Evidence-Based Reviews

Prescriber’s guide to using 3 new antidepressants: Vilazodone, levomilnacipran, vortioxetine

Current Psychiatry. 2015 February;14(2):28-29, 32-26

References

1. Andrade L, Caraveo-Anduaga JJ, Berglund P, et al. The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys. Int J Methods Psychiatr Res. 2003;12(1):3-21.
2. Ferrari AJ, Charlson FJ, Norman RE, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013;10(11):e1001547.
3. Warden D, Rush AJ, Trivedi MH, et al. The STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep. 2007;9(6):449-459.
4. Khan A. Vilazodone, a novel dual-acting serotonergic antidepressant for managing major depression. Expert Opin Investig Drugs. 2009;18(11):1753-1764.
5. Khan A, Sambunaris A, Edwards J, et al. Vilazodone in the treatment of major depressive disorder: efficacy across symptoms and severity of depression. Int Clin Psychopharmacol. 2014;29(2):86-92.
6. Robinson DS, Kajdasz DK, Gallipoli S, et al. A 1-year, open-label study assessing the safety and tolerability of vilazodone in patients with major depressive disorder. J Clin Psychopharmacol. 2011;31(5):643-646.
7. Saraceni MM, Venci JV, Gandhi MA. Levomilnacipran (Fetzima): a new serotonin-norepinephrine reuptake inhibitor for the treatment of major depressive disorder. J Pharm Pract. 2013;27(4):389-395.
8. Deardorff WJ, Grossberg GT. A review of the clinical efficacy, safety and tolerability of the antidepressants vilazodone, levomilnacipran and vortioxetine. Expert Opin Pharmacother. 2014;15(17):2525-2542.
9. Citrome L. Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant—what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2013;67(11):1089-1104.
10. Mørk A, Pehrson A, Brennum LT, et al. Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder. J Pharmacol Exp Ther. 2012;340(3):666-675.
11. Pehrson AL, Leiser SC, Gulinello M, et al. Treatment of cognitive dysfunction in major depressive disorder-a review of the preclinical evidence for efficacy of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and the multimodal-acting antidepressant vortioxetine [published online August 5, 2014]. Eur J Pharmacol. doi: 10.1016/j.ejphar.2014.07.044.
12. Baldwin DS, Hansen T, Florea I. Vortioxetine (Lu AA21004) in the long-term open-label treatment of major depressive disorder. Curr Med Res Opin. 2012;28(10):1717-1724.
13. Katona C, Hansen T, Olsen CK. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol. 2012;27(4):215-523.
14. Raskin J, Wiltse CG, Siegal A, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psychiatry. 2007;164(6): 900-909.
15. Boulenger JP, Loft H, Olsen CK. Efficacy and safety of vortioxetine (Lu AA21004), 15 and 20 mg/day: a randomized, double-blind, placebo-controlled, duloxetine-referenced study in the acute treatment of adult patients with major depressive disorder. Int Clin Psychopharmacol. 2014;29(3):138-149.
16. Mago R, Forero G, Greenberg WM, et al. Safety and tolerability of levomilnacipran ER in major depressive disorder: results from an open-label, 48-week extension study. Clin Drug Investig. 2013;33(10):761-771.
17. Khan A, Sambunaris A, Edwards J, et al. Vilazodone in the treatment of major depressive disorder: efficacy across symptoms and severity of depression. Int Clin Psychopharmacol. 2014;29(2):86-92.
18. Boinpally R, Gad N, Gupta S, et al. Influence of CYP3A4 induction/inhibition on the pharmacokinetics of vilazodone in healthy subjects. Clin Ther. 2014; 36(11):1638-1649.
19. Chen L, Boinpally R, Greenberg WM, et al. Effect of hepatic impairment on the pharmacokinetics of levomilnacipran following a single oral dose of a levomilnacipran extended-release capsule in human participants. Clin Drug Investig. 2014;34(5):351-359.
20. Asnis GM, Bose A, Gommoll CP, et al. Efficacy and safety of levomilnacipran sustained release 40 mg, 80 mg, or 120 mg in major depressive disorder: a phase 3, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2013;74(3):242-248.
21. Hvenegaard MG, Bang-Andersen B, Pedersen H, et al. Identification of the cytochrome P450 and other enzymes involved in the in vitro oxidative metabolism of a novel antidepressant, Lu AA21004. Drug Metab Dispos. 2012; 40(7):1357-1365.
22. Chen G, Lee R, Højer AM, et al. Pharmacokinetic drug interactions involving vortioxetine (Lu AA21004), a multimodal antidepressant. Clin Drug Investig. 2013; 33(10):727-736.
23. Areberg J, Søgaard B, Højer AM. The clinical pharmacokinetics of Lu AA21004 and its major metabolite in healthy young volunteers. Basic Clin Pharmacol Toxicol. 2012;111(3):198-205.
24. Areberg J, Petersen KB, Chen G, et al. Population pharmacokinetic meta-analysis of vortioxetine in healthy individuals. Basic Clin Pharmacol Toxicol. 2014;115(6):552-559.

