Cost-effectiveness evaluation of Vortioxetine
Hydrobromide (Trintellix)(Academic Group)[Version 1.0, March 25, 2021][Version 1.1, April 16, 2021]

1

[Table of contents][Table of abbreviations] .......................................................................................................... 3
0. Analytical framework .......................................................................................................... 4
1.Summary of other HTA agency reviews .............................................................................. 7
1.1 Overall summary ........................................................................................................... 7
1.2 Critique on manufacturer’s review .............................................................................. 14
2. Evaluation of additional benefit ........................................................................................ 16
2.1. Systematic review by academic group ...................................................................... 16
2.1.1 Research question ............................................................................................... 16
2.1.2 Flow of systematic review .................................................................................... 17
2.1.3 Inclusion and exclusion criteria ............................................................................ 18
2.1.4 Databases ............................................................................................................ 18
2.1.5 Search strategy .................................................................................................... 19
2.1.6 Search results ...................................................................................................... 22
2.1.7 Summary of clinical studies ................................................................................. 28
2.2. Summary of evaluation of additional benefit by manufacturer and critique by
academic group ....................................................................................................... 40
2.3 Summary of evaluation of additional benefit by academic group .............................. 42
3. Evaluation of cost-effectiveness ....................................................................................... 45
3.1. Summary of analysis by manufacture ....................................................................... 45
3.1.1 Critique on manufacture’s analysis ...................................................................... 48
3.2

Summary of revision by academic group ................................................................ 52

4. Revised analysis by academic group ............................................................................... 54
4.1

Base case analysis .................................................................................................. 54

4.2

Scenario analysis..................................................................................................... 55

4.3

Summary results ...................................................................................................... 57

4.4

Weight of price adjustment rate ............................................................................... 58

5. References ....................................................................................................................... 59
6. Supplementary material ................................................................................................... 622

[Table of abbreviations]
Abbreviation
AE
ASMR
CADTH
CENTRAL
CEA
CGI-I
CGI-S
CI
CINAHLCMA
C-SSRSDESSDSMEMBASE
HAMD
HAS
ICER
IQWiG
MADRS
MDD
MEDLINE
NaSSA
NICE
NMA
OR
PBAC
PRISMA
QALY
QIDS-SR
RCT
SAE
SMC
SMR
SNRI
SSRI

Formal description (English)
Adverse event
Amélioration du Service Médical Rendu
Canadian Agency for Drugs and Technologies in HealthCochrane Central Register of Controlled Trials
Cost-Effectiveness analysis
Clinical Global Impressions-Improvement
Clinical Global Impressions-Severity
Confidence interval
Cumulative Index to Nursing and Allied Health Literature
Cost-Minimization Analysis
Columbia-Suicide Severity Rating Scale
Discontinuation-Emergent Signs and Symptoms scale
Diagnostic and Statistical Manual of Mental Disorders
Excerpta Medica Database
Hamilton Depression Rating Scale
Haute Autorité de Santé
Incremental cost-effectiveness ratio
Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen
Montgomery-Åsberg Depression Rating Scale
Major depressive disorder
Medical Literature Analysis and Retrieval System Online
Noradrenergic and specific serotonergic antidepressantsNational Institute for Health and Care Excellence
Network meta-analysis
Odds ratio
Pharmaceutical Benefits Advisory Committee
Preferred Reporting Items for Systematic Reviews and MetaAnalyses
Quality-adjusted life year
Quick Inventory of Depressive Symptomatology-Self Report
Randomized controlled trial
Serious adverse event
Scottish Medicines Consortium
Service Médical Rendu
Serotonin noradrenaline reuptake inhibitor
Selective serotonin reuptake inhibitor3

0. Analytical framework
This analysis is for “Trintellix Tablets 10 or 20 mg (generic name, vortioxetine hydrobromide[hereinafter referred to as vortioxetine])”. The manufacturer is Takeda Pharmaceutical
Company Limited. Vortioxetine is for the treatment of patients with depression or in a
depressed state. It was selected as a subject of a cost-effectiveness evaluation in thegeneral meeting of Central Social Insurance Medical Council (CSIMC) on November 13,
2019. Vortioxetine was expected to have a peak market size of 22.7 billion yen and fell
under the H1 category of the cost-effectiveness evaluation (market size of ≥10 billion yen).
The analytical framework for vortioxetine is shown in Table 0-1 approved by the Expert
Committee of Cost-Effectiveness evaluation on March 19, 2020.

4

Table 0-1 Analytical framework(a) Patients with mild depression or in a mild depressed state1
Population(b) Patients with moderate or severe depression or in a moderateor severe depressed state
Population (a): no drug treatment 2

Comparator

Population (b): the cheapest drug4 of new generation
antidepressants (SSRI, SNRI, and NaSSA)3
Population (a): According to the Clinical Practice Guidelines for
Depression5 in Japan, antidepressants are not recommended as afirst-line treatment for patients with mild depression or in a mild
depressed state and appropriate comparator is considered as no
drug treatment.

Reason for selecting Population (b): According to the Clinical Practice Guidelines forthe comparator

Depression in Japan, antidepressant treatment is recommended
for moderate or severe depression or moderate or severe
depressed state. Among the antidepressants, new generation
antidepressants, including SSRI, SNRI, or NaSSA, are used as afirst-line treatment, though the superiority among these drugs has
not been indicated.

Other perspective in
addition to public

Yes (details:)No

healthcare payer
Outcome and thereason if QALY is

Not applicable

not used.
The following sensitivity analyses are performed6:
Population (a): scenario analysis with supportive psychotherapy or
Other

psychoeducation as a comparator
Population (b): scenario analysis with each new generation

antidepressant as a comparator
In principle, “patients with depression or in a depressed state” refers to those with major
depressive disorder as defined by Diagnostic and Statistical Manual of Mental Disorders(DSM) (hereinafter the same shall apply).
2 “No drug treatment ” is defined as continuing consultation with a healthcare professional
without any pharmacological interventions (hereinafter the same shall apply).
3 New generation antidepressants are shown below (hereinafter the same shall apply):
SSRI (selective serotonin reuptake inhibitor): fluvoxamine, paroxetine, sertraline, andescitalopram
1

5

SNRI (serotonin noradrenaline reuptake inhibitor): milnacipran, duloxetine, andvenlafaxine
NaSSA (noradrenergic and specific serotonergic antidepressant): mirtazapine
4
Drugs and dosing regimens falling under the category of “the cheapest drug” will be
discussed with the National Institute of Public Health (hereinafter the same shall apply).
5 Clinical Practice Guidelines for Depression (2016) supervised by the Japanese Society ofMood Disorders (hereinafter the same shall apply)
6
Details of the sensitivity analysis will be discussed with the National Institute of Public
Health.

6

1.Summary of other HTA agency reviews
1.1 Overall summary
The manufacturer reported the summary of evaluations of vortioxetine by HTA agencies in
the U.K., France, Germany, Canada, Australia, Ireland, Finland, Sweden, Korea, andTaiwan. The academic group investigated HTA evaluations in the U.K., France, Germany,
Canada, and Australia, and compared the results. (Tables 1-1,1-2)
Table 1-1 HTA evaluations in other countries
Country

AgencyEvaluation result
Manufacturer

NICE

U.K.
SMC

Academic group

Recommended for treating

Recommended as a third-line

adult MDD patients who failed

treatment for MDD

to respond to 2 antidepressants[November 2015] (1)Recommended for MDD

Recommended as a third-line

patients who have experienced

treatment for MDD

an inadequate response (either[June 2016] (2)due to lack of adequate efficacy
and/or safetyconcerns/intolerability to two or
more previous antidepressants)

FranceHAS

SMR: moderate

SMR: moderate

ASMR: V (No additional

ASMR: V (No additional

benefit)benefit)

Efficiency evaluation: not[June 2015] (3)performed

Germany

Canada

IQWiG

CADTH

Mild MDD: No additional benefit

Mild MDD: No additional benefit

Moderate MDD: No additional

Moderate MDD: No additional

benefitbenefitSevere MDD: No additional

Severe MDD: No additional

benefitbenefit [April 2015] (4)Recommended (It should be

Recommended on the following

reimbursed in a similar mannerconditions:to other antidepressants, and•Reimburse in a similar

the drug plan cost of treatment

manner to otherwith vortioxetine should not

antidepressants7

exceed the drug plan cost of•

The drug plan cost of

the antidepressant currently

treatment with vortioxetine

reimbursed.)should not exceed the drugplan cost of the least costly
antidepressant currently
reimbursed.
[April 2020] (5)Australia

PBAC

Not recommended

Not recommended (rejected)[July 2014] (6)Table 1-2 Implementation of cost-effectiveness evaluation in each agency
Country

Agency name

Manufacturer

Academic group

U.K.

NICE

✓

✓

SMC

✓

✓

FranceHAS✓

X

Germany

IQWiG

✓

X

Canada

CADTH

✓

✓

Australia

PBAC✓✓(CMA)

8

Table 1-3 Result of cost-effectiveness evaluation in the U.K. (NICE)Country

U.K.

Agency name

NICE

Reported by

Manufacturer

Academic group

URL

https://www.nice.org.uk/guidanc

https://www.nice.org.uk/guidance/

e/ta367

ta367

Recommended for treating adultRecommended as a third-line

MDD patients who failed totreatment for MDD

Resultrespond to 2 antidepressantsFor a conditional

Not applicableNot applicable

Treatment of MDD episodes inTreatment of MDD in adults

recommendation,
details of theconditions
Indication

adults (licensed indication)
Usage

Comparator

The recommended and starting

The recommended starting

dose of Brintellix is 10 mg (asdosage is 10 mg once daily invortioxetine) once daily in adult

adults <65 years, and 5 mg oncepatients <65 years.

daily in adults 65 years and older.

Depending on how the patients

Depending on how the symptoms

respond, the dose may be

respond, the dose may be

increased to a maximum of 20

increased to a maximum of 20 mg

mg once daily or decreased to aonce daily or decreased to aminimum of 5 mg once daily.

minimum of 5 mg once daily.

Treatment for at least 6 months

Treatment for at least 6 months is

is recommended after therecommended after the

depressive symptoms resolve.

symptoms resolve.

Three SSRIs, two SNRIs, andDirect comparison: agomelatine

agomelatineand escitalopram
Indirect comparison: agomelatine,
citalopram, sertraline,
venlafaxine, bupropion, andduloxetine

Main incremental

Reviewer’s results:

ICERs reported by thecost-

ICER≤£9,000/QALY

manufacturer: £378/QALY

9effectivenesscompared with venlafaxine as aratio (ICER)

second-line treatment
ICERs reported by the reviewer:£9,000/QALY (compared withother antidepressants)

Table 1-4 Result of cost-effectiveness evaluation in the U.K. (SMC)
Country

U.K.

Agency name

SMC

Reported by

Manufacturer

Academic group

URL

https://www.scottishmedicines.or

https://www.scottishmedicines.org

g.uk/media/2492/vortioxetine_bri.uk/media/2492/vortioxetine_brint

ntellix_final_june_2016_for_web

ellix_final_june_2016_for_website

site.pdf.pdf

Recommended for MDD

Conditional recommendation

patients who have experienced(SMC restriction)

Resultan inadequate response (either
due to lack of adequate efficacy
and/or safetyconcerns/intolerability to two or
more previous antidepressants)
For a conditional

Not applicableThird-line treatment for MDD

Treatment of major depressive

Treatment of MDD in adults

recommendation,
details of theconditions
Indication

episodes in adults
Usage

The recommended and starting

In adults <65 years, 10 mg takendose of Brintellix is 10 mg (asonce daily.

vortioxetine) once daily in adult

The dose may be increased to apatients <65 years.

maximum of 20 mg once daily or

Depending on how the patientsdecreased to a minimum of 5 mg

respond, the dose may beonce daily.

increased to a maximum of 20

In adults ≥65 years, 5 mg taken
once daily.
10mg once daily or decreased to a

After the depressive symptoms

minimum of 5 mg once daily.

resolve, treatment for at least 6

Treatment for at least 6 months

months is recommended.

is recommended after the
depressive symptoms resolve.
Comparator

Venlafaxine, mirtazapine, andVenlafaxine, venlafaxine IR,

duloxetine

venlafaxine XR, sertraline, andagomelatine

Main incremental

Reviewer’s results:

ICERs reported by thecost-

Despite the uncertainty of the

manufacturer:

effectivenesscomparison, the economic baseratio (ICER)

has been demonstrated.

