Relative Efficacy and Tolerability of Vortioxetine

Compared with Selected Antidepressants in

Patients with Major Depressive Disorder
with an Inadequate Response to Prior Therapy
Franoise Diamand, Caroline Painchault, Mlanie Brignone
PMH8

Remission Rate

AIM
Limited evidence exists to differentiate the clinical efficacy
of different treatment approaches for patients with MDD
with inadequate response to SSRI or SNRI therapy;
results from a few systematic reviews and therapeutic
guidelines provide recommendations for these patients.1
Inadequate response to antidepressants is common in
clinical practice with roughly two thirds of patients with
major depressive disorder (MDD) not responding
(reduction in depression rating scores by 50%) to
selective serotonin reuptake inhibitor (SSRI) or selective
norepinephrine reuptake inhibitor (SNRI) therapy.1,2
Vortioxetine is an antidepressant with a multimodal
activity, which has shown superior efficacy over agomelatine
in a head-to-head randomised controlled trial (RCT): the
REVIVE study3 (NCT01488071) in patients with MDD who
are inadequate responders to prior SSRI/SNRI therapy.

Direct comparisons based on the REVIVE RCT showed that the remission rate after 8 weeks was statistically significantly
higher in patients who switched to vortioxetine compared with those who switched to agomelatine (relative difference
-11.0%, [95% CI: -19.4; -2.6]).
Indirect comparisons showed that vortioxetine had numerically higher remission rates (not statistically significant) compared
with sertraline (risk difference -14.4%, [95% CI: -29.9; 1.1]), venlafaxine XR (risk difference -7.2%, [95% CI: -24.3; 9.9]), and
bupropion SR (risk difference -10.70%, [95% CI: -27.8; 6.4]) (Figure 2).
Withdrawals Due to AEs
Direct comparisons based on the REVIVE RCT showed that the rate of withdrawals due to AEs was numerically lower for
vortioxetine compared with agomelatine (risk difference 3.6%, [95% CI: -1.1; 8.3]).
Indirect comparisons showed that the risks of withdrawals due to AEs were statistically significantly lower for vortioxetine
compared with sertraline (risk difference 12.1%, [95% CI: 3.1; 21.1]), venlafaxine XR (risk difference 12.3%, [95% CI: 0.8;
23.8]), and bupropion SR (risk difference 18.3%, [95% CI: 6.4; 30.1]) (Figure 2).
Figure 2. Difference in Remission (upper panel) and Withdrawal Due to AEs (lower panel) Rates Between Treatments
and Vortioxetine

Favours vortioxetine

Using results from the REVIVE RCT as a basis, the

aim of the current study was to make indirect treatment
comparisons to compare the efficacy and tolerability of
vortioxetine with other treatments commonly used in
clinical practice for patients who switch antidepressant
therapy.

Favours comparator

Agomelatine
Risk Difference = -11
CI95% = [-19.4; -2.6]

methods

Sertraline
Risk Difference = -14.4
CI95% = [-29.9; 1.1]

A systematic literature review identified 27 RCTs in

patients with MDD, of which 10 studies employed a switch
monotherapy strategy in both arms.4
Efficacy and tolerability were assessed:
Efficacy: remission rate, defined as a score of 7 on the
Hamilton Depression rating (HAM-D) scale or 10 on the
Montgomerysberg Depression Rating scale (MADRS)
according to clinical recommendations.5
Tolerability: withdrawal rate due to adverse events (AEs).
Seven of the 10 studies were excluded on the basis of
heterogeneity in the patient population, differing doses
of treatment, unlinked comparators, use of placebo as
comparator for patients who have previously failed on
SSRI/SNRI treatment, and methodological limitations
(such as inadequate randomisation, unreported blinding
status, selective reporting).
Ultimately, three studies (REVIVE, Kasper 2013 and STAR*D)
contributed to the relevant network for indirect treatment
comparison of vortioxetine versus other antidepressants
commonly used in clinical practice (Figure 1).3,6,7

Venlafaxine XR
Risk Difference = -7.2
CI95% = [-24.3; 9.9]

Bupropion SR
Risk Difference = -10.7
CI95% = [-27.8; 6.4]

-30

-25

-20

-15

-10

-5

10

15

Risk
Favours comparator

Favours vortioxetine

The studies were assessed qualitatively, as well as

quantitatively by conducting simple adjusted indirect
comparisons of risk differences using Buchers method8:

Agomelatine
Risk Difference = 3.6
CI95% = [-1.1; 8.3]

Figure 1. Network Diagram

REVIVE

Sertraline
Risk Difference = 12.1
CI95% = [3.1; 21.1]

STAR*D

Kasper

Venlafaxine XR
Vortioxetine

Agomelatine

Sertraline

Venlafaxine XR
Risk Difference = 12.3
CI95% = [0.8; 23.8]

Bupropion SR

Bupropion SR
Risk Difference = 18.3
CI95% = [6.4; 30.1]

results
Baseline Characteristics
The patients characteristics in the REVIVE and Kasper
studies were comparable in terms of age, gender
distribution, and severity at baseline (Table 1).
A marginally younger population, with less severe baseline
depression and a higher proportion of men, was enrolled
into the STAR*D study (Table 1).
Table 1. Baseline Characteristics of the Three Studies
Used for Indirect Comparisons
Study Name

REVIVE3

Kasper 20136

STAR*D7

495

176

727

Age (meanSD)

4612

44.19.8

41.812.8

Sex (% female)

74.7

73.4

58.7

SSRI/SNRI
(75.9% treated
with SSRI)

66.7% treated
with SSRI

Citalopram
(100% treated
with SSRI)

23.7841.06

10.04.2

Study treatment
duration:
meanSD
(weeks)

