Levomilnacipran and vortioxetine: Review of new pharmacotherapies for major depressive disorder

Table 1 Basic drug information for levomilnacipran and vortioxetine[3,20]

	Levomilnacipran	Vortioxetine
Brand names	Fetzima	Brintellix
Mechanism of action	Serotonin-norepinephrine reuptake inhibitor	Serotonin receptor reuptake inhibitor, serotonin-3 receptor antagonist and serotonin-1A receptor agonist
FDA approval date	July 26, 2013	September 30, 2013
Recommended dosing range	40 mg to 120 mg once daily with or without food	10 mg to 20 mg once daily
Dosage form	Extended-release capsules in 20 mg, 40 mg, 80 mg and 120 mg	Immediate release tablets in 5 mg, 10 mg, 15 mg and 20 mg

FDA: Food and Drug Administration.

Table 2 Pharmacokinetic parameters for levomilnacipran and vortioxetine[3,20,21,24]

	Levomilnacipran	Vortioxetine
Bioavailability	92%	75% ± 9%
Tmax	6-8 h	3-16 h
Volume of distribution	387-473 L	2400 L
Metabolism	Oxidation (primarily through CYP3A4), glucuronidation	Oxidation (primarily through CYP2D6), glucuronidation
Elimination	58% urine	50% urine, 26% feces
Clearance	21-29 L/h	38 L/h
Half-life	12 h	57-66 h
Protein binding	22%	98%-99%

CYP: Cytochrome P450; T_max: Time to maximum plasma concentration.

Table 3 Randomized controlled trials of levomilnacipran for major depressive disorder[3,5,7-11]

Ref.	n	Duration	Key inclusion criteria	Doses	Primary outcome
Montgomery et al[7] Phase II	563	10 wk	Age 18-70 yr HAMD-17 > 22	Levomilnacipran 75-100 mg/d Placebo	Positive Change from baseline in MADRS Placebo: -14.5 Levomilnacipran: -18.7 (P < 0.001)
Greenberg[5] Phase III	362	11 wk	Age 18-80 yr Clinician-rated MADRS ≥ 30 Self-rated MADRS ≥ 26	Levomilnacipran 40-120 mg/d Placebo	Negative Change from baseline in MADRS Placebo: -14.2 Levomilnacipran: -15.7 (P = 0.249)
Asnis et al[8] Phase III	724	11 wk	Age 18-65 yr MADRS ≥ 30	Levomilnacipran 40 mg/d Levomilnacipran 80 mg/d Levomilnacipran 120 mg/d Placebo	Positive Change from baseline in MADRS Placebo: -11.6 40 mg: -14.8 (P < 0.05) 80 mg: -15.6 (P < 0.01) 120 mg: -16.5 (P < 0.001)
Bakish et al[9] Phase III	568	10 wk	Age 18-75 yr MADRS ≥ 26	Levomilnacipran 40 mg/d Levomilnacipran 80 mg/d Placebo	Positive Change from baseline in MADRS Placebo: -11.3 40 mg: -14.6 (P < 0.003) 80 mg: -14.4 (P < 0.004)
Sambunaris et al[10] Phase III	442	11 wk	Age 18-80 yr Clinician-rated MADRS ≥ 30 Self-rated MADRS ≥ 26	Levomilnacipran 40-120 mg/d Placebo	Positive Change from baseline in MADRS Placebo: -12.2 Levomilnacipran: -15.3 (P < 0.01)
Shiovitz et al[11] Phase III	734	24 wk	Age 18-65 yr MADRS ≥ 22	Levomilnacipran 40 mg/d Levomilnacipran 80 mg/d Levomilnacipran 120 mg/d Placebo	Failed Percent of patient relapse Placebo: 13.91% Levomilnacipran: 20.54% (P = 0.1651)

HAMD: Hamilton Rating Scale for Depression; MADRS: Montgomery-Asberg Depression Rating Scale.