£1,997/QALY compared withvenlafaxine IR£1,351/QALY compared withvenlafaxine XR£2,868/QALY compared withsertralinedominated by agomelatine

Reviewer’s results: Costeffectiveness conclusions were
found to vary according to theanalysis conditions.

11

Table 1-5 Result of cost-effectiveness evaluation in Canada
Country

CanadaAgency name

CADTH

Reported by

Manufacturer

Academic group

URL

https://www.cadth.ca/vortioxetin

https://www.cadth.ca/vortioxetine-

e-hydrobromidehydrobromide

Recommended (It should be

Conditional recommendation

Resultreimbursed in a similar manner
to other antidepressants, andthe drug plan cost of treatment
with vortioxetine should notexceed the drug plan cost of theantidepressant currently
reimbursed.)
For a conditional

Not applicable・Reimburse in a similar mannerrecommendation,

to other antidepressantsdetails of the・The drug plan cost of treatment

conditions

with vortioxetine should notexceed the drug plan cost of theleast costly antidepressantcurrently reimbursed.

Indication
Usage

Treatment of adult patients with

Treatment of adult patients with

MDD

MDD

The starting and recommended

The starting and recommended

dose is 10 mg (as vortioxetine)

dosage is 10 mg (as vortioxetine)

once daily in adults <65 years.

once daily for adults <65 years.

Depending on individual patient

Depending on individual patient

response and tolerability, theresponse and tolerability, thedose may be increased to adosage may be increased to a

maximum of 20 mg once daily.

maximum of 20 mg once daily.

A dose decrease to a minimum

A dosage decrease to a minimumof 5 mg once daily may beof 5 mg once daily may beconsidered for patients who do

considered for patients who do

not tolerate higher doses.

not tolerate higher doses.

12The recommended starting
dosage for patients ≥65 years is 5
mg once daily.
Comparator

SNRI, SSRI, bupropion, andDuloxetine, venlafaxine,

mirtazapine

citalopram, escitalopram,fluoxetine, fluvoxamine,paroxetine, sertraline, bupropion,and mirtazapine

Main incremental

Reviewer’s results:

ICER reported by thecost-

The difference in QALYs

manufacturer: CAD

effectivenessbetween vortioxetine and all

89,785/QALY compared withratio (ICER)

comparators was minimal,

duloxetine

suggesting a similar overall
treatment benefit for patients

Reviewer’s results:

with MDD.



dominated by escitalopram
and duloxetine

CAD 92,364/QALY comparedwith bupropion (scenario
analysis)

The difference in QALYs
between vortioxetine and allcomparators is minimal,suggesting a similar overall
treatment benefit for patientswith MDD.

13

1.2 Critique on manufacturer’s review
The review results of HTA agencies in foreign countries summarized by the manufacture
was consistent with the academic group, except for the following:
1.

There was a discrepancy in the interpretation of the evaluation result between SMC
and CADTH (i.e., “Recommendation” or “Conditional recommendation”).

2.

As for the implementation of cost-effectiveness evaluations in each agency, themanufacturer reported that all assessment agencies had “performed cost-effectivenessevaluations.” In contrast, the review of the academic group indicated that costeffectiveness evaluations had been performed in the U.K. and Canada, but not been
performed in any other countries.

3.

The manufacturer reported that the main ICER for NICE was “below £9,000/QALY(Appraisal Committee).” On the other hand, according to the review of the academic
group, the manufacturer first reported that the ICER for vortioxetine compared withvenlafaxine as a second-line treatment was £378/QALY and, based on the result of reanalysis, the ICER for vortioxetine compared with antidepressants, excluding SSRIs,
as a third-line treatment was shown as ≤£9,000/QALY.

4.

The manufacturer reported as the reviewer’s results that, despite the uncertainty of thecomparison, the economic case had been demonstrated for the main ICER for SMC.
On the other hand, according to the review of the academic group, the manufacturer
reported that the ICERs for vortioxetine versus venlafaxine IR and XR and sertraline
were £1,997, £1,351, and £2,868 per QALY, respectively, and vortioxetine wasdominated by agomelatine. The result of the re-analysis suggested that the costeffectiveness conclusions of vortioxetine would vary according to analysis conditions.

5.

The manufacturer reported that the evaluation result of CADTH was “recommended” (itshould be reimbursed in a similar manner to other antidepressants, and the drug plan
cost of treatment with vortioxetine should not exceed the drug plan cost of theantidepressant currently reimbursed). When reviewed by the academic group, theevaluation result was “conditional recommendation,” and the following conditions were
imposed:

Reimburse in a similar manner to other antidepressants for the treatment ofpatients with MDD.

The drug plan cost of treatment with vortioxetine should not exceed the drug plan
cost of the least costly antidepressant currently reimbursed.

6.

As for the main ICERs for CADTH, the manufacturer reported that the difference in
QALYs between vortioxetine and all comparators was minimal, suggesting a similar
14

overall treatment benefit for patients with MDD. On the other hand, according to thereview of the academic group, the base case analysis of CADTH showed thatvortioxetine was dominated by escitalopram and duloxetine (i.e., associated withgreater costs and fewer QALYs), and the scenario analysis revealed that the ICER for
vortioxetine compared with bupropion was CAD 92,364 per QALY. However, it waspointed out that the difference in QALYs between vortioxetine and all comparators was
minimal, suggesting a similar overall treatment benefit for patients with MDD.

15

2. Evaluation of additional benefit
2.1. Systematic review by academic group
2.1.1 Research question
To examine the additional benefit of vortioxetine, a systematic review was performed basedon the research questions as presented in Table 2-1. The populations were set as (a)patients with mild depression or in a mild depressed state and (b) patients with moderate orsevere depression or in a moderate or severe depressed state, the intervention as
vortioxetine, and the comparators as (a) no drug treatment for patients with mild depression
or in a mild depressed state and (b) new generation anti-depressants for patients withmoderate or severe depression or in a moderate or severe depressed state. The outcomes
were efficacy such as improvement in depressed state and safety. For the study design, asystematic review of existing systematic reviews was performed as Step 1, and then asystematic review that intended to identify relevant randomized controlled studies publishedafter the latest clinical studies identified in the previously reported systematic reviews was
carried out as Step 2. The search period was from before the start ofvortioxetine in Japan (of) to the date of the literature search in May 2020 for Step 1, andfrom after the period of the previously reported systematic reviews to the date of theliterature search in May 2020 for Step 2.
Table 2-1 Research questions of the systematic review in the academic group
Description
Population(a) Patients with mild depression or in a mild depressed state(b) Patients with moderate or severe depression or in a moderate orsevere depressed state

Intervention

Vortioxetine

Comparator(a) No drug treatment for patients with mild depression or in a mild
depressed state(b) New generation antidepressants for patients with moderate orsevere depression or in a moderate or severe depressed state

Outcome

Improvement in depressed state, selected as the primary endpoint
SafetyStudy design

Two-step systematic review
Step 1: Systematic review, meta-analysis, and network meta-analysis
16

Step 2: Randomized controlled studies
Period of(1)

literature(2) After the period of the previously reported systematic reviews until

searchto May 2020
May 2020

2.1.2 Flow of systematic review
2.1.2.1 Population (a) mild depression or in a mild depressed state
According to the Clinical Practice Guidelines for Depression published by the JapaneseSociety of Mood Disorders (7), DSM-5 is used to define mild depression as the individual
must be experiencing five or more symptoms, most of the day, nearly every day, during thesame 2-week period, and at least one of the symptoms should be either “depressed mood”
or “loss of interest or pleasure”. The guideline also states that “Some overseas guidelines
propose using depression severity rating scales to define mild depression. Patients are
given a diagnosis of a depressive state if they have a score of 8 to 13 on the Hamilton
Depression Rating Scale, and a diagnosis of mild depression if they have a score of 14 to
18 in the NICE guidelines in the U.K. According to the APA guidelines in the U.S., patientsare diagnosed with mild depression if they have a score of 8 to 13, and with moderate
depression if they have a score of 14 to 18. As we observe in these guidelines, there is noconsensus about the diagnosis of mild depression (p.29)”. It was anticipated that exact
screening of “patients with mild depression or in a mild depressed state” would have
limitations as a strategy for literature search. Therefore, the population was set as “patientswith depression or in a depressed state” in the search of evidence. Then, the patients
included in the identified studies were screened afterwards to determine whether any
patients in the studies met the criteria for mild depression defined as if they had a MADRS
score of 19 or lower (8) (9) since the MADRS scores were most commonly used in theclinical studies for vortioxetine.
2.1.2.2 Population (b) patients with moderate or severe depression or in a moderateor severe depressed state
For the assessment of additional benefits of vortioxetine in patients with moderate orsevere depression or in a moderate or severe depressed state, a two-step systematic
review was performed with reference to the Minds Handbook for Clinical Practice Guideline
Development (10) (Figure 2-1).
17

(1) Systematic review intended to identify previously
reported systematic reviews(2) Systematic review intended to identify relevant
randomized controlled studies published after thelatest randomized controlled studies searched for in
the previously reported systematic reviews(additional systematic review)

Identify the relevant randomized controlled
studies included in the previously reported
systematic reviews

Identify the relevant randomized controlled studies
conducted after the previously reported systematic
reviews

Identify the relevant randomized controlled
studies for additional benefit assessment

Figure 2-1 Flow of two-step systematic review
A medical information services/literature search expert developed the search strategy by
combining conditions for disease name, drug name, study design, and search period.
Screening based on literature abstracts was performed blinded by 2 independent
reviewers. Inclusion or exclusion of literature was determined on the basis of theprespecified inclusion and exclusion criteria, and inconsistencies between the reviewersthat occurred during the process were resolved through discussion by both reviewers.
2.1.3 Inclusion and exclusion criteria<Inclusion criteria>Disease as depression or depressed stateIntervention as vortioxetineStudy design as systematic review in Step 1 and a randomized controlled study in
Step 2

Published during the designated period



Written in English or Japanese<Exclusion criteria>
Abstracts or meeting minutes
2.1.4 Databases

18

PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane
Database of Systematic Reviews, and Ichushi-Web.
2.1.5 Search strategy
Search strategy for PubMed
Date of search: May 7, 2020
"Depressive Disorder"[MH] OR "Depression"[MH] OR "depressive"[TW] OR"depression"[TW]) AND ("Vortioxetine"[MH] OR vortioxetine[TIAB] OR brintellix[TIAB] OR"Lu AA21004"[TIAB]) AND (systematic[SB] OR "Network Meta-Analysis"[MH] OR "MetaAnalysis as Topic"[MH] OR "Randomized Controlled Trials as Topic"[MH] OR "MetaAnalysis"[PT] OR "meta analysis"[TI] OR "network meta analysis"[TI]) AND
2015:2020[PDAT]
A total of 51 publications
Search strategy for Embase
Date of search: May 7, 2020
(EMB.EXACT.EXPLODE("depression") AND EMB.EXACT("vortioxetine")) AND(EMB.EXACT.EXPLODE("systematic review") OR EMB.EXACT.EXPLODE("metaanalysis") OR EMB.EXACT("network meta-analysis")) AND PD(2015-2020)
A total of 93 publications
Search strategy for Cochrane
Date of search: May 7, 2020#1

(depressive):ti,ab,kw OR (depression):ti,ab,kw (Word variations have been
searched)#2

MeSH descriptor: [Depressive Disorder] explode all trees#3

MeSH descriptor: [Depression] explode all trees#4(vortioxetine):ti,ab,kw OR (brintellix):ti,ab,kw OR (Lu AA21004):ti,ab,kw (Wordvariations have been searched)#5

MeSH descriptor: [Vortioxetine] explode all trees#6(#1 OR #2 OR #3) AND (#4 OR #5) in Cochrane Reviews