Vortioxetine:
10.43.0
Agomelatine:
9.73.9

6 (overall
stated length
of treatment
for all
comparators)

Bupropion:
8.35.0
Sertraline:
9.15.0
Venlafaxine:
9.35.1

Comparators
(mg/day)

Vortioxetine
10-20
Agomelatine
25-50

Agomelatine
25-50
Sertraline 100

Sertraline 50-200
Venlafaxine XR
37.5-375
Bupropion SR
200-400

NR

Sertraline
135.557.4
Venlafaxine XR
193.6106.2
Bupropion SR
282.7104.4

Patients (n)

Previous
treatment
Previous
treatment
duration mean
SD (weeks)

Mean exit dose

NR

Study type

RCT

Population

Inadequate
response to a
previous SSRI/
SNRI monotherapy

Subgroup
of a RCT

Randomized trial

Pre-treated sub- Patients switch

group: patients after experiencing
treated with
lack of efficacy
antidepressant at
or tolerability
least once during issues, previously
the year before
treated with
the inclusion
citalopram

Baseline HAM-D

23.3*

26.53.0

18.97.3

Baseline MADRS

28.94.2

NA

NA

8 (primary
efficacy
endpoint),
12 (total study
duration)

14

Study length
(weeks)

Remission rate
(%)

Withdrawal rate
due to AEs (%)

Sertraline: 21.0
Venlafaxine XR:
21.2
Bupropion SR:
27.2

AE: Adverse event; HAM-D: Hamilton Depression rating scale; MADRS: Montgomery
sberg Depression Rating scale; NA: Not applicable; NR: Not reported; RCT: Randomised
controlled trial; SNRI: Serotonin-norepinephrine reuptake inhibitor; SR: Sustained release;
SSRI: Selective serotonin reuptake inhibitor; XR: Extended release. *HAM-D scores were
calculated using transformation equation by Heo 2007: HDRS17 = -1.58 + 0.86 * MADRS.
E007883

10

15

20

25

30

35

Risk
AE: Adverse event; SR: Sustained release; XR: Extended release.

conclusions
The recent REVIVE RCT compared efficacy of vortioxetine with agomelatine.3 The REVIVE RCT was used to link vortioxetine
with other frequently-prescribed SSRIs/SNRIs and antidepressants in other drug classes, in order to make indirect
treatment comparisons.
Indirect treatment comparisons indicate that vortioxetine has a numerically higher remission rate compared with sertraline,
venlafaxine XR, and bupropion SR, treatments which are widely used in clinical practice.9-12
Treatment with vortioxetine led to a statistically significantly lower withdrawal rate due to AEs compared with sertraline,
venlafaxine XR and bupropion SR.
Despite the limited number of studies and heterogeneity in the network, which led to broad confidence intervals in the
comparisons, estimated rates of efficacy and tolerability through indirect comparisons were all in favour of vortioxetine.
Results from this indirect treatment comparison must be considered in terms of the overall benefit for patients with MDD
switching from a previous antidepressant based on the balance between clinical efficacy (remission rate) and tolerability
(withdrawals due to AEs).
The network of evidence presented here provides the opportunity to perform additional studies such as cost effectiveness
evaluations; with the possibility to assess the impact of the inherent uncertainties in these results through multiple
sensitivity analyses.

references
1. Agency for Healthcare Research and Quality. Comparative Effectiveness Review Number 62: Treatment for depression after unsatisfactory
response to SSRIs. 2012.
2. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, et al. Evaluation of outcomes with citalopram for depression using
measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40.
3. Montgomery SA, Nielsen RZ, Poulsen LH, Haggstrom L. 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. 2014;29(5):470-482.
4. Brignone M, Painchault C, Diamand F. Systematic review with qualitative assessment of antidepressant monotherapies in patients with major
depressive disorder with an inadequate response to a prior SSRI or SNRI. ISPOR 20th Annual International Meeting, May 16-20, 2015,
Philadelphia, PA, USA.
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corresponding to the definition of remission on the Hamilton rating scale for depression. J Psychiatr Res. 2004;38(6):577-582.
6. Kasper S, Hajak G. The efficacy of agomelatine in previously-treated depressed patients. Eur Neuropsychopharmacol. 2013;23(8):814-821.
7. Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for
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trials. J Clin Epidemiol. 1997;50(6): 683-691.
9. American Psychiatric Association. Practice guidelines for the treatment of patients with MDD (Third edition). 2010.

Sertraline: 17.6
Venlafaxine XR:
Vortioxetine: 40.5 Agomelatine: 27.9
24.8
Agomelatine: 29.5 Sertraline: 24.5
Bupropion SR:
21.3

Vortioxetine: 5.9 Agomelatine: 3.7

Agomelatine: 9.5 Sertraline: 12.2

-5

10. Suehs B, Argo T, Bendele S, Crimson ML, Trivedi MH, et al. Medication Algorithm Project Procedural Manual: Major Depressive Disorder
Algorithms. 2008.
11. Lam RW, Kennedy SH, Grigoriadis S, McIntyre RS, Milev R, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical
guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J Affect Disord. 2009; 117 Suppl 1, S26-S43.
12. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, et al. 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. 2013;14(5):334-385.
13. Heo M, Murphy CF, Meyers BS. Relationship Between the Hamilton Depression Rating Scale and the Montgomery-Asberg Depression Rating
Scale in Depressed Elderly: A Meta-analysis. Am J Geriatr Psychiatry. 2007;15(10):899-905.

ISPOR 20th Annual International Meeting, May 1620, 2015, Philadelphia, PA, USA.
Financial Sponsorship:
Mlanie Brignone and Franoise Diamand are employed by Lundbeck SAS; Caroline Painchault is employed by Keyrus Biopharma.