European Neuropsychopharmacology (2017) 27, 773–781

www.elsevier.com/locate/euroneuro

Comparative evaluation of vortioxetine

as a switch therapy in patients with major
depressive disorder
Michael E. Thasea,n, Natalya Danchenkob, Melanie Brignoneb,
Ioana Floreac, Francoise Diamandb, Paula L. Jacobsend, Eduard Vietae

a
University of Pennsylvania School of Medicine, Philadelphia, PA, USA
b
Lundbeck SAS, Paris, France
c
H. Lundbeck A/S, Copenhagen, Denmark
d
Takeda Development Center Americas, Deerfield, IL, USA
e
Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain

Received 24 March 2017; accepted 22 May 2017

KEYWORDS Abstract
Vortioxetine; Switching antidepressant therapy is a recommended strategy for depressed patients who
Drug switching; neither respond to nor tolerate an initial pharmacotherapy course. This paper reviews the
Major depressive efficacy and tolerability of switching to vortioxetine. All three published studies of
disorder; patients with major depressive disorder (MDD) switched from SSRI/SNRI therapy to
Drug-related side
vortioxetine due to lack of efficacy or tolerability were selected. Vortioxetine was
effects and adverse
evaluated versus agomelatine directly (REVIVE) and versus sertraline, venlafaxine,
reactions;
Comparative bupropion, and citalopram in an indirect treatment comparison (ITC) from switch studies
effectiveness retrieved in a literature review. Vortioxetine's impact on SSRI-induced treatment-
research emergent sexual dysfunction (TESD) was assessed directly versus escitalopram
(NCT01364649) in stable patients with MDD. Vortioxetine's tolerability in the switch
population was compared to the overall MDD population. Vortioxetine showed significant
benefits over agomelatine on efficacy, functioning, and quality-of-life outcomes, with
fewer withdrawals due to adverse events (AEs) (REVIVE). Vortioxetine had numerically
higher remission rates versus all therapies included (ITC). Withdrawal rates due to AEs
were significantly lower for vortioxetine versus sertraline, venlafaxine, and bupropion,
and numerically lower versus citalopram. Switching to vortioxetine was statistically
superior to escitalopram in improving TESD (NCT01364649). Tolerability was similar in
the switch and overall MDD populations. These findings suggest that vortioxetine is an
effective switch therapy for patients with MDD whose response to SSRI/SNRI therapy is
inadequate. Vortioxetine was well tolerated and, for patients with a history of TESD,

n
Correspondence to: University of Pennsylvania School of Medicine, 3535 Market Street, Suite 670, Philadelphia, PA 19104, USA.
Fax: +1 215 898 0509.
E-mail address: thase@mail.med.upenn.edu (M.E. Thase).