A total of 1 publication

19

Search strategy for Ichushi
Date of search: May 7, 2020
うつ病/TH or 抑うつ/TH or 鬱/TA) and (Vortioxetine/TH or ボルチオキセチン/TA or トリン
テリックス/TA or Vortioxetine/TH or brintellix/TA) and PT=原著論文 and DT=2015:2020
A total of 2 publications
The search strategy for the systematic review intended to identify relevant randomized
controlled studies published after the latest randomized controlled studies identified in thepreviously reported systematic reviews are presented below:
Search strategy for PubMed
Date of search: May 7, 2020
"Depressive Disorder"[MH] OR "Depression"[MH] OR "depressive"[TW] OR"depression"[TW]) AND ("Vortioxetine"[MH] OR vortioxetine[TIAB] OR brintellix[TIAB] OR"Lu AA21004"[TIAB]) AND ("Randomized Controlled Trial"[PT] OR ("randomized"[TI]AND (trial[TI] OR trials[TI])) OR "double blind"[TIAB]) AND 2016:2020[PDAT]
A total of 54 publications
Search strategy for Embase
Date of search: May 7, 2020
EMB.EXACT.EXPLODE("depression") AND EMB.EXACT("vortioxetine") AND(EMB.EXACT.EXPLODE("randomized controlled trial")) AND PD(2016-2020)
A total of 55 publications
Search strategy for Cochrane
Date of search: May 7, 2020#1

(depressive):ti,ab,kw OR (depression):ti,ab,kw (Word variations have been
searched)#2

MeSH descriptor: [Depressive Disorder] explode all trees#3

MeSH descriptor: [Depression] explode all trees#4(vortioxetine):ti,ab,kw OR (brintellix):ti,ab,kw OR (Lu AA21004):ti,ab,kw (Wordvariations have been searched)#5

MeSH descriptor: [Vortioxetine] explode all trees#6(#1 OR #2 OR #3) AND (#4 OR #5) with Publication Year from 2016 to 2020, in
Trials20

A total of 85 publications
Search strategy for Ichushi
Date of search: May 7, 2020
うつ病/TH or 抑うつ/TH or 鬱/TA) and (Vortioxetine/TH or ボルチオキセチン/TA or トリン
テリックス/TA or Vortioxetine/TA or brintellix/TA) and PT=原著論文 and DT=2016:2020
A total of 2 publications

21

2.1.6 Search results
The results of the systematic review are summarized as shown in Figure 2-2.
Step 1: Systematic review intended
to identify previously reported
systematic reviews

Identification No. of publications identified throughdatabase search(n = 147)
Screening

No. of publications
after duplicates
removed (n = 78)

Step 2: Systematic review intended
to identify relevant randomized
controlled studies published after thelatest clinical studies searched for in
the previously reported systematic
reviews
No. of publications identified throughdatabase search(n = 196)
No. of publications
after duplicates
removed (n = 113)

No. of publications
screened(n = 78)

No. ofpublications
excluded(n = 64)

No. of publications
screened(n = 113)

No. ofpublications
excluded(n = 107)

Eligibility

No. of publications
assessed for
eligibility (n = 14)

No. ofpublications
excluded(n = 12)

No. of publications
assessed for
eligibility (n = 6)

No. ofpublications
excluded(n = 2)

Included

No. of systematic
review publications(n = 2)

No. ofpublications
excluded(n = 1)

No. of randomized
controlled studies(n = 4)

No. ofpublications
excluded(n = 1)

No. of randomized
controlled studies(n = 15)

No. ofpublications
excluded(n = 4)

No. of randomized
controlled studies(n = 3)

No. of randomized
controlled studies(n = 11)
Figure 2-2 Summary of results of systematic review

22

The following two systematic reviews were identified:1.

Cipriani, Andrea, et al. "Comparative efficacy and acceptability of 21 antidepressantdrugs for the acute treatment of adults with major depressive disorder: a systematic
review and network meta-analysis." Lancet 16.4 (2018): 420-429.

2.

Wagner, Gernot, et al. "Efficacy and safety of levomilnacipran, vilazodone andvortioxetine compared with other second-generation antidepressants for major
depressive disorder in adults: A systematic review and network meta-analysis." Journalof Affective Disorders 228 (2018): 1-12.

Table 2-2 Summary of the literature identified as previously reported systematic
reviews
Literature

Cipriani et al. (2018) (11)

Wagner et al. (2018) (12)No. of enrolled

522

24

116,477

4,023

Duration of subject

From the start of collection of

From January 2010 toregistration

the database to January 8,

September 2017

studiesNo. of enrolled
subjects

2016
Population

Patients with acute-phase

Adult patients with MDD

MDD aged ≥18 years
Key exclusion criteria

Studies that included 20% orStudies that enrolled patients

more of participants withaged ≥65 years

bipolar disorder, psychotic
depression, or treatmentresistant depression; orpatients with a serious
concomitant medical illness
Study design

Double-blind RCTs

Double-blind RCTs for efficacy
and non-randomized studies
with a sample size of ≥100 for
safety23

DrugsSecond-generation

Second-generation

antidepressants

antidepressantsAgomelatine, bupropion,

Bupropion, citalopram,

citalopram, desvenlafaxine,

desvenlafaxine, duloxetine,

duloxetine, escitalopram,

escitalopram, fluoxetine,

fluoxetine, fluvoxamine,

fluvoxamine, levomilnacipran,levomilnacipran, milnacipran,mirtazapine, nefazodone,

mirtazapine, paroxetine,paroxetine, sertraline,

reboxetine, sertraline,

venlafaxine, vilazodone,

venlafaxine, vilazodone,

vortioxetine, and trazodone

vortioxetine), tricyclic
antidepressants (amitriptyline,
clomipramine), trazodone, andnefazodone (21 drugs in total)
Bias assessment

The Cochrane Handbook for

Grades the strength of

Systematic Reviews ofevidence with Evidence-basedInterventions, the Grading of

Practice Center Program of

Recommendations

the Agency for Healthcare

Assessment, Development

Research and Quality

and Evaluation (GRADE)
framework
Primary endpoint

The efficacy outcome was

Response rate (a reduction of

response rate (proportion of≥50% of the HAM-D scorepatients who had a reduction

compared to baseline)of ≥50% of their total score ona standardized observer-rating
scale for depression compared
to baseline).
The safety outcome was the
proportion of patients who
discontinued treatment due toany cause.
Enrollment of patientsNo

No

with mild depression

24

The study by Wagner et al. (2018) enrolls adult patients with MDD and presents pooled
results of 24 previous clinical studies (placebo- and active-controlled studies) with 16
different new generation antidepressants (including those not marketed in Japan) as
comparators. This study was conducted to compare the efficacy and safety mainly on
levomilnacipran, vilazodone, and vortioxetine with those of other new generation
antidepressants; however, it was excluded from this review because levomilnacipran andvilazodone had not been approved in Japan .
The study by Cipriani et al. (2018) enrolls adult patients with MDD and presents
pooled results of 522 previous clinical studies (placebo- and active-controlled studies) using
21 different antidepressants (including those not marketed in Japan) as comparators. Thisis the most comprehensive study of the efficacy and safety of new generation
antidepressants, including vortioxetine, and it does not narrow the framework of theacademic group.
For the studies of vortioxetine enrolled in the study by Cipriani et al. (2018), 15
placebo- and active-controlled studies were identified. Of the 15 studies, two studies
conducted by McIntyre et al. (2014) (13) and Mahableshwarkar et al. (2015) (14) were
excluded from this analysis because the primary outcome was improvement in cognitive
function in both studies. Two studies (CCT002 involving Japanese subjects; CCT003
including Japanese subjects), which were not published at the time of publication of theresearch paper by Cipriani et al. (2018), were identified as previously reported RCT
publications in the additional systematic review described later. A total of 11 studies listed
below were identified as randomized controlled studies searched for in the previously
reported systematic review. None of the studies enrolled patients with mild depression.
<List of the randomized controlled studies>
1.

Alvarez E, Perez V, Dragheim M, Loft H, Artigas F. A double-blind, randomized,
placebo-controlled, active reference study of Lu AA21004 in patients with major
depressive disorder. International Journal of Neuropsychopharmacology.
2012;15(5):589-600.

2.

Baldwin DS, Loft H, Dragheim M. A randomised, double-blind, placebo controlled,
duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in acutetreatment of major depressive disorder (MDD). European Neuropsychopharmacology.
2012;22(7):482-91.

25

3.

Boulenger J-P, Loft H, Olsen CK. 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.
International clinical psychopharmacology. 2014;29(3):138.

4.

Henigsberg N, Mahableshwarkar AR, Jacobsen P, Chen Y, Thase ME. A randomized,
double-blind, placebo-controlled 8-week trial of the efficacy and tolerability of multiple
doses of Lu AA21004 in adults with major depressive disorder. The Journal of clinicalpsychiatry. 2012;73(7):953-9.

5.

Jacobsen PL, Mahableshwarkar AR, Serenko M, Chan S, Trivedi MH. 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. The Journal of clinical psychiatry.
2015;76(5):575-82.

6.

Jain R, Mahableshwarkar AR, Jacobsen PL, Chen Y, Thase ME. A randomized,
double-blind, placebo-controlled 6-wk trial of the efficacy and tolerability of 5 mg
vortioxetine in adults with major depressive disorder. International Journal of
Neuropsychopharmacology. 2013;16(2):313-21.

7.

Katona C, Hansen T, Olsen CK. 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. International clinicalpsychopharmacology. 2012;27(4):215-23.

8.

Mahableshwarkar AR, Jacobsen PL, Chen Y. A randomized, double-blind trial of 2.5
mg and 5 mg vortioxetine (Lu AA21004) versus placebo for 8 weeks in adults withmajor depressive disorder. Current medical research and opinion. 2013;29(3):217-26.

9.

Mahableshwarkar AR, Jacobsen PL, Chen Y, Serenko M, Trivedi MH. 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.
2015;232(12):2061-70.

10. Mahableshwarkar AR, Jacobsen PL, Serenko M, Chen Y, Trivedi MH. A randomized,
double-blind, placebo-controlled study of the efficacy and safety of 2 doses ofvortioxetine in adults with major depressive disorder. The Journal of clinical psychiatry.
2015;76(5):583-91.
11. Wang G, Gislum M, Filippov G, Montgomery S. Comparison of vortioxetine versus
venlafaxine XR in adults in Asia with major depressive disorder: a randomized, doubleblind study. Current medical research and opinion. 2015;31(4):785-94.

26

For Step 2, 4 studies, including 2 (CCT002 involving Japanese subjects; CCT003 including
Japanese subjects) that were not published at the time of publication by Cipriani et al.
(2018), were identified. Of them, the publication by Wang et al. (2019) (15) was excluded
from this review due to its withdrawal after publication. The following 3 studies wereidentified as relevant randomized controlled studies:1.

Nishimura A, Aritomi Y, Sasai K, Kitagawa T, Mahableshwarkar AR. Randomized,
double-blind, placebo-controlled 8-week trial of the efficacy, safety, and tolerability of 5,
10, and 20 mg/day vortioxetine in adults with major depressive disorder. Psychiatry andClinical Neurosciences. 2018;72(2):64-72.

2.

Inoue T, Nishimura A, Sasai K, Kitagawa T. Randomized, 8-week, double-blind, placebocontrolled trial of vortioxetine in Japanese adults with major depressive disorder,
followed by a 52-week open-label extension trial. Psychiatry and clinical neurosciences.
2018;72(2):103-15.

3.

Inoue T, Sasai K, Kitagawa T, Nishimura A, Inada I. Randomized, double-blind, placebocontrolled study to assess the efficacy and safety of vortioxetine in Japanese patientswith major depressive disorder. Psychiatry and clinical neurosciences. 2020;74(2):1408.

