methylene blue

15. Warnings/Precautions major psychiatric warnings: Suicidal thinking/behavior: [US Boxed Warning]: I ncreased the risk in pediatric and young adult patients Vilazodone is not approved for use in pediatric patients. Vilazodone is not FDA approved for the treatment of bipolar depression. Seizure disorder: Use with caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage or alcoholism. Discontinuation syndrome

16. Pregnancy and Breast-Feeding Category C Information related to the use of vilazodone in pregnancy is limited  If treatment for major depressive disorder is initiated for the first time during pregnancy, vilazodone is not one of the preferred agents (CANMAT [MacQueen 2016]; Patients treated for major depression and who are euthymic prior to pregnancy are more likely to experience a relapse when medication is discontinued (68%) as compared to pregnant patients who continue taking antidepressant medications (26%) (Cohen 2006). It is not known if vilazodone is present in breast milk. Information related to the postpartum use of vilazodone is limited

17. Reproductive Considerations If treatment for major depressive disorder is initiated for the first time in patients planning to become pregnant, vilazodone is not a preferred antidepressant Vilazodone may be associated with male and female treatment-emergent sexual dysfunction. Decreased libido and abnormal orgasm/anorgasmia have been reported in females; ejaculation disorder, decreased libido, and erectile dysfunction have been reported in males with vilazodone use.

18. Pricing: USKit  (Viibryd Starter Pack Oral) 10 & 20 mg (per each): $12.01 Tablets  (Viibryd Oral) 10 mg (per each): $12.01 20 mg (per each): $12.01 40 mg (per each): $12.01 Product Company Price (Rs.) (Nepalese) Valz 40 mg Tablet 10s Torrent Pharma 219.00 Vilarest 40 mg Tablet 10s CIPLA 230.00 Vilamid 40mg Tablet 10s LUPIN 258.00 Vilano 40mg Tablet 10s Sun Pharma 335.00

19. Sexual side effects sexual dysfunction occurred with sertraline and Escitalopram but not with vilazodone; instead, there was an improvement on the ASEX scale of sexual function. Weight gain there was weight gain in patients who were taking sertraline and Escitalopram, whereas there was no weight gain in the patients who were prescribed vilazodone. Bathla, M., & Anjum, S. (2020). A 12-week prospective randomized controlled comparative trial of vilazodone and sertraline in Indian patients with depression.  Indian journal of pharmacology ,  52 (1), 10–15. Bathla, M., Anjum, S., Singh, M., Panchal, S., & Singh, G. P. (2018). A 12-week Comparative Prospective Open-label Randomized Controlled Study in Depression Patients Treated with Vilazodone and Escitalopram in a Tertiary Care Hospital in North India.  Indian journal of psychological medicine ,  40 (1), 80–85.

20. Categorical improvements in disease severity in patients with major depressive disorder treated with vilazodone Durgam, S., Chen, C., Gommoll , C. P., Edwards, J., & Citrome , L. (2016). Categorical improvements in disease severity in patients with major depressive disorder treated with vilazodone: post hoc analysis of four randomized, placebo-controlled trials. Neuropsychiatric disease and treatment, 12, 3073–3081.

21. S exual function in patient taking Vilazodone Clayton, A. H., Durgam, S., Tang, X., Chen, C., Ruth, A., & Gommoll , C. (2016). Characterizing sexual function in patients with generalized anxiety disorder: a pooled analysis of three vilazodone studies.  Neuropsychiatric disease and treatment ,  12 , 1467–1476.

22. Comparative evaluation of efficacy and tolerability of vilazodone, escitalopram, and amitriptyline  Renuka L. Kadam,et,al , 2020

23. References: American Psychiatric Association (APA). Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. (CANMAT [MacQueen 2016]; (Cohen 2006). Stahl’s Essential Psychopharmacology, 4 th edition Bathla, M., & Anjum, S. (2020). Bathla, M., Anjum, et.al (2018) Durgam, S,et.al (2016) Renuka L. Kadam,et,al , 2020 2019 Updated AGS Beers Criteria Clayton, A. H.,et .al (2016) UpToDate