http://dx.doi.org/10.1016/j.euroneuro.2017.05.009
0924-977X/& 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
774
showed significant advantages versus escitalopram. Vortioxetine appears to be a valid
option for patients with MDD who have not been effectively treated with first-line
pharmacotherapies.
& 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
Clinical practice shows that 40–60% of patients with major
depressive disorder (MDD) do not respond adequately (e.g.,
do not achieve Z 50% reduction in depression rating scores)
to first-line pharmacotherapies (Bauer et al., 2013; Rush
et al., 2006a) and approximately one-third will not remit
even after a course of up to 4 sequential treatment steps
(Rush et al., 2006a). Tolerability problems also undermine
antidepressant pharmacotherapy; nonadherence and pre-
mature discontinuation of medication because of side
effects are two of the most common reasons that therapy
fails in current practice (Ashton et al., 2005; Masand, 2003).
On average, half of patients (46–52%) discontinue taking their
antidepressant medication as prescribed by the end of the first
six months of pharmacotherapy (Sansone and Sansone, 2012). In
one study, in which 60% of patients had completely discontinued
treatment, the most common reasons were lack of efficacy
(44%), not liking the way the drug made them feel (36%), lack of
interest in sex (22%), tiredness (17%), and weight gain (15%)
(Ashton et al., 2005). Furthermore, loss of interest in sex was
reported by 47% of all patients prescribed an antidepressant,
with inability to have an erection and difficulty reaching orgasm
considered to be “extremely difficult to live with” by 25% and
24% of the patients, respectively. Although there are few
studies assessing patient self-reported reasons for noncompli-
ance, sexual dysfunction is a commonly reported side effect
associated with treatment. A systematic review of the clinical
trial data showed that treatment with sertraline, venlafaxine,
citalopram, paroxetine, fluoxetine, imipramine, phenelzine,
duloxetine, escitalopram, and fluvoxamine was associated with
rates of treatment-emergent sexual dysfunction (TESD) that
were significantly greater than placebo and that ranged
between 25% and 80% (Serretti and Chiesa, 2009). Thus, a
large proportion of patients with MDD need to switch therapies
during the course of treatment.
In contemporary practice, switching antidepressants is one
of the more commonly used strategies when the initial course
of antidepressant therapy is either ineffective or poorly
tolerated. Indeed, in the UK Clinical Practice Research
Datalink database analysis, in the group of patients receiving
second-line treatment, switching occurred in 39% of cases
(Lamy et al., 2015). A recent multisite study conducted in
Spain found that psychiatrists switched 40% of patients who
were not well treated with their initial therapy to another
antidepressant (Garcia-Toro et al., 2012). They added a
second antidepressant for 24% of patients, while the remain-
der received augmentation (18%) or mixed strategies (19%). A
survey of psychopharmacologists in the United States
revealed similar treatment patterns (Goldberg et al., 2015).
Once the decision has been made to switch antide-
pressants due to a lack of efficacy or tolerability
M.E. Thase et al.
problems, there is limited evidence to guide the choice
of which new agent to prescribe (American Psychiatric
Association (APA), 2010; Gaynes et al., 2012; National
Collaborating Centre for Mental Health (NCCMH), 2010;
Santaguida et al., 2012; Tadic et al., 2016). A recent
meta-analysis found few randomized controlled trials
that assessed switching after nonresponse and an
absence of high-quality data to support switching versus
continuing on the same antidepressant (Bschor et al.,
2016). Only a small number of head-to-head studies have
assessed the efficacy and tolerability of different anti-
depressants as switch therapy in individuals who discon-
tinue treatment due to lack of efficacy or intolerable side
effects (Kasper and Hajak, 2013; Lenox-Smith and Jiang,
2008; Montgomery et al., 2014; Rush et al., 2006b). Only
one study (Jacobsen et al., 2015a) has undertaken a
direct comparison of switch therapies in patients with
TESD, one of the most bothersome side effects of anti-
depressant pharmacotherapy (Ashton et al., 2005).
Vortioxetine is an approved antidepressant with a multi-
modal mechanism of action different from that of SSRIs and
SNRIs. Vortioxetine has been evaluated as switch therapy
using both direct and indirect analyses in patients who
experienced inadequate response to SSRI or SNRI therapy
and in patients who discontinued therapy because of
intolerable TESD. The objective of this review is to sum-
marize the evidence pertaining to using switch therapy in
both of these patient populations.
2. Relative efficacy as switch therapy
2.1. Direct treatment comparison
The REVIVE study (Montgomery et al., 2014) (NCT01488071)
was a prospective, randomized, double-blind, flexible-dose,
12-week study to assess vortioxetine efficacy versus ago-
melatine in patients with MDD who had experienced an
inadequate treatment response after receiving a SSRI or
SNRI for a minimum of 6 weeks. Eligible patients were
directly switched to vortioxetine (10 or 20 mg/day, n= 252)
or agomelatine (25 or 50 mg/day, n= 241). Agomelatine was
chosen as the comparator because, like vortioxetine, it has
a mechanism of action that is different from SSRIs and SNRIs
(Stahl, 2014). The antidepressant effects of agomelatine are
thought to be mediated by its actions as a potent agonist at
melatonin MT1 and MT2 receptors and as a neutral antago-
nist at 5-HT2C receptors (Guardiola-Lemaitre et al., 2014).
This agent is currently not approved for the treatment of
MDD in the US, but received that indication from the
European Medicines Agency in 2009.
In the primary efficacy analysis, the mean change from
baseline in the Montgomery-Åsberg Depression Rating Scale
Comparative evaluation of vortioxetine
Figure 1 Change from baseline in MADRS total score, vortiox-
etine versus agomelatine (FAS, MMRM). **Po0.01 versus agome-
latine. Reprinted with permission from Montgomery et al. (2014).
(MADRS) total score at Week 8 (full analysis set, mixed
model for repeated measurements) was 16.5 points for
vortioxetine and 14.4 points for agomelatine (Figure 1).
The mean difference between treatments was 2.2 points
(95% confidence interval [CI]: 3.5 to 0.8; P = 0.0018),
establishing superior efficacy (European Medicines Agency,
2000) with vortioxetine. At Week 12, vortioxetine main-
tained superiority with a statistically significant mean
difference in change from baseline in MADRS total score of
2.0 points (Po0.01) (Figure 1).
Efficacy findings were consistent across endpoints
(Montgomery et al., 2014). At Week 8, 61.5% of the patients
in the vortioxetine group were MADRS responders (Z50%
improvement from baseline in MADRS total score) compared
with 47.3% of the agomelatine group (Po0.01), and 40.5%
of vortioxetine-treated patients were MADRS remitters (MADRS
total score r10) compared with 29.5% of agomelatine-
treated patients (Po0.01) (Figure 2). The difference between
study groups was sustained at Week 12: response rates were
69.8% with vortioxetine versus 56.0% with agomelatine
(Po0.01), and remission rates were 55.2% with vortioxetine
versus 39.4% with agomelatine (Po0.001) (Figure 2). These
Figure 2 Percentage of responders and remitters, vortioxetine
versus agomelatine (FAS, LOCF). **Po0.01, ***Po0.001 versus
agomelatine. Reprinted with permission from Montgomery et al.
(2014).
775
results translated to a statistically significantly higher prob-
ability of achieving remission in the vortioxetine group
compared with the agomelatine group (risk difference [RD],
11%; Po0.01) (Figure 3).
Moreover, treatment group differences in the change
from baseline at Week 8 in all patient-reported outcomes
favored vortioxetine. The mean change from baseline
(7 standard error [SE]) on the Sheehan Disability Scale (SDS)
total score was 9.28 (75.3) in the vortioxetine group versus
7.06 (70.55) in the agomelatine group (Po0.01) (decreases
from baseline scores indicate improvement in functioning).
Significant differences favoring vortioxetine were also observed
for the SDS family life, work, and social life subscales (Po0.01)
(Montgomery et al., 2014). The mean change from baseline
(7SE) in the EuroQol 5 Dimensions overall health state score
was 20.6 (71.2) with vortioxetine and 15.6 (71.3) with
agomelatine (Po0.01) (higher scores indicate better overall
health). The mean change from baseline (7SE) on the Work
Limitations Questionnaire global productivity index score was
0.06 (70.00) with vortioxetine versus 0.04 (70.02) with
agomelatine (Po0.05) (decreases from baseline scores indicate
improvement in productivity). The mean change from baseline
(7SE) on the Depression and Family Functioning Scale total
score for vortioxetine and agomelatine was 10.8 (70.7)
versus 7.9 (70.7) (Po0.01), respectively (Montgomery
et al., 2014) (decreases from baseline scores indicate
improvement).
2.2. Indirect treatment comparison
To further assess the relative efficacy and tolerability of
vortioxetine versus other monotherapies, a systematic
literature review and generation of the network of evidence
for indirect treatment comparisons (ITCs) were selected as
the most appropriate analytical methodology for the avail-
able data. The general methods used and partial results
have been published previously (Brignone et al., 2016). The
ITC included 2 outcomes of interest: rates of remission
(defined as either MADRS total score r10 or Hamilton
Depression Rating Scale [HAM-D] total score r 7) and rates
of withdrawal due to adverse events (AEs).
The network was expanded to include citalopram in
addition to vortioxetine, agomelatine, venlafaxine, sertra-
line, and bupropion, using data from 4 studies (Figure 4):
the REVIVE study (Montgomery et al., 2014); a post-hoc
analysis of a randomized controlled trial comparing agome-
latine with sertraline (Kasper and Hajak, 2013); the STAR*D
reporting data for sertraline, venlafaxine extended release
(XR), and bupropion sustained-release (SR) monotherapy use
after treatment failure with citalopram (Rush et al., 2006b);
and from a randomized, controlled trial comparing
venlafaxine XR to citalopram after failure with an SSRI
(Lenox-Smith and Jiang, 2008). Only active-comparator (not
placebo) studies evaluating pharmacological switch mono-
therapies were included in the network. In the original
publication, Brignone et al. (2016) included only 5 treat-
ments, excluding citalopram, because remission rates were
available only for the subgroup of patients with HAM-D total
score Z31 (Lenox-Smith and Jiang, 2008). This study has
been included in the current analysis because citalopram is
widely used in many countries, and clinical opinion was that
776 M.E. Thase et al.