27

2.1.7 Summary of clinical studies
Table 2-3 Summary of the clinical studies included in the previously reported systematic reviews
ID Literature Study
Sample Drug namePrescribed Key eligibility criteria
Key exclusion criteria
No.
name/
size
dose (mg)
year
1
(16)
11492A, 426
Placebo
MDD(DSM-IV-TR
Current psychiatric disorder
NCT008
criteria),
Current
MDE≥3other than MDD, History of
Vortioxetine
539423/2mths
and<12mths,Agemanic or hypomanic
10
007
≥18
and
≤65
years,
episode, schizophrenia, any
Venlafaxine
225
MADRS total score ≥30
other psychotic, mental orneurological disorder (otherthan MDD), Current
2(17)11984A, 766
Placebo
MDD(DSM-IV-TR
NCT006
criteria), Current MDE≥ 3 substance abuse,
Vortioxetine
2.5
Significant risk of suicide,35219/2
mths, MADRS≥26,
5009
Age≥18 and ≤75 yrs old, attempted suicide in past 6
10months, or score ≥5 on
Duloxetine
60
3
(18)
13267A, 607
Placebo
Recurrent MDD(DSM-IV- MADRS item 10 (suicidal
thoughts), TreatmentNCT011
TR criteria), Current
Vortioxetine
15
resistant depression
40906/2
MDE≥3 mths,
20(defined as non-response to
011
MADRS≥26, CGI-S
Duloxetine
60
2 antidepressant treatments
score ≥ 4, Age≥18 andVortioxetine
5of at least 6-week duration),≤75 yrs old
Duloxetine
60
History of lack of response
4
(19)
304,
611
Placebo
MDD(DSM-IV-TR
to duloxetine (11984A,
NCT006
criteria), Current MDE≥3
Vortioxetine
2.513267A, 12541A, 304, 315)
72620/2
mths, MADRS≥22,
5or venlafaxine (11492A,
008
Age≥18 and ≤75 yrs old
Duloxetine
60
13926A), Currently

Primary
outcome
Changefrombaseline
to week 6 in
MADRS
Changefrombaseline
to week 8 in
MADRS

Changefrombaseline toweek 8 in
HAM-D24

28

5

(14)

315,
NCT01153009/2
012

614

Placebo
Vortioxetine
Vortioxetine
Duloxetine

15
20
60

6

(20)

437

Vortioxetine
Venlafaxine

10
150

7

(21)

NCT01571453,
KCT0000432,
13926A/2013
12541A,
NCT00811252/2
010

453

Placebo
Vortioxetine
Duloxetine

5
60

8

(22)

305,
NCT00735709/2009

560

Placebo
Vortioxetine

1
5
10

Recurrent MDD(DSM-IVTR criteria), Current
MDE≥3 mths,
MADRS≥26, CGI-S
score ≥ 4, Age≥18 and≤75 yrs old
Recurrent MDD(DSM-IVTR criteria), Current
MDE≥3 mths,
MADRS≥26, CGI-S
score ≥ 4, Age≥18 and≤65 yrs old
MDD(DSM-IV-TR
criteria), MADRS≥26,
elderly ≥ 65yrs old, MDE≥4 weeks in duration, At
least 1 MDE before ageof 60 years

MDD(DSM-IV-TR
criteria), Current MDE≥3mths, MADRS≥26,
Age≥18 and ≤75 yrs oldreceiving cognitive or
behavioral therapy orsystematic psychiatry

Changefrombaseline
to week 8 in
MADRS

Current psychiatric disorder
other than MDD, History ofmanic or hypomanic
episode, schizophrenia, anyother psychotic, mental orneurological disorder (otherthan MDD), Current
substance abuse,
Significant risk of suicide,attempted suicide in past 6months, or score ≥5 on
MADRS item 10 (suicidal
thoughts), Mini-Mental
State Exam < 24
Current psychiatric disorder
other than MDD, History ofmanic or hypomanic
episode. schizophrenia, Anyother psychotic, mental or

Changefrombaseline toweek 8 in
HAM-D24

Changefrombaseline toweek 8 in
HAM-D24

29

9

(23)

316,
NCT011
63266
/2012

462

Placebo
Vortioxetine
Vortioxetine

10
20

Recurrent MDD(DSM-IVTR criteria), CGI-S score≥ 4, MADRS≥26,
Age≥18 and ≤75 yrs old

10

(24)

303,
NCT006
72958
/2008

600

Placebo
Vortioxetine

5

MDD (DSM-IV-TR
criteria), Current MDE≥3mths, MADRS≥30,
Age≥18 and ≤75 yrs old

11

(25)

317,
NCT01179516/2
012

469

Placebo
Vortioxetine
Vortioxetine

10
15

Recurrent MDD (DSMIV-TR criteria), CGI-S
score ≥ 4, Current
MDE≥3 mths,
MADRS≥26, Age≥18
and ≤75 yrs old

neurological disorder (otherthan MDD), Significant riskof suicide, attemptedsuicide in past 6 months, orscore 5 on MADRS item 10(suicidal thoughts),
Treatment-resistantdepression (defined as nonresponse to 2
antidepressant treatments
of at least 6-week duration)

Changefrombaseline
to week 8 in
MADRS
Changefrombaseline toweek 6 in
HAM-D24
and at eachweek oftreatment
Changefrombaseline
to week 8 in
MADRS

30

Table 2-4 Efficacy outcomes (1) change in MADRS (2) change in HAM-D24 (the primary outcomes are shaded with
)
ID
Study
Drug
Prescribed(1) Change in MADRS(2) Change in HAM-D24
name/year
namedose (mg)Mean difference of placebo versus the comparator
Mean (SE)
95% CI
p-value
Mean (SE)
95% CI
p-value
111492A,
Placebo
NCT00839423/ Vortioxetine 5-5.90 (1.39) -8.64 – -3.17<0.001-5.28 (1.22)-7.69 – -2.88<0.0012007
10-5.70 (1.42) -8.49 – -2.91<0.001-5.33 (1.25)-7.79 – -2.88<0.001
Venlafaxine 225-6.42 (1.38) -9.13 – -3.72<0.001-5.09 (1.21)-7.48 – -2.70<0.001
211984A,
Placebo
0.22-1.11 (1.12)-3.31 – 1.10
0.32
NCT00635219/ Vortioxetine 2.5-1.38 (1.12)-3.59 – 0.82
2009
5-1.70 (1.13)-3.92 – 0.51
0.13
-1.79 (1.13)-4.01 – 0.42
0.11
10-1.50 (1.13)-3.73 – 0.72
0.18
-1.63 (1.13)-3.85 – 0.59
0.15
Duloxetine60-2.04 (1.14)-4.27 – 0.20
0.07
-2.47 (1.13)-4.70 – 0.24
0.03
313267A,
Placebo
NCT01140906/ Vortioxetine 15-5.53 (1.09) -7.66 – -3.44<0.0012011
20-7.09 (1.08) -9.21 – -4.97<0.001
Duloxetine60-9.45 (1.07) -11.55 – -7.35<0.001

31

4

304,
NCT00672620/
2008

5

315,
NCT01153009/
2012

6

NCT01571453,
KCT0000432,
13926A/2013
12541A,
NCT00811252/
2010
305,
NCT00735709/
2009

7

8

5
60
15
20
60
10
150

-0.08 (1.12)-2.87 (1.13)-1.5(1.21)-2.8(1.21)-4.1(1.21)-1.20 (0.93)--2.28 – 2.12
-5.10 – -0.65-3.86 – 0.91
-5.12 – -0.38-6.46 – -1.69-3.03 – 0.63
-

0.94
0.01
0.22
0.02
<0.001
0.19-

Placebo
Vortioxetine
Duloxetine
Placebo
Vortioxetine

5
60
5
10

-4.29 (1.03)-6.83 (1.05)-4.18 (1.00)-4.75 (1.01)-6.32 – -2.26-8.89 – -4.78-6.14 – -2.22-6.74 – -2.76<0.001<0.001<0.001<0.001

Placebo
Vortioxetine
Duloxetine
Placebo
Vortioxetine
Duloxetine
Vortioxetine
Venlafaxine

9316,
NCT01163266/2012

Placebo
Vortioxetine

1020-2.19 (1.15)-3.64 (1.16)-4.45 – 0.08
-5.92 – -1.35

0.058
0.002

10

303,
NCT00672958
/2008
317,
NCT01179516/
2012

Placebo
Vortioxetine

5-0.32 (0.95)-2.19 – 1.55

0.74

Placebo
Vortioxetine

1015-0.79 (1.49)-0.49 (1.50)-3.71 – 2.14
-3.44 – 2.46

0.60
0.75

11

-0.58 (1.04)-2.96 (1.05)-2.61 – 1.46
-5.02 – -0.91

0.58
0.005

-3.32 (1.01)-5.48 (1.03)-5.31 – -1.34-7.50 – -3.46<0.001<0.001-4.12 (1.04)-4.93 (1.05)-6.17 – -2.08-6.99 – -2.86<0.001-0.74 (0.89)-2.48 – 1.01

0.41

32

Table 2-5 Safety outcomes (1) incidence of serious adverse events (any serious TEAE: treatment-emergent adverse event) (2)incidence of adverse events leading to discontinuation (any TEAE: treatment-emergent adverse event, leading to discontinuation)ID

Study name/year

Drug namePrescribed
dose (mg)1

11492A,
NCT00839423/2007

Placebo
Vortioxetine

211984A,
NCT00635219/2009

Venlafaxine
Placebo
Vortioxetine

313267A,
NCT01140906/2011

Duloxetine
Placebo
Vortioxetine

4304, NCT00672620/2008

5315, NCT01153009/2012

5
10
225
2.5
5
10
60
15
20
60
5
60
15
20
60
10
150

6

NCT01571453,
KCT0000432, 13926A/2013

Duloxetine
Placebo
Vortioxetine
Duloxetine
Placebo
Vortioxetine
Duloxetine
Vortioxetine
Venlafaxine

Samplesize(1) Incidence of serious
adverse events (anyserious TEAE: treatmentemergent adverse event)
n(%)

105
108
100
113
148
155
157
151
155
158
151
151
147
151
153
150
159
147
154
150
211
226

0
0
2(2)
1(1)
3(2)
1(0.7)
3(2)
2(1)
2(1)
0
0
2(1)
3(2)
2(1)
3(2)
2(1)
0
2(1)
0
0
2(1)
8(4)

(2) Incidence of adverse
events leading todiscontinuation (any
TEAE: treatmentemergent adverse event,leading to discontinuation)
n (%)
4(4)
3(3)
7(7)
16(14)12(8)10(6)
18(11)
15(10)
19(13)7(4)10(7)
17(11)
7(5)
8(5)
13(9)
16(11)
5(3)
14(10)
14(9)
11(7)
14(7)
32(14)
33

712541A,
NCT00811252/2010

8305, NCT00735709/2009

9316, NCT01163266/2012

Placebo
Vortioxetine

10

303, NCT00672958/2008
317, NCT01179516/2012

Placebo
Vortioxetine
Placebo
Vortioxetine

11

Placebo
Vortioxetine
Duloxetine
Placebo
Vortioxetine

5
60
5
10
10
20

145
156
151
140
140
139
157
155
150

4(3)
1(1)
1(1)
2(1)
1(1)
2(1)
0
2(1)
0

6(4)
10(6)
15(10)
2(1)
1(1)
5(4)
2(1)
9(6)
7(5)

5
10
15

298
299
160
154
151

4(1)
7(2)
1(1)
1(1)
0

9(3)
9(3)
6(4)
8(5)
12(8)

34

Table 2-6 Summary of the clinical studies published after the latest clinical studies included in the previously reported systematic
reviews
Study name,bibliographic
information

CCT002 (26)
Nishimura et al (2018)
ClinicalTrials.gov Identifier:
NCT01255787

CCT 003 (27)
Inoue et al (2018)
ClinicalTrials.gov Identifier:
NCT01395147

CCT 004 (28)
Inoue et al (2020)
ClinicalTrials.gov Identifier:
NCT02389816

Trintellix Tablets 10 mg, Trintellix Tablets 20 mg, Review Report (29) and Interview Form (30)Study period

November 2010 to April 2012

May 2011 to December 2012

April 2015 to March 2018

Study design

Randomized controlled study

Randomized controlled study

Randomized controlled study

Sample size

593 subjects (151 subjects in theplacebo group, 144 subjects in thevortioxetine 5 mg group, 148 subjects inthe vortioxetine 10 mg group, and 150
subjects in the vortioxetine 20 mggroup)

Patients mainly diagnosed withmajor depressive disorderaccording to DSM-IV-TR
Patients aged between 20 and 64
yearsPatients with current major
depressive episodes ≥3 months atscreening
Patients with a MADRS total score≥26 and a Clinical Global
Impressions-Severity (CGI-S)
score ≥4366 subjects (124 subjects in theplacebo group, 119 subjects in thevortioxetine 5 mg group, and 123
subjects in the vortioxetine 10 mg group)

493 subjects (164 subjects in theplacebo group, 165 subjects in thevortioxetine 10 mg group, and 164
subjects in the vortioxetine 20 mg group)

Eligibility
criteria








Patients mainly diagnosed withmajor depressive disorder according
to DSM-IV-TR
Patients aged between 20 and 75
years
Patients with current major
depressive episodes ≥3 months at
the start of run-in period
Patients with a MADRS total score≥26 and a Clinical Global
Impressions-Severity (CGI-S) score
≥4








Patients mainly diagnosed withrecurrent major depressive disorderaccording to DSM-IV-TR
Patients aged between 20 and 75
years
Patients with current major
depressive episodes ≥3 and ≤12monthsPatients with a MADRS total score≥26, a HAM-D17 total score ≥18,
and a CGI-S score ≥435