Suicidal ideation was reported in 11.2% of patients taking vortioxetine, compared with 12.5% of those given placebo15; 24% of patients taking levomilnacipran reported suicidal ideation, compared with 22% of those who took placebo.¹⁶ In a long-term study of 599 patients taking vilazodone, 4 given placebo exhibited suicidal behavior, compared with 2 who took vilazodone.¹⁷

Drug-drug interactions are an important consideration when vilazodone, levomilnacipran, and vortioxetine are prescribed in combination with other medications. See the following discussion.

Vilazodone should be taken with food because it has 72% bioavailability after a meal.¹⁸ The drug is metabolized primarily by cytochrome P (CYP) 3A4 and CYP3A5; it does not affect CYP substrates or, it’s likely, produce significant changes to other medications metabolized by the CYP pathway.

Conversely, the dosage of vilazodone should be reduced to 20 mg/d if it is co- administered with a strong CYP3A4 inhibitor (eg, ketoconazole). The dosage should be increased as much as 2-fold when vilazodone is used concomitantly used with a strong CYP3A4 inducer (eg, carbamazepine) for >14 days. The maximum daily dosage should not exceed 80 mg/d.

Levomilnacipran. Unlike vilazodone and vortioxetine, levomilnacipran is affected by renal function.¹⁹ Concomitant medications, however, including those that influence CYP renal transporters (particularly CYP3A4, which metabolizes levomilnacipran), do not show an impact on the blood level of levomilnacipran.

No dosage adjustment is needed for patients who have mild renal impairment, but the maintenance dosage of levomilnacipran for patients who have moderate or severe renal impairment should not exceed 80 mg/d in 1 dose, and 60 mg/d in 1 dose, respectively.²⁰

Vortioxetine. Seventy percent of a dose of vortioxetine is absorbed independent of food; the drug has a half-life of 66 hours. Vortioxetine is metabolized primarily by the CYP450 enzyme system, including 2D6, and, to a lesser extent, by CYP3A4, CYP3A5, CYP2C9, and CYP2C19.²¹

Vortioxetine has minimal effect on P450 substrates in in vitro studies, which was confirmed in 4 other in vivo studies.^21-23 In studies of hormonal contraception, bupropion, and omeprazole, vortioxetine did not produce significant changes in the blood level of the other medications. The blood level of vortioxetine increased by 128% when taken with the CYP2D6 inhibitor bupropion,²⁴ but the blood level did not markedly change with other inhibitors because the drug utilizes uses several CYP pathways. Use caution, therefore, when adding bupropion to vortioxetine because the combination elevates the risk of nausea, diarrhea, and headache.

With each agent, specific benefit
Vilazodone, levomilnacipran, and vortioxetine each add distinct benefit to the clinician’s toolbox of treatments for major depressive disorder. Although all antidepressants to some extent alleviate anxiety and pain and reverse cognitive decline associated with depression, our experience suggests using vilazodone for anxious depressed patients; levomilnacipran for depressed patients who experience pain; and vortioxetine for depressed patients who suffer cognitive decline and for geriatric patients.

Bottom Line
The FDA has approved 3 antidepressants in the past 4 years: vilazodone, levomilnacipran, and vortioxetine. The hope is that these agents will bolster treatment options for major depression—perhaps especially so, as we have seen, in the anxious depressed (vilazodone), the depressed in pain (levomilnacipran), and the depressed with cognitive decline, or geriatric patients (vortioxetine).

Related Resources
• Kalia R, Mittal M, Preskorn S. Vilazodone for major depressive disorder. Current Psychiatry. 2011;10(4):84-86,88.
• Lincoln J, Wehler C. Vortioxetine for major depressive disorder. Current Psychiatry. 2014;13(2):67-70.
• Macaluso M, Kazanchi H, Malhotra V. Levomilnacipran for the treatment of major depressive disorder. Current Psychiatry. 2013;12(12):50-52,54,55.
• McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-1567.
• Thase ME, Chen D, Edwards J, et al. Efficacy of vilazodone on anxiety symptoms in patients with major depressive disorder. Int Clin Psychopharmacol. 2014;29(6):351-356.

Drug Brand Names
Aripiprazole • Abilify Levomilnacipran • Fetzima
Bupropion • Wellbutrin, Zyban Lubiprostone • Amitiza
Buspirone • BuSpar Milnacipran • Savella
Carbamazepine • Tegretol, Equetro Omeprazole • Prilosec
Desvenlafaxine • Pristiq Tizanidine • Zanaflex
Duloxetine • Cymbalta Venlafaxine • Effexor
Escitalopram • Lexapro Vilazodone • Viibryd
Fluoxetine • Prozac Vortioxetine • Brintellix
Ketoconazole • Nizoral

Prescriber’s guide to using 3 new antidepressants: Vilazodone, levomilnacipran, vortioxetine

References

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