Figure 3 Risk difference for remission, vortioxetine versus comparator. Adapted from Brignone et al. (2016).

the baseline severity of depression would not be an effect- 3. Relative tolerability/safety as switch
modifier. Simple adjusted ITCs were made using the Bucher therapy
method, which can be applied to both risk differences and
odds ratios (Bucher et al., 1997). 3.1. Direct treatment comparison in patients
When calculated by ITC, there was a numerically higher
switching due to a lack of efficacy
probability of remission in favor of vortioxetine versus sertra-
line (RD, 14.4%), venlafaxine XR (RD, 7.2%), bupropion SR
In the REVIVE study, tolerability was assessed by collecting
(RD, 10.7%), and citalopram (RD, 16.8%) (Figure 3).
physician-observed and patient-reported AEs as well as
Overall, in patients with MDD who have switched from
rates of withdrawal due to AEs. The most common
SSRI/SNRI therapy, there is direct evidence that vortiox-
treatment-emergent AEs (TEAEs; reported by Z 5% of
etine offers clinical benefits over agomelatine and suppor-
patients in either treatment group) were nausea, headache,
tive evidence that vortioxetine may offer clinical benefits
dizziness, and somnolence (Montgomery et al., 2014). Only
over other antidepressants in this patient population. In
nausea had a higher incidence with vortioxetine compared
these patients, vortioxetine has demonstrated statistically
to agomelatine (16.2% vs 9.1%, respectively). Withdrawal
significant and clinically relevant superior efficacy versus
due to AEs occurred in 5.9% of the vortioxetine group and
agomelatine. In addition, potentially better efficacy of
9.5% of the agomelatine group (Montgomery et al., 2014).
vortioxetine compared to other commonly used antidepres-
Patients receiving vortioxetine had a numerically lower
sants (sertraline and citalopram as representatives of SSRIs,
probability of discontinuing treatment because of an AE
venlafaxine as an SNRI, and bupropion as an atypical
(RD, 3.6%) compared with agomelatine, based on this direct
antidepressant) has also been suggested through indirect
comparison (Figure 5).
comparisons in switching patients.