Table 4 Randomized controlled trials of vortioxetine for major depressive disorder[21-23,27,29,31-36]

Ref.	n	Duration	Key inclusion criteria	Doses	Primary outcome
Alvarez et al[21] Phase II	429	6 wk	Age 18-65 yr MADRS ≥ 30	Vortioxetine 5 mg/d Vortioxetine 10 mg/d Placebo Venlafaxine XR 225 mg/d	Positive Change from baseline in MADRS Placebo: -14.5 5 mg: -20.4 (P < 0.001) 10 mg: -20.2 (P < 0.001) Venlafaxine: -20.9 (P < 0.001)
Baldwin et al[29] Phase III	776	8 wk	Age 18-75 yr MADRS ≥ 26	Vortioxetine 2.5 mg/d Vortioxetine 5 mg/d Vortioxetine 10 mg/d Placebo Duloxetine 60 mg/d	Failed Change from baseline in MADRS Placebo: -14.8 2.5 mg: -16.2 (P = 0.219) 5 mg: -16.5 (P = 0.132) 10 mg: -16.3 (P = 0.185) Duloxetine: -16.8 (P = 0.074)
Jain et al[32] Phase III	600	6 wk	Age 18-75 yr MADRS ≥ 30	Vortioxetine 5 mg/d Placebo	Negative/failed Change from baseline in HAM-D24 Placebo: -13.87 5 mg: -14.61 (P = 0.407)
Mahableshwarkar et al[33] Phase III	611	8 wk	Age 18-75 yr MADRS ≥ 22	Vortioxetine 2.5 mg/d Vortioxetine 5 mg/d Placebo Duloxetine 60 mg/d	Negative Change from baseline in HAM-D24 Placebo: -10.5 2.5 mg: -12.05 (P = 0.138) 5 mg: -11.08 (P = 0.577) Duloxetine: -13.47 (P = 0.005)
Henigsberg[23] Phase III	560	8 wk	Age 18-75 yr MADRS ≥ 26	Vortioxetine 1 mg/d Vortioxetine 5 mg/d Vortioxetine 10 mg/d Placebo	Positive Change from baseline in HAM-D24 Placebo: -11.3 1 mg: -14.82 (P < 0.001) 5 mg: -15.42 (P < 0.001) 10 mg: -16.23 (P < 0.001)
Boulenger et al[31] Phase III	608	8 wk	Age 18-75 yr MADRS ≥ 26	Vortioxetine 15 mg/d Vortioxetine 20 mg/d Placebo Duloxetine 60 mg/d	Positive Change from baseline in MADRS Placebo: -11.7 15 mg: -17.2 (P < 0.0001) 20 mg: -18.8 (P < 0.0001) Duloxetine: -21.2 (P < 0.0001)
NCT01153009[34] Phase III	614	8 wk	Age 18-75 yr MADRS ≥ 26	Vortioxetine 15 mg/d Vortioxetine 20 mg/d Placebo Duloxetine 60 mg/d	Positive Change from baseline in MADRS Placebo: -12.83 15 mg: -14.3 (NS) 20 mg: -15.57 (P < 0.05) Duloxetine: -16.9 (P < 0.001)
NCT01163266[36] Phase III	462	8 wk	Age 18-75 yr MADRS ≥ 26	Vortioxetine 10 mg/d Vortioxetine 20 mg/d Placebo	Positive Change from baseline in MADRS Placebo: -10.8 10 mg: -13.0 (NS) 20 mg: -14.4 (P < 0.01)
NCT01179516[35] Phase III	469	8 wk	Age 18-75 yr MADRS ≥ 26	Vortioxetine 10 mg/d Vortioxetine 15 mg/d Placebo	Negative/failed Change from baseline in MADRS Placebo: -12.87 10 mg: -13.66 (P = 0.597) 15 mg: -13.36 (P = 0.745)
NCT01255787[27] (unpublished) Phase III	600	8 wk	Age 20-64 yr MADRS ≥ 26	Vortioxetine 5 mg/d Vortioxetine 10 mg/d Vortioxetine 20 mg/d Placebo	Negative Change from baseline in MADRS Placebo: -13.99 5 mg: -14.61 (P = 0.907) 10 mg: -15.68 (P = 0.301) 20 mg: -15.82 (P = 0.240)
Boulenger et al[22] Phase III	400	24-64 wk	Age 18-75 yr MADRS ≥ 26	Vortioxetine 5-10 mg/d Placebo	Positive Time to relapse-vortioxetine vs placebo HR = 2.01 (95%CI: 1.26-3.21) (P = 0.0035)

NCT: National clinical trial; MADRS: Montgomery-Asberg Depression Rating Scale; HAM-D₂₄: Hamilton Rating Scale for Depression (24-items).