Vortioxetine: a review of efficacy, safety and tolerability with a focus on cognitive symptoms in major depressive disorder

Figures & data

Box 1. Drug summary.

Drug name (generic)	Vortioxetine
Phase (for indication under discussion)	Phase III
Indication (specific to discussion)	Treatment of major depressive disorder
Pharmacology description/mechanism of action	Serotonin transporter inhibition and serotonin receptor modulation (agonist at 5-HT1A; partial agonist at 5-HT1B; antagonist at 5-HT1D, 5-HT3, 5-HT7)
Route of administration	Oral
Chemical structure	1-(2-((2,4-Dimethylphenyl)thio)phenyl)piperazine
Pivotal trial(s)	[19-31,37,38]

Pharmaprojects – copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).

Table 1. Proposed effects and significance of vortioxetine action at various receptors [2,7-10].

Receptor/protein	Affected neurotransmitter(s)	Vortioxetine action	Significance/proposed clinical effect
SERT	5-HT	Inhibition	Improve mood via increased synaptic serotonin levels [7]
5-HT1A	5-HT; glutamate	Agonist	Accelerate vortioxetine action via presynaptic autoreceptor desensitization and postsynaptic activation [7-10] Anxiolytic effects [7]
5-HT1B	5-HT; glutamate	Partial agonist	Improve cognition [2]
5-HT1D	5-HT	Antagonist	Potentiate increase in synaptic serotonin levels [10]
5-HT3	5-HT; glutamate; NE; Ach	Antagonist	Improve cognition [2,7]
5-HT7	5-HT; glutamate	Antagonist	Improve mood [2,7,9] Improve cognition [2]

5-HT: Serotonin; Ach: Acetylcholine; NE: Norepinephrine; SERT: Serotonin transporter.

Table 2. Efficacy of vortioxetine versus placebo in short-term, randomized, double-blind placebo-controlled trials in major depressive disorder.