̂
Figure 4 Base-case network for indirect treatment comparison. Studies reported remission using Hamilton Depression Rating Scale
total score. #Studies reported remission using MADRS total score;  Remission could be calculated from scores.
Comparative evaluation of vortioxetine
Figure 5 Risk difference for withdrawal due to adverse events, vortioxetine versus comparator. Adapted from Brignone et al. (2016).
A post-hoc analysis of REVIVE data indicated that the
tolerability profiles (i.e., withdrawal rates and TEAE inci-
dences) of vortioxetine and agomelatine were independent
of previous antidepressant treatment, including the division
by class (SSRI or SNRI) and by individual therapy (citalo-
pram, escitalopram, paroxetine, sertraline, duloxetine, or
venlafaxine) (Papakostas et al., 2014b). However, the data
from the REVIVE study also showed that the incidence of
nausea with vortioxetine was lower in patients who had
switched therapy compared with treatment-naïve patients
included in the overall vortioxetine clinical program.
Because the tolerability results from REVIVE were similar
to those observed in the total MDD population (Baldwin
et al., 2016) and did not differ by previous treatment
(Papakostas et al., 2014a), the tolerability profile observed
in the overall MDD population may be generalizable to
patients who switch to vortioxetine from another antide-
pressant. To further examine the potential for general-
izability, a post-hoc analysis of TEAE incidence was
performed on the subset of patients with MDD who had
received antidepressant pharmacotherapy for their current
major depressive episode prior to their inclusion in 1 of 12
short-term studies in the vortioxetine clinical trial program
(Alvarez et al., 2012; Baldwin et al., 2012; Boulenger et al.,
2014; Henigsberg et al., 2012; Jacobsen et al., 2015b; Jain
et al., 2013; Katona et al., 2012; Mahableshwarkar et al.,
2015a, 2015b, 2013; McIntyre et al., 2014; Nishimura et al.,
2014). The TEAE profile of previously treated patients was
similar to that observed in the overall clinical study
population (Table 1); however, for many of the most
frequent TEAEs, the incidence occurred at a lower rate in
the treatment arms of the previously treated subgroup.
Rates of study discontinuation also were similar in the
switch subgroup and in the overall clinical study population.
Interestingly, the incidence of nausea was lowest in
patients who had switched therapy compared with the
overall patient population and with treatment-naïve indivi-
duals (Table 1). In treatment-naïve individuals, the inci-
dence rate of nausea was 21.8% for vortioxetine 5 mg/day,
24.6% for 10 mg/day, 34.9% for 15 mg/day, and 32.9% for
777
20 mg/day, whereas for previously treated patients the
incidence of nausea was 16.0%, 18.8%, 25.0%, and 17.7%,
respectively, for the same dosages. Additionally, the data
from the REVIVE study showed that the incidence of nausea
was lower in patients who had switched therapy (16.2%;
vortioxetine 10–20 mg/day) than in those who had not
received a previous treatment (from the total MDD
population).
3.2. Indirect treatment comparison
In the ITC, tolerability was assessed as risk differences for
withdrawal due to AEs. These risk differences were statis-
tically significantly lower with vortioxetine than with sertra-
line (RD, 12.1%), venlafaxine XR (RD, 12.3%), and bupropion
SR (RD, 18.3%) and were numerically lower than with
citalopram (RD, 12.1%) (Figure 5). Using this network-of-
evidence approach for the ITC, vortioxetine was found to be
numerically more efficacious and better tolerated than a
variety of comparator antidepressants commonly prescribed
in clinical practice. Although this ITC is limited by the fact
that each treatment comparison is based on one study in the
network—preventing statistical assessment of the hetero-
geneity between studies and preventing the ability to
account for factors other than the treatment effects in
the model—sensitivity analyses (data not shown) supported
these conclusions.
3.3. Tolerability in patients switching due to
intolerable sexual dysfunction
In the study by Jacobsen et al. (2015a), eligible patients
experiencing intolerable TESD while stable on a SSRI regi-
men for at least 8 weeks were randomized to vortioxetine
(10 or 20 mg/day, n = 225) or escitalopram (10 or 20 mg/day,
n= 222) in a double-blind, parallel-group, flexible-dose, 8-
week study. Patients had depressive symptoms of MDD that
were well treated while on an SSRI (citalopram, paroxetine,
or sertraline) regimen (MADRS total score at baseline mean
7 standard deviation [SD]: vortioxetine, 7.9 7 6.28;
778 M.E. Thase et al.

Table 1 TEAEs with incidence Z5% in any treatment group in the overall MDD population and the subpopulation of MDD
patients who had received previous pharmacotherapy.

Percentage of patients (%)

Placebo Vortioxetine 5 mg Vortioxetine 10 mg Vortioxetine 15 mg Vortioxetine 20 mg

Total Previous Total Previous Total Previous Total Previous Total Previous
(N =1817) (n =479) (N=1013) (n=169) (N =894) (n =303) (N =449) (N =128) (N =662) (n =283)

Any TEAE 57.9 53.9 64.9 62.7 61.1 55.8 68.8 64.1 75.2 56.9
Nausea 8.1 7.5 20.9 16.0 23.3 18.8 31.2 25.0 27.8 17.7
Headache 13.1 11.9 14.2 12.4 12.8 9.9 14.7 16.4 12.5 14.5
Dizziness 5.6 5.8 5.7 4.1 5.4 6.3 7.1 5.5 6.3 7.1
Nasopharyngitisa – 4.4 – 4.7 – 5.6 – 3.9 – 6.7
Dry mouth 5.9 4.4 7.0 3.6 5.7 6.6 6.0 3.9 6.6 4.6
Diarrhea 5.3 4.4 7.0 4.7 5.6 5.0 9.4 7.0 6.0 3.9
Vomiting 1.1 1.5 2.9 3.6 4.1 4.0 6.5 7.8 4.5 3.5
Constipation 3.0 1.7 3.3 1.8 3.8 3.0 5.6 6.3 4.2 3.2
Somnolence 2.4 1.9 3.1 5.9 2.6 2.0 2.7 1.6 3.2 3.2
Insomniab 4.0 2.5 5.1 7.1 3.7 2.6 2.0 3.9 3.3 2.5

Previous, previously treated MDD patient population from 12 short-term trials (Takeda, data on file); Total, total MDD patient
population from 11 short-term trials (Baldwin et al., 2016).
a
Results for nasopharyngitis not reported in Baldwin et al. (2016) and occurred at incidences o5%.
b
For the total MDD population, insomnia includes the preferred terms: insomnia, initial insomnia, middle insomnia, hyposomnia,
sleep disorder, dyssomnia, poor quality sleep, and terminal insomnia.

