Pharmacology and clinical potential of vortioxetine in the treatment of major depressive disorder

Figures & data

Table 1 Vortioxetine double-blind randomized trials in patients with major depressive disorder

Country and authors	Patient setting	Design double-blind; Number of centers	Primary efficacy outcome; Rater training	Duration (weeks)	Active comparator	Placebo	Dosage	Number of patients	Females, %	P-value (vortioxetine versus placebo)	P-value (active comparator versus placebo
11 countries Alvarez et al^Citation24	Outpatients	Yes 49	MADRS Yes	6	Venlafaxine 225 mg	Yes	5 mg 10 mg (fixed dose)	429	62.7	P<0.0001	P<0.0001
20 countries Baldwin et al^Citation17	Inpatients	Yes	MADRS Yes	8	Duloxetine 60 mg	Yes	2.5 mg 5 mg 10 mg	766	78	NS	NS
US Mahableshwarkar et al^Citation18	Outpatients 18–75 years old	Yes 47	HAMD-24 No	8	Duloxetine 60 mg	Yes	2.5 mg 5 mg (fixed dose)	611	63.52	NS	P<0.005
US Jain et al^Citation16 (Primary care, psychiatrist, private practice, academic centers, etc)	Outpatients	Yes 47	HAMD-24 No	6	No	Yes	5 mg	600	58.3	NS	–
14 countries Henigsberg et al^Citation25	Outpatients 18–75 years old	Yes Not specified (14 countries)	HAMD-24 Yes	8	No	Yes	1 mg 5 mg 10 mg (fixed dose)	560	62.5	P<0.001 (dose 10 mg)	–
7 countries Katona et al^Citation26	Elderly (mean age 70.5 years)	Yes 81	MADRS HAMD-24 HAMA CGI MMSE DSST RAVLT	8	Duloxetine 60 mg	Yes	5 mg	452	65.7	P=0.0011	P=0.0001
13 countries Boulenger et al^Citation27	In and outpatients 18–75 years old	Yes 72	MADRS-24 CGI HAMA SDS	8	Duloxetine	Yes	15 mg 20 mg	608	65.87	P<0.0001 (doses 15 and 20 mg)	P<0.0001
14 countries (EUR) Häggström et al^Citation20	In and outpatients Non or partial response to 6 weeks SSRI/SRNI 18–75 years old	Yes 71	MADRS-24 CGI HAMA SDS	12	Agomelatine 25 mg 50 mg	No	10 mg 20 mg	495	74.7	VOR >AGO Remission rate: 55.2% vs 38.4% P<0.001
US Jacobsen et al^Citation21	Not specified 18–75	Yes 37	MADRS HAMA SDS	8	No	Yes	10 mg 20 mg (first week 10 mg)	462 (screened from 792)	72.5	20 mg P=0.002	–
US Mahableshwarkar et al^Citation22	Not specified 18–75	Yes 65	MADRS HAMA CGI	8	No	Yes	10 mg 15 mg	469 (screened from 1,111)	70.2	NS	–
US Mahableshwarkar et al^Citation23	Not specified 18–75	Yes 58	MADRS HAMA CGI SDS	8	Duloxetine 60 mg	Yes	15 mg 20 mg	614 (screened from 1,141)	73.7	20 mg P=0.023	P<0.001
12 countries McIntyre et al^Citation19	Not specified 18–65	Yes	MADRS DSST RAVLT	8	No	Yes	10 mg 20 mg	602	66.26	P<0.001

Note: The main variable in each study is underlined in the table.

Abbreviations: AGO, agomelatine; CGI, Clinical Global Impression; DSST, Digit Symbol Substitution Test; EUR, Europe; HAMA, Hamilton Rating Scale for Anxiety; HAMD, Hamilton Rating Scale for Depression (24 or 17 MADRS, Montgomery–Åsberg Depression Rating Scale; MMSE, Mini–Mental State Examination; NS, not significant; RAVLT, Rey Auditory Verbal Learning Test; SDS, Sheehan Disability Scale; SNRI, serotonin–norepinephrine reuptake inhibitors; SSRI, selective serotonin reuptake inhibitors; VOR, vortioxetine.