Exclusion
criteriaPatients who have concurrent
psychiatric disorders other thanmajor depressive disorder(however, those with anxiety
symptoms will also be eligible forthe study unless they meet thediagnostic criteria for anxiety
disorder as defined by DSM-IV-TR)
Patients who have concurrent or ahistory of manic or hypomanic
episodes, schizophrenia, or otherpsychotic disorders as defined by
DSM-IV-TR (including major
depressive disorder with psychotic
features, mental retardation, an
organic mental disorder, or a
psychiatric disorder accompaniedby general somatic disorders)Patients with DSM-IV-TR Axis II
disorders that could potentiallyaffect evaluation of the study
results

Patients who have concurrent
psychiatric disorders other thanmajor depressive disorder as
defined by DSM-IV-TR
Patients who have concurrent or ahistory of manic or hypomanic
episodes, schizophrenia, or otherpsychotic disorders as defined by
DSM-IV-TR (including major
depressive disorder with psychotic
features, mental retardation, an
organic mental disorder, or a
psychiatric disorder accompanied bygeneral somatic disorders)Patients with DSM-IV-TR Axis II
disorders that could potentiallyaffect evaluation of the study results











Patients who have concurrent
psychiatric disorders other thanmajor depressive disorder as
defined by DSM-IV-TR
Patients who have concurrent or ahistory of manic, mixed, or
hypomanic episodes, major
depressive disorder with psychotic
features, schizophrenia, or otherpsychotic disorders as defined by
DSM-IV-TR (including substancerelated mental disorder or a
psychiatric disorder accompanied bygeneral somatic disorders)Patients who have experienced an
inadequate response to a sufficientamount of two or more
antidepressants for at least 6 weeks
for the treatment of current or pastmajor depressive episodes
Patients who have undergone
escalated drug therapy (i.e., theaddition of lithium,triiodothyronine/thyroxine,
lamotrigine, valproic acid,carbamazepine, or atypicalantipsychotics, or concomitant useof antidepressants) for the treatmentof current major depressive
episodesPatients who have undergone
electroconvulsive therapy, vagal
nerve stimulation, or repetitivetranscranial magnetic stimulation
within 6 months of the run-in period

36Patients who are receiving cognitive
behavior therapy or psychotherapy
at the time of informed consent, orare scheduled to receive treatment
during the study period
Placebo lead-in period: Administer one
tablet of a placebo once daily for 1 week.
Treatment period: Administer one tabletof vortioxetine 10 or 20 mg or theplacebo once daily for 8 weeks.
• Patients who experienced an
improvement or reduction in their
MADRS total score ≥25% during theplacebo lead-in period are excluded fromrandomization during the treatment
period.
Primary endpoint: Change from baseline
in MADRS total score at Week 8
Secondary endpoints: MADRS response
and remission rates at Week 8 andchange from baseline in HAM-D17 totalscore


Method ofadministration

Administer one tablet of vortioxetine 5,
10, or 20 mg or a placebo once daily for
8 weeks.

Administer one tablet of vortioxetine 5 or
10 mg or a placebo once daily for 8
weeks.
Observation period (1): Administer one
tablet of the placebo once daily for 2
weeks.
Observation period (2): Follow-up for 2
weeks

Efficacy
outcomes

Primary endpoint: Change frombaseline in MADRS total score at Week
8
Secondary endpoints: MADRS
response and remission rates at Week
8

Safety

Primary endpoint: Change from baseline
in MADRS total score at Week 8
Secondary endpoints: MADRS response
and remission rates at Week 8 andchange from baseline in Hamilton
Depression Rating Scale 17 item (HAMD17) total score
Adverse events, laboratory tests(hematology, blood biochemistry,
and urinalysis), vital signs, 12-lead
ECG, body weight, and physicalexamination
Suicidal ideation or suicidal behavior(evaluation using the ColumbiaSuicide Severity Rating Scale [CSSRS])When analyzed using ANCOVA, thechanges from baseline in the
MADRS total score at Week 8 were

Results(efficacy)Adverse events, laboratory tests(hematology, blood biochemistry,
and urinalysis), vital signs, 12-lead
ECG, body weight, and physicalexamination
Suicidal ideation or suicidal
behavior (evaluation using theColumbia-Suicide Severity Rating
Scale [C-SSRS])
The changes from baseline in the
MADRS total score at Week 8
were −13.99 in the placebo group,







Adverse events, laboratory tests(hematology, blood biochemistry,
and urinalysis), vital signs, 12-lead
ECG, and body weight
Suicidal ideation or suicidal behavior(evaluation using the C-SSRS)

The changes from baseline in the
MADRS total score at Week 8 were
−12.37 in the placebo group, −15.03

37





Results(safety)−14.61 in the vortioxetine 5 mggroup, −15.68 in the vortioxetine
10 mg group, and −15.82 in thevortioxetine 20 mg group.
The point estimates of thedifferences between thevortioxetine 5, 10, and 20 mggroups and the placebo group(each vortioxetine group – placebogroup) were –0.61, –1.69, and –1.82, respectively.
There were no statisticallysignificant differences among thetreatment groups.
The incidence of adverse event
was 40.4% (61/151 subjects) in theplacebo group, 47.2% (68/144
subjects) in the vortioxetine 5 mggroup, 48.6% (72/148 subjects) in
the vortioxetine 10 mg group, and56.7% (85/150 subjects) in thevortioxetine 20 mg group.
Adverse event that occurred in thevortioxetine 5, 10, or 20 mg groups
with an incidence of ≥5% were
nausea, dry mouth, headache, anddizziness. Serious adverse event
occurred in 2 subjects: suicide
attempt and suicidal ideation
reported in 1 subject in thevortioxetine 20 mg group, andabortion missed in 1 subject in thevortioxetine 20 mg group.











−13.81 in the placebo group, −15.84
in the vortioxetine 5 mg group, and−14.85 in the vortioxetine 10 mggroup.
The point estimates of thedifferences between the vortioxetine
5 or 10 mg groups and the placebogroup were –2.03 and –1.04,
respectively.
There were no statisticallysignificant differences between thetreatment groups.

The incidence of adverse event was
33.1% (41/124 subjects) in theplacebo group, 41.2% (49/119
subjects) in the vortioxetine 5 mggroup, and 57.4% (70/122 subjects)
in the vortioxetine 10 mg group.
Adverse event that occurred in thevortioxetine 5 or 10 mg groups withan incidence of ≥5% were nausea,
diarrhea, somnolence, andheadache.
The incidence of severe adverse
event was 0.8% (1/124 subjects) inthe placebo group, 0.8% (1/119
subjects) in the vortioxetine 5 mggroup, and 0% in the vortioxetine 10
mg group.
A serious adverse event was
suicidal behaviour reported in 1







(p=0.0080) in the vortioxetine 10 mggroup, and −15.45 (p=0.0023) in thevortioxetine 20 mg group.
Analysis was performed using amixed-effects model for measuresover time, with change frombaseline in the MADRS total scoreas a dependent variable andevaluation time point, treatmentgroup, interaction of treatment groupwith evaluation time point, andinteraction of baseline MADRS total
score with evaluation time point as
fixed effects.
Major adverse event (those with anincidence of ≥5%) were nausea
reported in 1 (0.6%), 20 (12.1%),
and 25 (15.3%) subjects,
respectively, in the placebo,
vortioxetine 10 mg, and vortioxetine
20 mg groups, vomiting in 0 (0%), 9(5.5%), and 4 (2.5%) subjects,
respectively, and somnolence in 6
(3.7%), 7 (4.2%), and 11 (6.7%)
subjects, respectively.
Adverse event leading to treatment
discontinuation were headache,akathisia, and sleep attacks in 1
subject each in the placebo group,
vomiting in 3 subjects, andheadache and insomnia in 1 subject
each in the vortioxetine 10 mggroup, and vomiting in 3 subjects
and abdominal discomfort and38

The incidence of adverse event
leading to discontinuation was
2.0% (3/151 subjects) in theplacebo group, 1.4% (2/144
subjects) in the vortioxetine 5 mggroup, 5.4% (8/148 subjects) in thevortioxetine 10 mg group, and
4.0% (6/150 subjects) in thevortioxetine 20 mg group.

subject in the vortioxetine 10 mggroup.
The incidence of adverse event
leading to discontinuation was 2.4%
(3/124 subjects) in the placebogroup, 0.8% (1/119 subjects) in thevortioxetine 5 mg group, and 2.5%
(3/122 subjects) in the vortioxetine
10 mg group.

nausea in 1 subject each in thevortioxetine 20 mg group.
A serious adverse event, including
death, was cerebral hemorrhage
reported in 1 subject (fatal) in thevortioxetine 20 mg group.
The incidence of adverse eventswas 13.0%, 24.8%, and 26.4%,
respectively, in the placebo,
vortioxetine 10 mg, and vortioxetine
20 mg groups between Day 1 andDay 7.

39

2.1.7.1 Summary of clinical trials
As shown in Tables 2-3 to 2-6, the distribution of patient characteristics (such as age,
medical history, severity at baseline, and whether recurrent major depressive disorder isstudied) in the clinical studies evaluating vortioxetine included in the study by Cipriani et al.
(2018) varies across the studies. Of 11 studies, 7 were active-controlled studies and therest were placebo-controlled. Four of the studies demonstrated a statistically significant
difference in the primary outcome, improvement in depressed state. In contrast, nosignificant differences were found in 5 of the studies, and a significant difference was
detected only in the maximum dose group in the remaining two studies.
Phase 3 studies have been conducted three times in Japan so far: CCT002 and
CCT003 in patients with MDD demonstrated no statistically significant differences in
improvement in depressed state compared to the placebo group. In CCT004, vortioxetine
was evaluated in patients with “recurrent major depressive disorder” characterized by therecurrence of depressive episodes, and patients who experienced an improvement or
reduction in their MADRS total score ≥25% during the lead-in period were excluded fromrandomization during the treatment period. The changes from baseline in the MADRS total
score for depression assessment were −12.73 in the placebo group, −15.03 in thevortioxetine 10 mg group, and −15.45 in the vortioxetine 20 mg group, indicating astatistically significant difference.
Patients with mild depression, treatment-resistant depression, comorbid psychiatricdisorders, drug abuse, or those who are at risk of suicide are excluded from the overseas
and Japanese studies. The outcomes are only verified for short-term acute-phasetreatment.
2.2. Summary of evaluation of additional benefit by manufacturer and critique by
academic group
According to the report by the manufacturer, for population (a): patients with mild
depression or in a mild depressed state, no relevant clinical studies were identified. Thus,
the manufacturer concluded as “no additional benefit” or “additional benefit cannot be
determined”. The academic group reached the same conclusion as the manufacture.

40

In addition, the manufacturer performed an additional systematic review
expanding “intervention” in their search strategy as vortioxetine to new generation
antidepressants to assess whether there was other evidence in patients with mild
depression or in a mild depressed state as shown in the supplementary material. The
manufacturer submitted the results to report that they did not find any clinical studies
relevant to this context (dated November 10, 2020).
As for the additional benefit of vortioxetine for population (b): patients withmoderate or severe depression or in a moderate or severe depressed state, themanufacturer limited the results of the study by Cipriani et al. (2018) to 8 new generation
antidepressants (SSRI, SNRI, and NaSSA) approved in Japan, and performed an
additional systematic review of the literature published after the search period for Cipriani etal. by reintegrating the relevant study data for NMA. The results of NMA did not find any
clear differences in effect between vortioxetine and other new generation antidepressants.
The systematic review performed for the evaluation of additional benefit showed that theresults of the manufacturer were consistent with those of the academic group in that the
study by Cipriani et al. (2018) was identified as the relevant publication. However, there
were discrepancies in the following two aspects of the systematic review between the
manufacturer and the academic group:<Outcome>
The manufacturer included studies that had their primary endpoint as
improvement in cognitive function or sexual function, while having improvement indepression state as secondary endpoint. Since the drug was indicated for thetreatment of patients with depression or in a depressed state, the academic group
included studies focusing on improvement in depressed state as a primary
outcome.
<Using indirect comparison based on NMA by Cipriani et al. (2018) >The evaluation of additional benefit conducted by the manufacturer via NMA
updates by Cipriani et al. (2018) has validity for the following reasons:The study by Cipriani et al. (2018) does not limit the research questions set
by the academic group in that it is conducted to compare the efficacy andsafety of 21 different antidepressants prescribed to adult patients with acutephase major depressive disorder.