escitalopram, 8.3 7 6.53) with mean baseline CGI-S r 3,
consistent with remission (Jacobsen et al., 2015a).
The primary endpoint was the change from baseline in
the Changes in Sexual Functioning Questionnaire Short Form
(CSFQ-14), where higher scores indicate better functioning
(Keller et al., 2006). At Week 8, mean increases in CSFQ-14
total score were significantly greater in the vortioxetine
group (least squares mean 7 SE: 8.8 7 0.64) than in the
escitalopram group (6.6 7 0.64; P= 0.013) (Jacobsen et al.,
2015a). Additionally, improvements in sexual functioning
were greater with vortioxetine regardless of age, gender,
and baseline depression severity (as measured by CGI-S
scores (Guy, 1976)) (Figure 6).
The most common TEAEs (reported by Z5% of patients in
either treatment group) were nausea, headache, dizziness,
generalized pruritus, irritability, fatigue, and anxiety
(Jacobsen et al., 2015a). Nausea (25.0% vs 5.4%), headache
(9.4% vs 7.7%), dizziness (8.0% vs 5.0%), and generalized
pruritus (5.8% vs 0%) occurred with a higher incidence with
vortioxetine than with escitalopram, respectively. Irritability

Figure 6 Change from baseline to week 8 in CSFQ-14 total score, vortioxetine versus escitalopram (FAS, MMRM). *Po0.05 versus
escitalopram. Adapted from Jacobsen et al. (2015a).
Comparative evaluation of vortioxetine
(7.2% vs 4.9%), fatigue (5.4% vs 4.5%), and anxiety (5.4% vs
2.2%) occurred at a higher incidence with escitalopram than
with vortioxetine, respectively. Withdrawal due to an AE
occurred in 9.4% of patients in the vortioxetine group and
in 6.3% of those in the escitalopram group.
Although the rate of nausea in the vortioxetine group was
higher than in the escitalopram group, the rate in the
escitalopram group was lower than the 15% seen in phase
3 clinical trials (Forest Pharmaceuticals Inc., 2014), whereas
rates in the vortioxetine group were similar to rates in prior
trials. Also consistent with prior trials, most cases of nausea
associated with vortioxetine were transient, with a median
duration of 7–7.5 days.
Among the patients who were well treated on their
previous antidepressant (baseline MADRS total scores 7
SD: vortioxetine, 7.9 7 6.28; escitalopram, 8.3 7 6.53;
mean baseline CGI-S r 3 for both groups), efficacy was
maintained at Week 8 in both treatment groups (remission
rates were 78.7% with vortioxetine and 77.3% with escita-
lopram; P= 0.902) (Jacobsen et al., 2015a). Both the
vortioxetine and escitalopram groups exhibited further
small reductions in mean MADRS total scores during the 8-
week treatment period; there were no statistically signifi-
cant differences or clinically relevant differences between
the treatment arms.
The results of this direct comparison suggest that patients
who experienced intolerable sexual dysfunction on an SSRI/
SNRI can improve sexual functioning if switched to vortiox-
etine without losing efficacy of their MDD treatment.
Overall, vortioxetine has been shown to have a favorable
safety and tolerability profile consistently across the clinical
data package, especially with respect to weight change,
sleep, and sexual dysfunction. The vortioxetine tolerability
profile was similar to that of agomelatine, an agent
considered to have lower rates of adverse events than other
antidepressants (Plesnicar, 2014), and better than that of
other commonly used antidepressants (sertraline, venlafax-
ine XR, bupropion SR, and, with a numerical difference,
citalopram).
4. Discussion
Given the prevalence of MDD and its negative impact on
health, economic productivity, and quality of life, the
overlapping problems of nonresponse and intolerance to
commonly prescribed antidepressant medications is an
important public health problem and a critical unmet need
in psychopharmacology. For individuals who do not respond
adequately to their initial or current treatment, making a
decision about the next course of treatment requires multi-
factorial consideration, including the patients’ clinical
profile, treatment history, and patient preferences. It is
important to offer physicians and patients treatment
options that have different mechanisms of action and that
have demonstrated efficacy and tolerability in patients
needing to switch antidepressant therapy. Patients who do
not respond to SSRIs and SNRIs that are typically prescribed
in the first 2 “lines” of treatment, may require the use of
novel medications with other mechanisms of action.
This review provides a summary of the utility of vortiox-
etine, a recently introduced antidepressant with a unique
779
profile of receptor effects. Antidepressant effects of SSRIs are
attributed to elevations of serotonin (5-HT), mediated via
blockade of the 5-HT transporter; SNRIs mediate their anti-
depressant effects via elevations of 5-HT and (at higher doses)
noradrenaline via blockade of the 5-HT transporter and the
norepinephrine transporter, respectively. Vortioxetine inhibits