Table 2 Tolerability and adverse effects. Vortioxetine clinical trials

Country and authors	ECG	Vital signs	Laboratory test	Sexual dysfunction	Suicide behavior	>5% reported	Severe AEs	Other relevant data
11 countries Alvarez et al^Citation24	Not relevant	Not relevant	No difference versus [vs] placebo	PLC: 1.9% VOR 5 mg: 1.9% VOR 10 mg: 1% VLFX: 12.4%	Item 10 MADRS: decrease in active treatment groups vs placebo from week 2 No suicidal behavior	PLC: 61% VOR 5 mg: 67.6% VOR 10 mg: 74.0% VLFX: 75.2	PLC: 4.6% VOR 5 mg: 6% VOR 10 mg: 6% VLFX: 12%	Rater training was undertaken to increase inter-rater reliability
20 countries Baldwin et al^Citation17	No difference vs placebo	No difference vs placebo	No difference vs placebo	PLC: 0 VOR 2.5 mg: 2% VOR 5 mg: 4% VOR 10 mg: 4% DLX: 14% (vs PLC, P<0.01)	One patient in every VOR group had potentially suicidal behavior These events were considered not related to VOR by the treating investigators	PLC: 62.2% VOR 2.5 mg: 59.4% VOR 5 mg: 63.7% VOR 10 mg: 65.6% DLX: 71.0%	No difference between groups. No more than one patient in every group
US Mahableshwarkar et al^Citation18	No difference vs placebo	No difference vs placebo	No difference vs placebo	ASEX No significant differences vs placebo (more cases in VOR 2.5 mg and DLX vs PLC)	C-SSRS No difference between groups (PLC, 2, 3, 5, and DLX)	PLC: 63.6% VOR 2.5 mg: 64.4% VOR 5 mg: 70.6% DLX: 85.3%	PLC: 9.3% VOR 2.5 mg: 6.0% VOR 5 mg: 7.2% DLX: 10.7%
US Jain et al^Citation16 (Primary care, psychiatrist, private practice, academic centers, etc)	No difference vs placebo	No difference vs placebo	No difference vs placebo	PLC: 0.3% VOR: 1.3%	C-SSRS No difference vs placebo	PLC: 64.4% VOR: 69.9% Not significant	PLC: 1.3% VOR: 2.3%	Fewer screening failures and slower patient enrollment resulted in less difference vs placebo in participating centers
14 countries Henigsberg et al^Citation25	No difference vs placebo	No difference vs placebo	No difference vs placebo	No reports in PLC, 1 and 5 mg of VOR One decreased libido in 10 mg group	C-SSRS No difference vs placebo	PLC: 42.9% VOR 1 mg: 39.3% VOR 5 mg: 56.4% VOR 10 mg: 41.7%	No differences between groups (1.1% of sample)
7 countries Katona et al^Citation26	No difference vs placebo	No difference vs placebo	No difference vs placebo	PLC: 0 VOR 5 mg: 0 DLX: 6%	C-SSRS No difference vs placebo	PLC: 61% VOR 5 mg: 62% DLX: 78%	PLC: 4.4% VOR 5 mg: 0.93% DLX: 1%	Cognitive function assessed. Significant differences vs PLC
13 countries Boulenger et al^Citation27	No difference vs placebo	No difference vs placebo	No difference vs placebo	Not assessed	Suicide ideation PLC: 11.5% VOR 15 mg: 9.9% VOR 20 mg: 9.3% DLX: 6.1%	PLC: 50.6% VOR 15 mg: 57.0% VOR 20 mg: 66.2% DLX: 65.3%	Unspecified
14 countries (EUR) Häggström et al^Citation20	No differences between groups	No differences between groups	No differences between groups	Not assessed	Not assessed	VOR 10 and 20 mg: 54.2% AGO 25 and 50 mg: 52.5%	VOR: 1% AGO: 1.45%	Patients partially resistant to SSRI/SNRI
US Jacobsen et al^Citation21	No difference vs placebo	No difference vs placebo	No difference vs placebo	PLC: 26% VOR 10 mg: 46.9% VOR 20 mg: 41.7%	C-SSRS No differences in PLC vs 20 mg One suicide attempt in 10 mg group	PLC: 62.4% VOR 10 mg: 73.5% VOR 20 mg: 68.7%	No severe AEs 3.7 dropouts due to AEs
US Mahableshwarkar et al^Citation22	Not relevant	Not relevant	Not relevant	ASEX No significant differences vs placebo (10 and 15 mg)	C-SSRS Suicide ideation: PLC 3 and VOR 2 No suicide attempts	PLC: 71.3% VOR 10 mg: 77.3% VOR 15 mg: 78.1%	PLC: 5.6% VOR 10 mg: 7.8% VOR 15 mg: 7.9%	469 patients included from 1,111 screened. Evaluated by video conferencing
US Mahableshwarkar et al^Citation23	No difference vs placebo	No difference vs placebo	No difference vs placebo	ASEX No significant differences vs placebo in 15 and 20 mg VOR (36%) DLX group 53%	C-SSRS No differences in VOR groups vs PLC One subject in 15 and 20 mg group had suicidal ideation No suicide attempts	PLC: 70.4% VOR 15 mg: 73.5% VOR 20 mg: 81.2% DLX: 81.3%	Only the two subjects with suicidal ideation were considered as serious AEs	Randomization was stratified by baseline sexual function status according to ASEX

Abbreviations: AEs, adverse events; AGO, agomelatine; ASEX, Arizona Sexual Experience Scale; C-SSRS, Columbia Suicide Severity Rating Scale; DLX, duloxetine; ECG, electrocardiography; EUR, MADRS, Montgomery–Åsberg Depression Rating Scale; PLC, placebo; SNRI, serotonin–norepinephrine reuptake inhibitors; SSRI, selective serotonin reuptake inhibitors; VLFX, venlafaxine; VOR, vortioxetine.

Table 3 Withdrawal due to AEs in VOR double-blind, randomized trials in patients with major depressive disorder

Country and authors	Placebo	1–2.5 mg/day of VOR	5 mg/day of VOR	10–15 mg/day of VOR	20 mg/day of VOR	60 mg/day of DLX	225 mg/day of VLFX	25–50 mg/day of AGO
11 countries Alvarez et al^Citation24	3.8		2.7	7			14.2
20 countries Baldwin et al^Citation17	8	6	11	9		12
US Mahableshwarkar et al^Citation18	4.57	4.57	7.84			11.18
US Jain et al^Citation16 (Primary care, psychiatrist, private practice, academic centers, etc)	3.66		3
14 countries Henigsberg et al^Citation25	1.42	2.14	0.71	3.57
7 countries Katona et al^Citation26	4.13		6.41			9.93
13 countries Boulenger et al^Citation27	3.75			6.71	11.2	4.79
14 countries (EUR) Häggström et al^Citation20					5.9			9.5
US Jacobsen et al^Citation21	1.27			5.81	4.66
US Mahableshwarkar et al^Citation22	3.75			5.09/7.89
US Mahableshwarkar et al^Citation23	2.48			9.52	9	6.57
12 countries McIntyre et al^Citation19	4.1			3.6	5.3

Abbreviations: AEs, adverse effects; AGO, agomelatine; DLX, duloxetine; EUR, Europe; VLFX, venlafaxine; VOR, vortioxetine.

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