Study (n*)	Methodology	Population	Primary efficacy measure (related to depression)	Statistical method for primary efficacy analysis	Intervention/comparator (n*)	Mean change from baseline (in primary measure score)
Alvarez et al. [19] (425)	Randomized, 6-week, double-blind, fixed-dose, placebo-controlled, active-referenced multi-country (non-US)	Adults with current MDE MADRS ≥ 30 at baseline	Change from baseline to week 6 in MADRS total score	LOCF, ANCOVA	1. Vortioxetine 5 mg/day (108) 2. Vortioxetine 10 mg/day (100) 3. Venlafaxine 225 mg/day; titrated up from 75 mg/day (112) 4. Placebo (105)	(-20.4)^‡ (-20.2)^‡ (-20.9)^‡ (-14.5)
Katona et al. [20] (446)	Randomized, 8-week, double-blind, fixed-dose, placebo-controlled, active-referenced multi-country (including US)	Elderly adults (age ≥ 65 years) with current MDE MADRS ≥ 26 at baseline	Change from baseline to week 8 in HAMD-24 total score	LOCF, ANCOVA	1. Vortioxetine 5 mg/day (154) 2. Duloxetine 60 mg/day (147) 3. Placebo (145)	(-13.7)^§ (-15.8)^‡ (-10.3)
Baldwin et al. [21] (755)	Randomized, 8-week, double-blind, fixed-dose, placebo-controlled, active-referenced multi-country (non-US)	Adults with current MDE MADRS ≥ 26 at baseline	Change from baseline to week 8 in MADRS total score	LOCF, ANCOVA	1. Vortioxetine 2.5 mg/day (155) 2. Vortioxetine 5 mg/day (155) 3. Vortioxetine 10 mg/day (151) 4. Duloxetine 60 mg/day (149) 5. Placebo (145)	(-16.2) (-16.5) (-16.3) (-16.8) (-14.8)
Mahableshwarkar et al. [22] (597)	Randomized, 8-week, double-blind, fixed-dose, placebo-controlled, active-referenced single country (US)	Adults with current MDE MADRS ≥ 22 at baseline	Change from baseline to week 8 in HAMD-24 total score	LOCF, ANCOVA	1. Vortioxetine 2.5 mg/day (146) 2. Vortioxetine 5 mg/day (153) 3. Duloxetine 60 mg/day (149) 4. Placebo (149)	(-12.04) (-11.08) (-13.47)^¶ (-10.5)
Boulenger et al. [23] (604)	Randomized, 8-week, double-blind, fixed-dose, placebo-controlled, active-referenced multi-country (non-US)	Adults with current MDE MADRS ≥ 26 at baseline CGI-S ≥ 4 at baseline	Change from baseline to week 8 in MADRS total score	MMRM	1. Vortioxetine 15 mg/day (149) 2. Vortioxetine 20 mg/day (151) 3. Duloxetine 60 mg/day (146) 4. Placebo (158)	(-17.2)^‡ (-18.8)^‡ (-21.2)^‡ (-11.7)
Mahableshwarkar et al. [24] (591)	Randomized, 8-week, double-blind, fixed-dose, placebo-controlled, active-referenced single country (US)	Adults with current MDE MADRS ≥ 26 at baseline CGI-S ≥ 4 at baseline	Change from baseline to week 8 in MADRS total score	MMRM	1. Vortioxetine 15 mg/day (145) 2. Vortioxetine 20 mg/day (147) 3. Duloxetine 60 mg/day (146) 4. Placebo (153)	(-14.3) (-15.57)^# (-16.9)** (-12.83)
Henigsberg et al. [25] (503)	Randomized, 8-week, double-blind, fixed-dose, placebo-controlled multi-country (non-US)	Adults with current MDE MADRS ≥ 26 at baseline	Change from baseline to week 8 in HAMD-24 total score	MMRM	1. Vortioxetine 1 mg/day (124) 2. Vortioxetine 5 mg/day (129) 3. Vortioxetine 10 mg/day (122) 4. Placebo (128)	(-14.82)** (-15.42)** (-16.23)** (-11.3)
Jain et al. [26] (578)	Randomized, 6-week, double-blind, fixed-dose, placebo-controlled single country (US)	Adults with current MDE MADRS ≥ 30 at baseline	Change from baseline to week 6 in HAMD-24 total score	LOCF, ANCOVA	1. Vortioxetine 5 mg/day (292) 2. Placebo (286)	(-14.61) (-13.87)

*Based on full analysis set (unless otherwise stated).

^‡p < 0.0001 vs placebo.

^§p = 0.0011 vs placebo.

^¶p = 0.005 vs placebo.

^#p = 0.023.

**p < 0.001 vs placebo.

ANCOVA: Analysis of covariance; CGI-S: Clinical global impression – severity; HAMD-24: Hamilton rating scale for depression (24 items); LOCF: Last observation carried forward; MADRS: Montgomery-Åsberg depression rating scale; MDE: Major depressive episode; MMRM: Mixed model for repeated measures.

Table 3. Cognitive efficacy of vortioxetine versus placebo in short-term, randomized, double-blind placebo-controlled trials in major depressive disorder.

Study (n*)	Methodology	Population	Efficacy measure (related to cognition)	Statistical method for efficacy analysis	Intervention/comparator (n*)	Mean change from baseline (in efficacy measure score)
Katona et al. [20] (446)	Randomized, 8-week, double-blind, fixed-dose, placebo-controlled, active-referenced	Elderly adults (age ≥ 65 years) with current MDE MADRS ≥ 26 at baseline	Predefined exploratory analyses: change from baseline to week 8 in DSST – Number of correct symbols, RAVLT (acquisition), and RAVLT (delayed recall)	LOCF, ANCOVA	1. Vortioxetine 5 mg/day (154) 2. Duloxetine 60 mg/day (147) 3. Placebo (145)	DSST: 2.79^‡; RAVLT (acquisition): 1.14^‡; RAVLT (recall): 0.47^‡ DSST: 0.77; RAVLT (acquisition): 1.41^§; RAVLT (recall): 0.64^§ not reported
McIntyre et al. [37] (591)	Randomized, 8-week, double-blind, fixed-dose, placebo-controlled	Adults with current MDE MADRS ≥ 26 at baseline	Primary efficacy measure: change from baseline to week 8 in composite z-score (weighted sum of z-scores in the DSST and RAVLT)	MMRM	1. Vortioxetine 10 mg/day (193) 2. Vortioxetine 20 mg/day (204) 3. Placebo (194)	0.13^¶ 0.1^¶ (-0.24)
Mahableshwarkar et al. [38] (529)	Randomized, 8-week, double-blind, flexible dose, placebo-controlled, active-referenced	Adults with current MDE MADRS ≥ 26 at baseline DSST < 70 at baseline	Primary efficacy measure: change from baseline to week 8 in DSST – Number of correct symbols	MMRM	1. Vortioxetine 10–20 mg/day (175)** 2. Duloxetine 60 mg/day (187) 3. Placebo (167)	4.60^# 4.06 2.85