the 5-HT transporter and acts as an antagonist at 5-HT3, 5-HT7,
and 5-HT1D receptors, a partial agonist at 5-HT1B receptors,
and an agonist at 5-HT1A receptors (Bang-Andersen et al.,
2011; Westrich et al., 2012). These actions lead to modulation
of neurotransmission in several systems, including predomi-
nantly via serotonin, but possibly also via the norepinephrine,
dopamine, histamine, acetylcholine, gamma-aminobutyric
acid, and glutamate systems (Sanchez et al., 2015).
Direct comparisons of vortioxetine with agomelatine
demonstrated the efficacy and tolerability of vortioxetine
in patients who have failed first-line therapy due to a lack of
efficacy and/or tolerability problems. Using a network-of-
evidence approach for the ITC, vortioxetine was found to be
numerically more efficacious and better tolerated than a
variety of comparator antidepressants commonly prescribed
in clinical practice. Furthermore, compared with escitalo-
pram, vortioxetine demonstrated greater improvement in
sexual functioning, with no loss of efficacy, in patients who
were well treated on their previous antidepressant but who
switched from an SSRI due to intolerable sexual side effects.
Based on the evidence presented here, vortioxetine is a
reasonable treatment choice for switching patients with
MDD who experience inadequate response to and/or intol-
erable side effects during antidepressant treatment with an
SSRI or SNRI.
Role of funding source
This work was supported by Takeda Pharmaceutical Company, Ltd.
and H. Lundbeck A/S, who were involved in study design; in the
collection, analysis, and interpretation of data; in the writing of the
report; and in the decision to submit the paper for publication.
Contributors
All authors were responsible for the interpretation of the
analysis, contributed to critically revising the content, and
approved the final manuscript for submission to European
Neuropsychopharmacology.
Conflict of interest
Michael Thase is a consultant for H. Lundbeck A/S and Takeda
Pharmaceutical Company Ltd. He also has received research funding
from both companies. Dr. Thase discloses similar relationships with
other pharmaceutical companies. Natalya Danchenko, Melanie
Brignone, Ioana Florea, and Francoise Diamand are full-time
employees of H. Lundbeck A/S. Paula L. Jacobsen is a full-time
employee of Takeda Development Center Americas. Eduard Vieta is
a consultant for H. Lundbeck A/S and Takeda Pharmaceutical
Company Ltd. He also has received grants and served as consultant,
advisor, or CME speaker for the following entities: AstraZeneca, the
Brain and Behaviour Foundation, Bristol-Myers Squibb, Ferrer,
Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Jans-
sen, H. Lundbeck A/S, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier,
the Seventh European Framework Programme (ENBREC), Shire, the
780
Spanish Ministry of Science and Innovation (CIBERSAM), the Stanley
Medical Research Institute, Sunovion, and Takeda.
Acknowledgments
Assistance with manuscript preparation was provided by Ann C.
Sherwood, PhD, Nicole Coolbaugh, and Philip Sjostedt, BPharm,
with The Medicine Group, and was paid for by the Takeda
Pharmaceutical Company, Ltd. and H. Lundbeck A/S.
Appendix A. Supporting information
Supplementary data associated with this article can be
found in the online version at http://dx.doi.org/10.1016/
j.euroneuro.2017.05.009.
References
Alvarez, E., Perez, V., Dragheim, M., Loft, H., Artigas, F., 2012. A
double-blind, randomized, placebo-controlled, active reference
study of Lu AA21004 in patients with major depressive disorder.
Int. J. Neuropsychopharmacol. 15, 589–600.
American Psychiatric Association (APA), 2010. Work Group on Major
Depressive Disorder, Practice Guideline for the Treatment of
Patients With Major Depressive Disorder third ed. American
Psychiatric Association, Arlington, VA.
Ashton, A.K., Jamerson, B.D., Weinstein L.W, Wagoner, C., 2005.
Antidepressant-related adverse effects impacting treatment
compliance: results of a patient survey. Curr. Ther. Res. Clin.
Exp. 66, 96–106.
Baldwin, D.S., Chrones, L., Florea, I., Nielsen, R., Nomikos, G.G.,
Palo, W., Reines, E., 2016. The safety and tolerability of
vortioxetine: analysis of data from randomized placebo-
controlled trials and open-label extension studies. J. Psycho-
pharmacol. 30, 242–252.
Baldwin, D.S., Loft, H., Dragheim, M., 2012. A randomised, double-
blind, placebo controlled, duloxetine-referenced, fixed-dose
study of three dosages of Lu AA21004 in acute treatment of
major depressive disorder (MDD). Eur. Neuropsychopharmacol.
22, 482–491.
Bang-Andersen, B., Ruhland, T., Jorgensen, M., Smith, G., Freder-
iksen, K., Jensen, K.G., Zhong, H., Nielsen, S.M., Hogg, S.,
Mork, A., Stensbol, T.B., 2011. Discovery of 1-[2-(2,4-dimethyl-
phenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multi-
modal compound for the treatment of major depressive
disorder. J. Med. Chem. 54, 3206-3221.
Bauer M. Pfennig A., Severus E., Whybrow P.C. Angst J. Moller H.
