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ABSTRACT
Background: This 8-week, randomized, double-blind,
placebo-controlled study, conducted August 2010May
2012 in the United States, evaluated the safety and
efficacy of vortioxetine 10 mg and 15 mg in patients with
major depressive disorder (MDD). The mechanism of
action of vortioxetine is thought to be related to direct
modulation of serotonin (5-HT) receptor activity and
inhibition of the serotonin transporter.
Method: Adults aged 1875 years with MDD (DSM-IVTR) and Montgomery-Asberg Depression Rating Scale
(MADRS) total score 26 were randomized (1:1:1) to
receive vortioxetine 10 mg or 15 mg or placebo once
daily, with the primary efficacy end point being change
from baseline at week 8 in MADRS analyzed by mixed
model for repeated measures. Adverse events were
recorded during the study, suicidal ideation and behavior
were assessed using the Columbia-Suicide Severity Rating
Scale (C-SSRS), and sexual dysfunction was assessed using
the Arizona Sexual Experience (ASEX) scale.
Results: Of the 1,111 subjects screened, 469 subjects were
randomized: 160 to placebo, 157 to vortioxetine 10 mg,
and 152 to vortioxetine 15 mg. Differences from placebo
in the primary efficacy end point were not statistically
significant for vortioxetine 10 mg or vortioxetine 15 mg.
Nausea, headache, dry mouth, constipation, diarrhea,
vomiting, dizziness, and flatulence were reported in 5%
of subjects receiving vortioxetine. Discontinuation due
to adverse events occurred in 7 subjects (4.4%) in the
placebo group, 8 (5.2%) in the vortioxetine 10 mg group,
and 12 (7.9%) in the vortioxetine 15 mg group. ASEX total
scores were similar across groups. There were no clinically
significant trends within or between treatment groups on
the C-SSRS, laboratory values, electrocardiogram, or vital
sign parameters.
Conclusions: In this study, vortioxetine did not differ
significantly from placebo on MADRS total score after 8
weeks of treatment in MDD subjects.
Trial Registration: ClinicalTrials.gov identifier:
NCT01179516
J Clin Psychiatry 2015;76(5):583591
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Mahableshwarkar et al
Clinical Points
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Figure 1. Disposition of Subjects
Enrollment
Screened (N = 1,111)
Randomized (N = 469)
Allocation
Placebo (n = 160)
Vortioxetine 10 mg (n = 157)
Vortioxetine 15 mg (n = 152)
Follow-up
Prematurely discontinued (n = 27)
Adverse event (n = 6)
Lack of efficacy (n = 4)
Noncompliance (n = 2)
Protocol deviation (n = 4)
Withdrawal of consent (n = 2)
Lost to follow-up (n = 7)
Other (n = 2)
Adverse event (n = 8)
Lack of efficacy (n = 2)
Noncompliance (n = 0)
Protocol deviation (n = 3)
Withdrawal of consent (n = 6)
Lost to follow-up (n = 7)
Other (n = 0)
Analysis
Safety seta (n = 160)
aAll
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Table 2. Primary and Secondary End Points
Variable
n=149
22.1
.670
n=143
26.6
4.5
.352
n=74
10.30
0.921.250
.464
.451
n=142
23.9
1.8
.694
n=62
8.69
0.691.322
.600
n=77
SDS total score change at week 8, LS mean
9.38
Difference from placebo, LS meanSE
P value
aPrimary efficacy analysis.
bThe testing strategy stopped at this step for all subsequent endpoints with this dose.
cLogistic regression analyses for response and remission (last observation carried forward);
values are percentage differences from placebo.
Abbreviations: CGI-S=Clinical Global Impressions-Severity of Illness Scale, HARS=Hamilton
Anxiety Rating Scale, LS=least squares, MADRS=Montgomery-Asberg Depression Rating
Scale, SDS=Sheehan Disability Scale, SE=standard error.
Placebo
Vortioxetine 10 mg
Vortioxetine 15 mg
Event
Any treatment-emergent
adverse event
Nausea
Headache
Diarrhea
Dizziness
Dry mouth
Constipation
Vomiting
Flatulence
3.0
6.0
9.0
12.0
15.0
18.0
3
4
5
Study Visit (week)
Placebo
(n=160)
114 (71.3)
Vortioxetine
10 mg
(n=154)
119 (77.3)
Vortioxetine
15 mg
(n=151)
118 (78.1)
17 (10.6)
29 (18.1)
10 (6.3)
15 (9.4)
11 (6.9)
6 (3.8)
4 (2.5)
4 (2.5)
47 (30.5)
24 (15.6)
10 (6.5)
6 (3.9)
24 (15.6)
16 (10.4)
7 (4.5)
10 (6.5)
51 (33.8)
25 (16.6)
15 (9.9)
12 (7.9)
8 (5.3)
14 (9.3)
18 (11.9)
5 (3.3)
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Table 5. Change in Baseline Sexual Dysfunctiona During Study, Stratified by Baseline Sexual
Dysfunction
Variable
Placebo
Vortioxetine 10 mg
Vortioxetine 15 mg
Subjects without sexual dysfunction at baseline, n
36
42
41
Without sexual dysfunction during the study, n (%)
25 (69.4)
28 (66.7)
25 (61.0)
With sexual dysfunction during the study, n (%)
11 (30.6)
14 (33.3)
16 (39.0)
Difference in incidence from placebo, %
2.8
8.5
17.95 to 23.51
12.73 to 29.67
95% CI for differenceb
Subjects with sexual dysfunction at baseline, n
120
109
109
Did not worsen during the study, n (%)
95 (79.2)
84 (77.1)
80 (73.4)
Worsened during the study, n (%)
25 (20.8)
25 (22.9)
29 (26.6)
Difference in incidence from placebo, %
2.1
5.8
95% CI for difference, %b
8.63 to 12.83
5.26 to 16.80
aSexual dysfunction was defined as Arizona Sexual Experience Scale total score 19, score 5 on any item, or
score 4 on any 3 items at the same visit.
bAsymptotic 95% CIs are calculated for proportion difference.
Abbreviation: CI=confidence interval.
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