*Based on full analysis set.

^‡p < 0.05 vs placebo.

^§p < 0.01 vs placebo.

^¶p < 0.001 vs placebo.

^#p = 0.019 vs placebo.

**All patients randomized to vortioxetine received 10 mg for the first week.

ANCOVA: Analysis of covariance; DSST: Digit symbol substitution test; LOCF: Last observation carried forward; MADRS: Montgomery-Åsberg depression rating scale; MDE: Major depressive episode; MMRM: Mixed model for repeated measures; RAVLT: Rey auditory verbal learning test.

Table 4. Percentage of individuals with common adverse events (incidence of at least 5% in 1 clinical trial).

Adverse event	Placebo	Vortioxetine: short-term trials				Vortioxetine: long-term trials
		5 mg	10 mg	15 mg	20 mg	2.5* – 20 mg
Constipation	1 – 7.3	3 – 6.1	5 – 10.4	6 – 9.3	6	NR
Diarrhea	3.8 – 8.9	1.9 – 9.2	5.3 – 12.9	9.9 – 10.6	7 – 12.6	4.9 – 7.2
Dizziness	2.1 – 9.4	2.5 – 9	2.5 – 8.4	4.6 – 19.7	5.3 – 19.7	2.5 – 19.7
Dry mouth	3.2 – 9.6	2 – 10.5	2 – 15.6	3.3 – 7	6 – 8	NR
Fatigue	2 – 5.7	1.5 – 7.1	1.5 – 6	4	3.3	NR
Gastroenteritis	NR	1.9 – 5.4	1.9 – 5.4	NR	NR	5.4
Headache	7.6 – 24.8	10.2 – 21.3	12.3 – 25	16.6 – 19.7	16 – 19.7	12.3 – 19.7
Hyperhydrosis	0.7 – 3.8	NR	10	3.3	0	NR
Influenza	NR	1.1 – 6.9	1.1 – 6.9	7	7	5 – 6.9
Insomnia	4 – 4.8	1.5 – 7.1	1.5 – 7.1	9.9	9.9	1.5 – 9.9
Nasopharyngitis	4.1 – 8.6	7 – 10.8	2.6 – 10.8	12.7	3.3 – 12.7	9.8 – 12.7
Nausea	4.3 – 10.6	8.8 – 29.6	8.8 – 38	26.5 – 33.8	29.3 – 32	8.8 – 31
Sexual dysfunction – ASEX (male:female)	14:20	16:22	20:23	19:33	29:34	< 2 (overall)
Sinusitis	NR	NR	NR	NR	NR	7
Somnolence	2.1 – 4	2.5 – 5.9	NR	NR	NR	NR
Upper respiratory tract infection	NR	NR	NR	NR	NR	6.4
Vomiting	1 – 3.4	1.9 – 3.8	4.5 – 9	6 – 11.9	5.3 – 6	NR
Weight gain	NR	NR	NR	NR	NR	5.8

Adapted from Pearce and Murphy [40].

*Note that vortioxetine 2.5 mg daily is not an approved dose for major depressive disorder.

ASEX: Arizona sexual experiences scale; NR: Not reported.

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