J. World Federation of Societies of Biological Psychiatry
(WFSBP) guidelines for biological treatment of unipolar
depressive disorders, part 1: update 2013 on the acute and
continuation treatment of unipolar depressive disorders-
World J. Biol. Psychiatry 14, 2013, 334-385.
Boulenger, J.P., Loft, H., Olsen, C.K., 2014. 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. 29, 138–149.
Brignone, M., Diamand, F., Painchault, C., Takyar, S., 2016. Efficacy
and tolerability of switching therapy to vortioxetine versus other
antidepressants in patients with major depressive disorder. Curr.
Med. Res. Opin. 32, 351–366.
Bschor, T., Kern, H., Henssler, J., Baethge, C., 2016. Switching the
antidepressant after nonresponse in adults with major
M.E. Thase et al.
depression: a systematic literature search and meta-analysis.
J. Clin. Psychiatry. http://dx.doi.org/10.4088/JCP.16r10749.
Bucher, H.C., Guyatt, G.H., Griffith, L.E., Walter, S.D., 1997. The
results of direct and indirect treatment comparisons in meta-
analysis of randomized controlled trials. J. Clin. Epidemiol. 50,
683–691.
European Medicines Agency, 2000. European Medicines Agency
(EMEA). Committee for Medicinal Products for Human Use
(CHMP). Points to consider on switching between superiority
and non-inferiority. 〈http://www.ema.europa.eu/docs/en_GB/
document_library/Scientific_guideline/2009/09/WC500003658.
pdf〉. (Accessed 17 June 2016).
Forest Pharmaceuticals Inc., 2014. Lexapro [package insert], St.
Louis, MO.
Garcia-Toro, M., Medina, E., Galan, J.L., Gonzalez, M.A., Maurino,
J., 2012. Treatment patterns in major depressive disorder after
an inadequate response to first-line antidepressant treatment.
BMC Psychiatry 12, 143.
Gaynes, B.N., Dusetzina, S.B., Ellis, A.R., Hansen, R.A., Farley, J.F.,
Miller, W.C., Sturmer, T., 2012. Treating depression after initial
treatment failure: directly comparing switch and augmenting
strategies in STAR*D. J. Clin. Psychopharmacol. 32, 114–119.
Goldberg, J.F., Freeman, M.P., Balon, R., Citrome, L., Thase, M.E.,
Kane, J.M., Fava, M., 2015. The American Society of Clinical
Psychopharmacology survey of psychopharmacologists' practice
patterns for the treatment of mood disorders. Depress. Anxiety
32, 605–613.
Guardiola-Lemaitre, B., Bodinat, C., Delagrange, P., Millan, M.J.,
Munoz, C., Mocaer, E., 2014. Agomelatine: mechanism of action
and pharmacological profile in relation to antidepressant prop-
erties. Br. J. Pharmacol. http://dx.doi.org/10.1111/bph.12720.
Guy, W., 1976. Clinical Global Impressions (028-CGI). In: Guy, W. (Ed.),
ECDEU Assessment Manual for Psychopharmacology. U.S. Dept. of
Health, Education, and Welfare, Public Health Service, Alcohol,
Drug Abuse, and Mental Health Administration, Rockville, MD.
Henigsberg, N., Mahableshwarkar, A.R., Jacobsen, P., Chen, Y.,
Thase, M.E., 2012. A randomized, double-blind, placebo-
controlled 8-week trial of the efficacy and tolerability of multi-
ple doses of Lu AA21004 in adults with major depressive
disorder. J. Clin. Psychiatry 73, 953–959.
Jacobsen, P.L., Mahableshwarkar, A.R., Chen, Y., Chrones, L.,
Clayton, A.H., 2015a. Effect of vortioxetine vs. escitalopram
on sexual functioning in adults with well-treated major depres-
sive disorder experiencing SSRI-Induced sexual dysfunction. J.
Sex. Med. 12, 2036–2048.
Jacobsen, P.L., Mahableshwarkar, A.R., Serenko, M., Chan, S.,
Trivedi, M., 2015b. A randomized, double-blind, placebo-
controlled study of the efficacy and safety of vortioxetine
10 mg and 20 mg in adults with major depressive disorder. J.
Clin. Psychiatry 76, 575–582.
Jain, R., Mahableshwarkar, A.R., Jacobsen, P., Chen, Y., Thase, M.
E., 2013. A randomized, double-blind, placebo-controlled 6-wk
trial of the efficacy and tolerability of 5 mg vortioxetine in
adults with major depressive disorder. Int. J. Neuropsychophar-
macol. 16, 313–321.
Kasper, S., Hajak, G., 2013. The efficacy of agomelatine in
previously-treated depressed patients. Eur. Neuropsychophar-
macol. 23, 814–821.
Katona, C., Hansen, T., Olsen, C.K., 2012. 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. Psychophar-
macol. 27, 215–223.
Keller, A., McGarvey, E.L., Clayton, A.H., 2006. Reliability and
construct validity of the Changes in Sexual Functioning Ques-
tionnaire short-form (CSFQ-14). J. Sex Marital Ther. 32, 43–52.
Lamy, F., Chollet, J., Clay, E., Brignone, M., Rive, B., Saragoussi,
D., 2015. Pharmacotherapeutic strategies for patients treated
Comparative evaluation of vortioxetine
for depression in UK primary care: a database analysis. Curr.
Med. Res. Opin. 31, 795–807.
Lenox-Smith, A.J., Jiang, Q., 2008. Venlafaxine extended release versus
citalopram in patients with depression unresponsive to a selective
serotonin reuptake inhibitor. Int. Clin. Psychopharmacol. 23,
113–119.
Mahableshwarkar, A.R., Jacobsen, P., Chen, Y., Serenko, M.,
Trivedi, M., 2015a. A randomized, double-blind, duloxetine-
referenced study comparing efficacy and tolerability of 2 fixed