41



A total of 522 studies were included in the final NMA, and it is the mostcomprehensive study with new generation antidepressants as comparators,
providing a certain level of evidence for the research questions by theacademic group.

The systematic review includes a wider range of databases, such as
Cochrane Central, CINAHL, Embase, LILACS, MEDLINE, MEDLINE InProcess, PsycINFO, websites of regulatory authorities, and international
clinical study registries, to enroll studies registered by January 8, 2016.
Because pair-wise comparison and network meta-analysis are performed
using the random effect model for the primary efficacy and safety endpoints,
and integrated data are also published, data on the drugs can also be
extracted for re-analysis, and the transparency of the data used for thestudies is ensured to some extent.

On the other hand, there are some concerns about the use of indirect comparison
data from NMA in the evaluation of the additional benefit of vortioxetine for thefollowing reasons:

Inclusion and exclusion criteria for patients differ among the clinical studies,and there may be a bias in the results of integrated heterogeneity of thestudies.

Of the 522 studies, 46 (9%), 380 (73%), and 96 (18%) were considered high,moderate, and low risk for bias, respectively, and it has been concluded thatthe certainty of the overall evidence is moderate to very low.



Only short-term efficacy and safety data collected during the clinical study
period are evaluated, lacking evidence of the long-term efficacy and safety.

With respect to the evaluation period for the outcomes, vortioxetine isevaluated for 6 to 8 weeks in the clinical studies, and results collected at thetime point closest to Week 8 are used if data are reported at more than one
evaluation time point. However, results may be affected by variation in thedata evaluation time between studies because remission and withdrawal
rates are more likely to be dependent on time.

2.3 Summary of evaluation of additional benefit by academic group
The results of the evaluation are summarized in Tables 2-7 and 2-8.

42

Table 2-7 Evaluation of additional benefit for population (a)Population

Patients with mild depression or in a mild depressed state

Intervention

Vortioxetine

Comparator

No drug treatment

Outcome

Improvement in depressed state Additional benefit is shown

Whether or not
additional benefit isshown

 “No additional benefit” or “additional benefit cannot be
determined”
 Impossible to analyze because of the lack of clinical study data
used for evaluation

Data used as thebasis for thedecision
Reason for thedecision on whether
additional benefit isshown Meta-analysis of RCTs  Single RCT Prospective, controlled, observational study Indirect comparison of RCTs
 Comparison of single-arm studies  No relevant clinical data
As a result of the systematic review, no clinical studies of vortioxetine
were identified, and similar results were also obtained for other new
generation antidepressants.

43

Table 2-8 Evaluation of additional benefit for population (b)Population
Intervention

Patients with moderate or severe depression or in a moderate orsevere depressed state
Vortioxetine
SSRI: fluvoxamine, paroxetine, sertraline, and escitalopram

Comparator

SNRI: milnacipran, duloxetine, and venlafaxine
NaSSA: mirtazapine

Outcome

Improvement in depressed state Additional benefit is shown

Whether or not

additional benefit isshown“No additional benefit” or “additional benefit cannot be
determined”

 Impossible to analyze because of the lack of clinical study data
used for evaluation

Meta-analysis of RCTs (pooled analysis of several RCTs)

Data used as the Single RCT

basis for the Prospective, controlled, observational study

decision Indirect comparison of RCTs
 Comparison of single-arm studies  No relevant clinical data

Reason for thedecision on whether
additional benefit isshown

Considering the results of direct and indirect comparison studies,
there is no significant difference in treatment effect between
vortioxetine and other new generation antidepressants.

44

3. Evaluation of cost-effectiveness3.1. Summary of analysis by manufacture
The manufacturer performed a cost-minimization analysis on the assumption thatvortioxetine had no additional benefit compared to other new generation antidepressants.
In the cost-minimization analysis, a decision tree model showing the pathology ofdepression or depressed state (acute phase, maintenance phase, and recovery phase) anda Markov model-based model were used (Figures 3-1 and 3-2). The population of theanalysis was patients with moderate or severe depression or in a moderate or severe
depressed state. The population was classified into two groups: those receiving first-line
treatment (%) and those receiving second-line treatment (%). The duration of theanalysis was 1 year. The drug costs and the consultation fees were estimated in the firstline and second-line treatment populations, and then weighted averages were calculated
from individual analysis results.
The main assumptions in the model used for analysis were as follows:

The daily drug price of milnacipran is used as the drug cost of the comparator in thebase case analysis.

The daily drug prices of new generation antidepressants other than milnacipran(venlafaxine, escitalopram, and duloxetine) are used in the sensitivity analysis.

Dose titration is not considered.



The mean prescribed dose is considered in selecting the drug costs.

The duration of remission is 8 weeks for antidepressant treatment.



Patients recover from depression or depressed state when they have achieved
remission for 6 months and their symptoms do not recur after attainment ofremission (for a maximum of 4 months during the analysis period).



Only remission rates after treatment switch and recurrence rates after remission in
the Markov model differ between the first-line and second-line treatment populations.
Other settings are identical between these populations.



Only the drug costs differ between vortioxetine and the comparator. Other settings
between them are identical.

45

Treatment
continuation
No long-term AEs
reported
Treatment
discontinuation

Treatment
continuation

Remission
First-line/
second-line
treatment

Treatment
adjustment

Long-term AEs
reported

Treatment
discontinuation

Attainment of remission
Recurrence: Proceed
to the next treatment
Attainment of remissionNo
response

RecoveryRecurrence: Proceed
to the next treatment
Attainment of remission
Recurrence: Proceed
to the next treatment
Attainment of remission
Recurrence: Proceed
to the next treatment
Attainment of remission

Switching to thenext treatment
No response:
Proceed to thenext treatment

RecoveryRecurrence: Proceed
to the next treatment

RecoveryNo
response

RecoveryNo
response

RecoveryNo
response

RemissionNo
response

Interruption due to short-term AEs:
Proceed to the nextNotreatment
response

Acute phase(0 to 2 months)

Maintenance phase (2 to 8 months)

Recovery phase(8 to 12 months)

Chance nodeMarkov node
Terminal node

Figure 3-1 Model for the transition until switching to the next treatment (decision treemodel) [(31)]No response

Remission

RecoveryFigure 3-2 Model for the transition after switching to the next treatment (Markov
model, 2-month cycle) [(31)]46

The results of the base case analysis by the manufacturer were summarized as shown in
Tables 3-1 and 3-2, and there was a cost increase of 16,053 yen for vortioxetine.
Table 3-1 Results of the base case analysis (comparison with milnacipran)
Total cost (yen)Incremental cost (yen)Vortioxetine

274,454

16,053Comparator

258,401-

Table 3-2 Detailed breakdown of costs
Vortioxetine

Comparator

Drug cost of vortioxetine (yen)Drug cost of milnacipran (yen)Drug cost after treatment switch (yen)Consultation (status) fees (yen)Sensitivity analyses are shown in Tables 3-3 to 3-8.
Table 3-3 Results of the sensitivity analysis (comparison with venlafaxine)
Total cost (yen)Incremental cost (yen)Vortioxetine

267,128-14,521

Comparator

281,648-

Table 3-4 Detailed costs
Vortioxetine

Comparator

Drug cost of vortioxetine (yen)Drug cost of venlafaxine (yen)Drug cost after treatment switch (yen)Consultation (status) fees (yen)Table 3-5 Results of the sensitivity analysis (comparison with escitalopram)
Total cost (yen)Incremental cost (yen)Vortioxetine

261,177-1,030Comparator

262,207-47

Table 3-6 Detailed costs
Vortioxetine

Comparator

Drug cost of vortioxetine (yen)Drug cost of escitalopram (yen)Drug cost after treatment switch (yen)Consultation (status) fees (yen)Table 3-7 Results of the sensitivity analysis (comparison with duloxetine)
Total cost (yen)Incremental cost (yen)Vortioxetine

271,391-2,771Comparator

274,162-

Table 3-8 Detailed costs
Vortioxetine

Comparator

Drug cost of vortioxetine (yen)Drug cost of duloxetine (yen)Drug cost after treatment switch (yen)Consultation (status) fees (yen)3.1.1 Critique on manufacture’s analysis
Since no additional benefit was suggested in the earlier section (2-3), it is appropriate toperform a cost-minimization analysis, assuming that there is no difference in treatment
effect between vortioxetine and other new generation antidepressants.
In the cost-minimization analysis done by the manufacture, healthcare costs wasestimated by using a decision tree model and a Markov model to show the pathology ofdepression or depressed state. Although health technology assessment agencies in foreigncountries have used similar model structures for cost-effectiveness analyses to evaluate
vortioxetine, these models have not been utilized for cost-minimization analyses (1)(2)(5).
As for the method of the cost-minimization analysis submitted by the manufacturer, thefollowing points need to be addressed:The major issue is the estimation of the drug cost in this analysis because healthresource consumption is the same for vortioxetine and comparator other than the priceof drug itself.

48

The drug costs in the model is estimated by multiplying the daily drug costs by the
duration of treatment, and the duration of treatment (resulting differences in drug costs)
depends on the structure of the decision tree model, probability parameters, andsettings for the duration of treatment in each scenario (Figure 3-3).

Comparison of the daily drug costs suffices for the cost-minimization analysis, because
the duration of treatment does not differ between vortioxetine and other new
generation antidepressants.

Scenario
Treatment
continuation
No long-term
AEs reported
Treatment
discontinuation
Treatment
continuation
Remission
First-line/
second-line
treatment

Treatment
adjustment

Long-term AEs
reported

No response:
Proceed to thenext treatment

Treatment
discontinuation
Switching to thenext treatment

Attainment of remission
Recurrence: Proceed
to the next treatment
Attainment of remission

RecoveryNo
response

224 days (32 weeks)
140 days (20 weeks)

RecoveryRecurrence: Proceed
to the next treatment
Attainment of remission
Recurrence: Proceed
to the next treatment
Attainment of remission
Recurrence: Proceed
to the next treatment
Attainment of remission
Recurrence: Proceed
to the next treatment

RecoveryNo
response

RecoveryNo
response

RecoveryNo
response

Remission

224 days (32 weeks)
140 days (20 weeks)
84 days (12 weeks)
84 days (12 weeks)

28 days (4 weeks)No
response

Chance node

140 days (20 weeks)

28 days (4 weeks)Interruption due to short-term AEs: Proceed
to the next treatment

Maintenance phase (2 to 8 months)

224 days (32 weeks)

84 days (12 weeks)No
response

Acute phase(0 to 2 months)

Duration of treatment withvortioxetine and thecomparator

Recovery phase(8 to 12 months)

Markov node
Terminal node

Figure 3-3 Structure of the decision tree model and duration of treatment in eachscenario*The names of the scenarios and duration of treatment were added by the academic group.
<Settings for probability parameters>
For the estimation, the manufacturer integrated the values reported in the study ofvortioxetine and milnacipran, in which milnacipran was selected as the comparator in thebase case analysis, and probability parameters (remission rates and rates of treatment
discontinuation due to AEs) for the decision tree model were included in NMA. The
following points need to be noted for the above study:49

Using different comparators is associated with varying remission rates and treatment
discontinuation rates due to AEs for vortioxetine, making it difficult to interpret theresults from the base case analysis and sensitivity analysis.

The evaluation of vortioxetine has indicated no additional benefit of vortioxetine
compared to other new generation antidepressants; therefore, it is appropriate toestimate remission rates and rates of treatment discontinuation due to AEs by
integrating the values reported in all clinical studies included in NMA.

There is uncertainty about estimating the duration of treatment using models because
the evaluation time points for remission rates and rates of treatment discontinuation due
to AEs are in the range of 6 to 8 weeks in each clinical study.

<Settings for the duration of treatment>
The manufacturer assumed that patients who had achieved remission in the acute phase (2months) would have recovered from depression or depressed state when they had
achieved remission for 6 months, and their symptoms would not recur after attainment ofremission (for a maximum of 4 months during the analysis period) (Figure 3-3). In otherscenarios, analysis was also performed according to some hypotheses about the durationof treatment with vortioxetine and the comparator (Figure 3-3). The following points need tobe addressed:The manufacturer reports that, “the duration of treatment should be at least 4 to 9months after remission for an initial manifestation, and at least 2 years for arecurrence, and the dose should be the same as that used for acute treatment (p.16)”(31), and therefore, the duration of treatment may be underestimated.