doses of vortioxetine in the acute treatment of adults with MDD.
Psychopharmacology 232, 2061–2070.
Mahableshwarkar, A.R., Jacobsen, P., Serenko, M., Chen, Y., Trivedi, M.,
2015b. A randomized, double-blind, placebo-controlled study of the
efficacy and safety of 2 doses of vortioxetine in adults with major
depressive disorder. J. Clin. Psychiatry 76, 583–591.
Mahableshwarkar, A.R., Jacobsen, P.L., Chen, Y., 2013. A rando-
mized, double-blind trial of 2.5 mg and 5 mg vortioxetine (Lu
AA21004) versus placebo for 8 weeks in adults with major
depressive disorder. Curr. Med. Res. Opin. 29, 217–226.
Masand, P.S., 2003. Tolerability and adherence issues in antidepres-
sant therapy. Clin. Ther. 25, 2289–2304.
McIntyre, R.S., Lophaven, S., Olsen, C.K., 2014. A randomized, double-
blind, placebo-controlled study of vortioxetine on cognitive function
in depressed adults. Int. J. Neuropsychopharmacol. 17, 1557–1567.
Montgomery, S.A., Nielsen, R.Z., Poulsen, L.H., Häggström, L., 2014. A
randomised, double-blind study in adults with major depressive
disorder with an inadequate response to a single course of selective
serotonin reuptake inhibitor or serotonin–noradrenaline reuptake
inhibitor treatment switched to vortioxetine or agomelatine. Hum.
Psychopharmacol. Clin. Exp. 29, 470–482.
National Collaborating Centre for Mental Health (NCCMH), 2010.
Depression: The Treatment and Management of Depression in
Adults (Updated Edition). National Institute for Health and
Clinical Excellence, London, UK.
Nishimura, A., Hirochi, K., Asari, K., Otake, K., Mahableshwarkar, A.R.,
2014. 06. A multinational, randomized, double-blind, placebo-
controlled study to assess the efficacy and safety of vortioxetine
5, 10, and 20 mg in adults with major depressive disorder [abstract],
27th Annual US Psychiatric and Mental Health Congress, Orlando, FL.
Papakostas, G., Dragheim, M., Nielsen, R.Z., 2014a. NR6-118
Efficacy and tolerability of vortioxetine vs agomelatine is
independent of previous treatment in MDD patients switched
after an inadequate response [abstract], 167th Annual Meeting
of the American Psychiatric Association, New York, NY.
Papakostas, G., Dragheim, M., Nielsen, R.Z., 2014b. P.2.f.024
Efficacy and tolerability of vortioxetine is independent of
previous treatment in MDD patients switched after an
781
inadequate response. Eur. Neuropsychopharmacol. 24 (Supple-
ment 2), S466 [abstract].
Plesnicar, B.K., 2014. Efficacy and tolerability of agomelatine in the
treatment of depression. Patient Prefer. Adherence 8, 603–612.
Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A.,
Stewart, J.W., Warden, D., Niederehe, G., Thase, M.E., Lavori,
P.W., Lebowitz, B.D., McGrath, P.J., Rosenbaum, J.F., Sackeim,
H.A., Kupfer, D.J., Luther, J., Fava, M., 2006a. Acute and
longer-term outcomes in depressed outpatients requiring one or
several treatment steps: a STAR*D report. Am. J. Psychiatry 163,
1905–1917.
Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Stewart, J.W., Nieren-
berg, A.A., Thase, M.E., Ritz, L., Biggs, M.M., Warden, D.,
Luther, J.F., Shores-Wilson, K., Niederehe, G., Fava, M., 2006b.
Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs
for depression. N. Engl. J. Med. 354, 1231–1242.
Sanchez, C., Asin, K.E., Artigas, F., 2015. Vortioxetine, a novel
antidepressant with multimodal activity: review of preclinical
and clinical data. Pharmacol. Ther. 145, 43-57.
Sansone, R.A., Sansone, L.A., 2012. Antidepressant adherence: are
patients taking their medications? Innov. Clin. Neurosci. 9,
41–46.
Santaguida, P., MacQueen, G., Keshavarz, H., Levine, M., Beyene,
J., Raina, P., 2012. Treatment for Depression After Unsatisfac-
tory Response to SSRIs. Comparative Effectiveness Review No.
62. (Prepared by McMaster University Evidence-based Practice
Center under Contract No. HHSA 290 2007 10060 I.) AHRQ
Publication No.12-EHC050-EF. Rockville, MD: Agency for Health-
care Research and Quality, April 2012.
Serretti, A., Chiesa, A., 2009. Treatment-emergent sexual dysfunc-
tion related to antidepressants: a meta-analysis. J. Clin. Psy-
chopharmacol. 29, 259–266.
Stahl, S.M., 2014. Mechanism of action of agomelatine: a novel
antidepressant exploiting synergy between monoaminergic and
melatonergic properties. CNS Spectr. 19, 207–212.
Tadic, A., Wachtlin, D., Berger, M., Braus, D.F., van Calker, D.,
Dahmen, N., Dreimuller, N., Engel, A., Gorbulev, S., Helmreich,
I., Kaiser, A.K., Kronfeld, K., Schlicht, K.F., Tuscher, O., Wagner,
S., Hiemke, C., Lieb, K., 2016. Randomized controlled study of
early medication change for non-improvers to antidepressant
therapy in major depression - The EMC trial. Eur. Neuropsycho-
pharmacol. 26, 705–716.
Westrich, L., Pehrson, A., Zhong, H., Nielsen, S.M., Frederiksen, K.,
Stensbol, T.B., Boyle, N.J., Hentzer, M., Sanchez, C., 2012. In
vitro and in vivo effects for the multimodal antidepressant
vortioxetine (Lu AA21004) at human and rat targets. Int. J.
Psychiatry Clin. Pract. 16, 47.