The mean duration of treatment based on the model submitted by the manufacturer is89.2 days; however, to date, no data are available on the duration of treatment withvortioxetine in clinical practice, and there is uncertainty about the settings for theduration of treatment (Figure 3-4).

50

80%
60%
40%
20%

352

336

320

304

288

272

256

240

224

208

192

176

160

144

128

96

112

80

64

48

32

0

0%
16

with vortioxietin and comparator

Proportion of patients receiving treatment

100%

Duration of treatment (days)

Figure 3-4 Distribution of the duration of treatment in the model submitted by the
manufacturer(Mean duration of treatment = 89.2 days)51

3.2 Summary of revision by academic group<Base case analysis>

Perform a cost-minimization analysis, assuming that the effects are similar among
vortioxetine and other new generation antidepressants.

Estimate costs using the drug price of milnacipran, which is the cheapest drug of all
the other new generation antidepressants selected as comparator because thesuperiority or inferiority of these drugs has not been indicated.

Compare the daily drug price, because no studies have shown that the duration oftreatment and health resource consumption, other than the relevant drug price itself,
differ among vortioxetine and the comparators.

<Sensitivity analysis>

Perform sensitivity analyses considering the drug prices of new generation
antidepressants other than milnacipran.

Methods for revied analysis
Estimate the daily drug price from the drug price per mg and the mean prescribed dose(mg) of commonly used specifications for vortioxetine and other new generation
antidepressants.



For the mean prescribed dose (mg) of vortioxetine and other new generation
antidepressants, we use the claim data from the National Database of Health
Insurance Claims and Specific Health Checkups of Japan.
-

Patients to whom the ICD-10 code (F32, depressive episode; F33, recurrent
depressive disorder) corresponding to depression or depressed state was
assigned in medical claims and DPC admission claims during the analysis
period (medical treatment given between April 1, 2019 and March 31, 2020)
were extracted. The exclusion criteria were claims with flags for suspicious
illness and those involving patients aged <20 years on the day of the first
medical treatment recorded during the analysis period. Prescriptions found in
the medical (not hospitalized) and pharmacist’s fee claims recorded for theabove patients were counted when they included the anti-depressants shownin Attached Table S-3. The prescription was excluded when it included two or
more generic names of different categories for antidepressants.

52

For the calculation of the daily mean prescribed dose, the number of drugs
included in a prescription was counted by generic name during the analysis
period. The prescription was issued for the same patient in the same claim on
the same date. For the calculation of the daily mean prescribed dose, the sumof the drug usage multiplied by the amount of ingredient per tablet for thesame genetic name in the same prescription was used to determine the mean
dose.

53

4. Revised analysis by academic group
4.1 Base case analysis
By using the National Database of Health Insurance Claims and Specific Health Checkups
of Japan, the data on 2,432,892 patients, and 38.8% of them were male with a mean age of
55.8 years were obtained. The results of the mean daily prescribed dose are shown in
Table 4-1.

Table 4-1 Daily mean prescribed dose of the new generation antidepressantsStarting dose
Medicine

Generic

indicated on the

category

namepackage insert(mg)

Fluvoxamine

MaximumDailydose indicatedprescribedon thepackage insert

No. ofprescriptions

%

dose
Mean

(mg)

(mg)

Daily
prescribed
doseStandard
deviation(mg)

18,873,484-

1,514,316

8.0%

75.2

59.8

3,268,647

17.3%

19.1

14.8

50

150

10-20 (tablets)

40 (tablets)

12.5 (CR tablets)

50 (CR tablets)

Sertraline

25

100

3,076,447

16.3%

49.8

32.8

Escitalopram

10

20

3,158,921

16.7%

11.9

6.6

Milnacipran

25

100

447,274

2.4%

50.1

38.0

Duloxetine

2060

3,752,168

19.9%

35.1

18.7

Venlafaxine

37.5

225

862,909

4.6%

115.3

67.9

NaSSA

Mirtazapine

1545

2,738,212

14.5%

20.3

22.0

OthersVortioxetine

1020

54,590

0.3%

13.5

7.3

SSRI

SNRI

Paroxetine

The results of the re-analysis of the base case analysis are presented in Table 4-2. The
comparison of the daily drug price revealed that the drug price of vortioxetine was 186.23
yen higher than milnacipran.

54

Table 4-2 Cost-minimization analysis of vortioxetine versus milnacipran
Unit Drug price (yen)*
Vortioxetine

Mean prescribed
dose (mg)

(yen)

(yen)

13.5

228.02

-

50.1

41.78

186.2310 mg 168.90
20 mg 253.40
12.5 mg 14.30

Milnacipran

Daily drug price Incremental cost

15 mg 17.30
25 mg 24.70
50 mg 41.70*The commonly used specifications are underlined.
*If there was more than one originator drug, the drug with the cheapest unit price wasadopted.
4.2 Scenario analysis
The results of the scenario analyses considering the drug prices of new generation
antidepressants other than milnacipran are presented in Table 4-3.
Table 4-3 Results of the scenario analysis

Vortioxetine

Unit Drug price

Mean prescribed

Daily drug price

Incremental cost(yen)*

dose (mg)

(yen)

(yen)

10 mg 168.90

13.5

228.02

-

75.2

72.94

155.0719.1

115.21112.8020 mg 253.40
SSRI
Fluvoxamine

25 mg 28.70
50 mg 48.50
75 mg 65.40

Paroxetine

5 mg (tablets) 42.60
10 mg (tablets)
75.80
20 mg (tablets)
131.706.25 mg (CRtablets) 43.70
12.5 mg (CRtablets) 75.40

55

25 mg (CR tablets)
130.60Sertraline

25 mg (tablets/OD

49.8

157.37

70.65

11.9

230.27

-2.25

35.1

254.83-26.81

115.3

364.50-136.4920.3

160.1067.92

tablets) 79.00
50 mg (tablets/OD
tablets) 135.70
100 mg (tablets/OD
tablets) 233.80
Escitalopram

10 mg 193.50
20 mg 293.90

SNRI
Duloxetine

20 mg 145.20
30 mg 196.60

Venlafaxine

37.5 mg 141.40
75 mg 237.10

NaSSA
Mirtazapine

15 mg 118.30
30 mg 196.20*The commonly used specifications are underlined.
*If there was more than one originator drug, the drug with the cheapest unit price wasadopted.

56

4.3 Summary results
The summary result of revised analysis of vortioxetine is shown in Tables 4-3 and 4-4.
Table 4-3 Summary of revised analysis result of population (a)Population

Patients with mild depression or in a mild depressed state

Comparator

No drug treatment

Referencevalue for

 Regular product  Product requiring special consideration

ICER
 Cost reduction or dominant  <5 million yen (<7.5 million yen) ≥5 million yen (≥7.5 million yen) and <7.5 million yen (<11.25 million
Interval towhich theyen)
 ≥7.5 million yen (≥11.25 million yen) and <10 million yen (<15 million

ICER is mostyen)likely to ≥10 million yen (≥15 million yen)belong

 Comparable (or inferior in) effect and higher cost
 Impossible to analyze because of the lack of clinical study data used
for evaluation

Reason forthe decision

No clinical data available

Table 4-4 Summary of revised analysis result of population (b)Population
Comparator

Patients with moderate or severe depression or in a moderate or severe
depressed state
The cheapest drug (milnacipran) of the new generation antidepressants(SSRI, SNRI, and NaSSA)

Referencevalue for

Regular product  Product requiring special consideration

ICER
Interval to Cost reduction or dominant  <5 million yen (<7.5 million yen)which the ≥5 million yen (≥7.5 million yen) and <7.5 million yen (<11.25 million

ICER is most
likely tobelongyen) ≥7.5 million yen (≥11.25 million yen) and <10 million yen (<15 million
yen)

57

 ≥10 million yen (≥15 million yen)Comparable (or inferior in) effect and higher cost

 Impossible to analyze because of the lack of clinical study data used
for evaluation
Reason for

The cost of vortioxetine increases by 186.23 yen per day compared tothe decision

milnacipran.

4.4 Weight of price adjustment rate
The manufacturer reported the proportion of each population for analysis based on aprospective observational study on functional outcomes for MDD (PERFORM-J). In the
PERFORM-J, the severity of MDD in 518 patients was evaluated according to MADRS and109, 312, 95, and 2 patients were rated as mild, moderate, severe, and not applicable,
respectively. Based on this result, the manufacturer excluded the 2 patients rated as notapplicable from the population for analysis, and calculated the proportion of 516 patients byseverity: 21.1% (109/516) of patients were rated mild and 78.9% ([312+95]/516) were rated
moderate or severe. The academic group accepted the validity of the manufacturer’s view,and considered it appropriate to use 21.1% for mild and 78.9% for moderate or severecases as the proportion of patients in each population for analysis.

58

5. References
1.

NICE. Vortioxetine for treating major depressive episodes 2015. Available from:https://www.nice.org.uk/guidance/ta367.

2.

SMC. vortioxetine 5mg, 10mg, 20mg film-coated tablet (Brintellix®) 2016 Available from:https://www.scottishmedicines.org.uk/media/2492/vortioxetine_brintellix_final_june_2016_f
or_website.pdf.

3.

HAS. BRINTELLIX (vortioxetine), antidepressant. 2015.

4.

IQWiG. [A15-16] Vortioxetine - Benefit assessment according to § 35a Social Code Book V(dossier assessment) 2015. Available from: https://www.iqwig.de/en/projectsresults/projects/drug-assessment/a15-16-vortioxetine-benefit-assessment-according-to35a-social-code-book-v-dossier-assessment.6723.html.

5.

CADTH. vortioxetine hydrobromide 2020. Available from: https://www.cadth.ca/vortioxetinehydrobromide.

6.

PBAC. VORTIOXETINE, tablets, 5 mg, 10 mg, 15 mg and 20 mg, Brintellix®, Lundbeck
Australia Pty Ltd 2014. Available from:https://www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd/201407/voritioxetine-psd-07-2014.

7.

Japanese Society of Mood Disorders. Clinical Practice Guidelines for Depression publishedby Japanese Society of Mood Disorders II. Depression (DSM-5)/Major depressive disorder2016. 2016.

8.

Montgomery S, Åsberg M. A new depression scale designed to be sensitive to change:
Acad. Department of Psychiatry, Guy's Hospital; 1977.

9.

McDowell I. Measuring health: a guide to rating scales and questionnaires: Oxford
University Press, USA; 2006.

10. Noriko Kojimahara, Takeo Nakayama, Toshio Morizane, Naohito Yamaguchi, Masahiro
Yoshida. Minds Handbook for Clinical Practice Guideline Development 2017. 2017.
11. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative
efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults withmajor depressive disorder: a systematic review and network meta-analysis. Focus.
2018;16(4):420-9.
12. Wagner G, Schultes M-T, Titscher V, Teufer B, Klerings I, Gartlehner G. Efficacy and safetyof levomilnacipran, vilazodone and vortioxetine compared with other second-generation
antidepressants for major depressive disorder in adults: A systematic review and network
meta-analysis. Journal of Affective Disorders. 2018;228:1-12.

59

13. McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled studyof vortioxetine on cognitive function in depressed adults. International Journal of
Neuropsychopharmacology. 2014;17(10):1557-67.
14. Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RS. A randomized, placebocontrolled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetineon cognitive function in major depressive disorder. Neuropsychopharmacology.
2015;40(8):2025-37.
15. Wang J, Liu X-F, Feng C, Bao Q, Fu H-R. Efficacy and safety of vortioxetine for thetreatment of major depressive disorder: a randomised double-blind placebo-controlled
study. International journal of psychiatry in clinical practice. 2019;23(4):245-50.
16. Alvarez E, Perez V, Dragheim M, Loft H, Artigas F. A double-blind, randomized, placebocontrolled, active reference study of Lu AA21004 in patients with major depressive
disorder. International Journal of Neuropsychopharmacology. 2012;15(5):589-600.
17. Baldwin DS, Loft H, Dragheim M. A randomised, double-blind, placebo controlled,
duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in acute treatmentof major depressive disorder (MDD). European Neuropsychopharmacology.
2012;22(7):482-91.
18. Boulenger J-P, Loft H, Olsen CK. Efficacy and safety of vortioxetine (Lu AA21004), 15 and
20 mg/day: a randomized, double-blind, placebo-controlled, duloxetine-referenced study inthe acute treatment of adult patients with major depressive disorder. International clinicalpsychopharmacology. 2014;29(3):138.
19. Mahableshwarkar AR, Jacobsen PL, Chen Y. A randomized, double-blind trial of 2.5 mg
and 5 mg vortioxetine (Lu AA21004) versus placebo for 8 weeks in adults with major
depressive disorder. Current medical research and opinion. 2013;29(3):217-26.
20. Wang G, Gislum M, Filippov G, Montgomery S. Comparison of vortioxetine versus
venlafaxine XR in adults in Asia with major depressive disorder: a randomized, doubleblind study. Current medical research and opinion. 2015;31(4):785-94.
21. Katona C, Hansen T, Olsen CK. 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. International clinicalpsychopharmacology. 2012;27(4):215-23.
22. Henigsberg N, Mahableshwarkar AR, Jacobsen P, Chen Y, Thase ME. A randomized,
double-blind, placebo-controlled 8-week trial of the efficacy and tolerability of multiple
doses of Lu AA21004 in adults with major depressive disorder. The Journal of clinicalpsychiatry. 2012;73(7):953-9.

60

23. Jacobsen PL, Mahableshwarkar AR, Serenko M, Chan S, Trivedi MH. 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. The Journal of clinical psychiatry.
2015;76(5):575-82.
24. Jain R, Mahableshwarkar AR, Jacobsen PL, Chen Y, Thase ME. A randomized, doubleblind, placebo-controlled 6-wk trial of the efficacy and tolerability of 5 mg vortioxetine inadults with major depressive disorder. International Journal of Neuropsychopharmacology.
2013;16(2):313-21.
25. Mahableshwarkar AR, Jacobsen PL, Serenko M, Chen Y, Trivedi MH. A randomized,
double-blind, placebo-controlled study of the efficacy and safety of 2 doses of vortioxetine
in adults with major depressive disorder. The Journal of clinical psychiatry. 2015;76(5):58391.
26. Nishimura A, Aritomi Y, Sasai K, Kitagawa T, Mahableshwarkar AR. Randomized, doubleblind, placebo-controlled 8-week trial of the efficacy, safety, and tolerability of 5, 10, and 20
mg/day vortioxetine in adults with major depressive disorder. Psychiatry and Clinical
Neurosciences. 2018;72(2):64-72.
27. Inoue T, Nishimura A, Sasai K, Kitagawa T. Randomized, 8-week, double-blind, placebocontrolled trial of vortioxetine in Japanese adults with major depressive disorder, followed
by a 52-week open-label extension trial. Psychiatry and clinical neurosciences.
2018;72(2):103-15.
28. Inoue T, Sasai K, Kitagawa T, Nishimura A, Inada I. Randomized, double-blind, placebocontrolled study to assess the efficacy and safety of vortioxetine in Japanese patients withmajor depressive disorder. Psychiatry and clinical neurosciences. 2020;74(2):140-8.
29. PMDA. Trintellix Tablets 10 mg, Trintellix Tablets 20 mg, Review Report 2019. Available
from:https://www.pmda.go.jp/drugs/2019/P20191010004/400256000_30100AMX00246_A100_1.pdf.
30. Trintellix Tablets 10 mg, 20 mg Interview Form (2nd version). 2019.
31. Takeda Pharmaceutical Company Limited. Cost-effectiveness evaluation of vortioxetine(Trintellix®). August 11, 2020.

61

6. Supplementary material<Additional systematic review by the manufacturer>
To examine the additional benefit of vortioxetine and other new generation antidepressantsfor no drug treatment in patients with mild depression or in a mild depressed state, themanufacturer selected I from the PICO framework for the systematic review, and focusedon all new generation antidepressants.
Research questions

Research questions about this examination are as shown in Table S-1.
Table S-1 Research questions for the additional systematic review of the mild
population by the manufacturer
Item

Description

Population

Patients with mild depression or in a mild depressed state1

Intervention

Vortioxetine
SSRI: fluvoxamine, paroxetine, sertraline, and escitalopram
SNRI: milnacipran, duloxetine, and venlafaxine
NaSSA: mirtazapine

Comparator

No drug treatment2

Outcomes- Improvement in depressed state (remission and response rates)- Tolerability (rate of treatment discontinuation)

Study design

Double-blind RCTs

Period ofFrom the start of collection of the relevant database toliteraturesearch1 In principle, patients “with depression or in a depressed state” refers to those with MDD as

defined by DSM.
2 “No drug treatment” is defined as continuing consultation with a healthcare professional

without any pharmacological interventions.


Examination method

The examination was performed according to the following steps:62(1) Of the clinical studies adopted according to the inclusion and exclusion criteria shownin Table S-2, those including a placebo are extracted. As with the systematic review ofpatients with moderate or severe depression or in a moderate or severe depressedstate, the results from the systematic reviews performed on the literature published
before January 8, 2016 (systematic review using the report by Cipriani et al. [2018])(additional systematic review) are utilized.

and those published after

Table S-2 Inclusion and exclusion criteria for the additional systematic review of themild population by the manufacturer
Item

Inclusion criteria

Language

English and Japanese

Population

Adult (≥18 years) patients with

Exclusion criteria

MDD
Study design and type ofDouble-blind RCTs

publication- Unpublished literature- Abstracts- Studies that include 20%
or more of participants
with bipolar disorder,
psychotic depression, or
treatment-resistantdepression

Treatment- Vortioxetine- Fluvoxamine- Paroxetine- Sertraline- Escitalopram- Milnacipran- Duloxetine- Venlafaxine- Mirtazapine- Placebo

Outcomes- Improvement in depressedstate (remission andresponse rates)- Tolerability (rate of treatment
discontinuation)63

(2) As for the inclusion criteria and baseline values in each relevant study in (1), severity isevaluated by reference to the severity scale, MADRS, HAMD17, CGI-S, and QIDS-SR.
(3) Based on the severity in (2), eligible clinical studies falling under the category of“clinical studies only involving mild cases” are extracted.
Examination results

Of the 179 clinical studies (167 publications) adopted in the systematic review, thoseincluding a placebo were evaluated for severity based on the severity scales, MADRS,HAMD17, CGI-S, and QIDS-SR, revealing that there were no “clinical studies only involving
mild cases.”

64

Table S-3 List of antidepressants to be tabulated
Medicine
category

System code forcomputerizedprocessing of healthinsurance claims

SSRI

610432006

DEPROMEL TABLETS 25 25 mg

Fluvoxamine

SSRI

610432007

DEPROMEL TABLETS 50 50 mg

Fluvoxamine

SSRI

620006991

DEPROMEL TABLETS 75 75 mg

Fluvoxamine

SSRI

610432019

Luvox Tablets 25 25 mg

Fluvoxamine

SSRI

610432020

Luvox Tablets 50 50 mg

Fluvoxamine

SSRI

620007147

Luvox Tablets 75 75 mg

Fluvoxamine

SSRI

621998401

Fluvoxamine Maleate Tablets 25 mg “EMEC”

Fluvoxamine

SSRI

621998501

Fluvoxamine Maleate Tablets 50 mg “EMEC”

Fluvoxamine

SSRI

621998601

Fluvoxamine Maleate Tablets 75 mg “EMEC”

Fluvoxamine

SSRI

622000101

Fluvoxamine Maleate Tablets 25 mg “YD”

Fluvoxamine

SSRI

622000201

Fluvoxamine Maleate Tablets 50 mg “YD”

Fluvoxamine

SSRI

622000301

Fluvoxamine Maleate Tablets 75 mg “YD”

Fluvoxamine

SSRI

622000901

Fluvoxamine Maleate Tablets 25 mg “AMEL”

Fluvoxamine

SSRI

622001001

Fluvoxamine Maleate Tablets 50 mg “AMEL”

Fluvoxamine

SSRI

622001101

Fluvoxamine Maleate Tablets 75 mg “AMEL”

Fluvoxamine

SSRI

622001901

Fluvoxamine Maleate Tablets 25 mg “TCK”

Fluvoxamine

SSRI

622002001

Fluvoxamine Maleate Tablets 50 mg “TCK”

Fluvoxamine

SSRI

622002101

Fluvoxamine Maleate Tablets 75 mg “TCK”

Fluvoxamine

SSRI

622004401

Fluvoxamine Maleate Tablets 25 mg “TAKATA”

Fluvoxamine

SSRI

622004501

Fluvoxamine Maleate Tablets 50 mg “TAKATA”

Fluvoxamine

SSRI

622004601

Fluvoxamine Maleate Tablets 75 mg “TAKATA”

Fluvoxamine

SSRI

622007702

Fluvoxamine Maleate Tablets 25 mg “Pfizer”

Fluvoxamine

SSRI

622007802

Fluvoxamine Maleate Tablets 50 mg “Pfizer”

Fluvoxamine

SSRI

622007902

Fluvoxamine Maleate Tablets 75 mg “Pfizer”

Fluvoxamine

SSRI

622010601

Fluvoxamine Maleate Tablets 25 mg “SAWAI”

Fluvoxamine

SSRI

622010701

Fluvoxamine Maleate Tablets 50 mg “SAWAI”

Fluvoxamine

SSRI

622010801

Fluvoxamine Maleate Tablets 75 mg “SAWAI”

Fluvoxamine

SSRI

622018101

Fluvoxamine Maleate Tablets 25 mg “CH”

Fluvoxamine

SSRI

622018201

Fluvoxamine Maleate Tablets 50 mg “CH”

Fluvoxamine

SSRI

622018301

Fluvoxamine Maleate Tablets 75 mg “CH”

Fluvoxamine

SSRI

622020302

Fluvoxamine Maleate Tablets 25 mg “TYK”

Fluvoxamine

SSRI

622020402

Fluvoxamine Maleate Tablets 50 mg “TYK”

Fluvoxamine

Medicine name

Generic
name

65

SSRI

622020502

Fluvoxamine Maleate Tablets 75 mg “TYK”

Fluvoxamine

SSRI

622021101

Fluvoxamine Maleate Tablets 25 mg “FFP”

Fluvoxamine

SSRI

622021201

Fluvoxamine Maleate Tablets 50 mg “FFP”

Fluvoxamine

SSRI

622021301

Fluvoxamine Maleate Tablets 75 mg “FFP”

Fluvoxamine

SSRI

622022701

Fluvoxamine Maleate Tablets 25 mg “JG”

Fluvoxamine

SSRI

622022801

Fluvoxamine Maleate Tablets 50 mg “JG”

Fluvoxamine

SSRI

622022902

Fluvoxamine Maleate Tablets 75 mg “JG”

Fluvoxamine

SSRI

622031101

Fluvoxamine Maleate Tablets 25 mg “KYORIN”

Fluvoxamine

SSRI

622031201

Fluvoxamine Maleate Tablets 50 mg “KYORIN”

Fluvoxamine

SSRI

622031301

Fluvoxamine Maleate Tablets 75 mg “KYORIN”

Fluvoxamine

SSRI

622032501

Fluvoxamine Maleate Tablets 25 mg “NP”

Fluvoxamine

SSRI

622032601

Fluvoxamine Maleate Tablets 50 mg “NP”

Fluvoxamine

SSRI

622032701

Fluvoxamine Maleate Tablets 75 mg “NP”

Fluvoxamine

SSRI

622035001

Fluvoxamine Maleate Tablets 25 mg “Nichi-Iko”

Fluvoxamine

SSRI

622035101

Fluvoxamine Maleate Tablets 50 mg “Nichi-Iko”

Fluvoxamine

SSRI

622035201

Fluvoxamine Maleate Tablets 75 mg “Nichi-Iko”

Fluvoxamine

SSRI

622055001

Fluvoxamine Maleate Tablets 25 mg “TOWA”

Fluvoxamine

SSRI

622055101

Fluvoxamine Maleate Tablets 50 mg “TOWA”

Fluvoxamine

SSRI

622055201

Fluvoxamine Maleate Tablets 75 mg “TOWA”

Fluvoxamine

SSRI

610443045

Paxil Tablets 10 mg

Paroxetine

SSRI

610443046

Paxil Tablets 20 mg

Paroxetine

SSRI

622003001

Paxil Tablets 5 mg

Paroxetine

SSRI

622135901

Paxil CR Tablets 12.5 mg

Paroxetine

SSRI

622136001

Paxil CR Tablets 25 mg

Paroxetine

SSRI

622659901

Paxil CR Tablets 6.25 mg

Paroxetine

SSRI

622133801

Paroxetine Tablets 5 mg “MEIJI”

Paroxetine

SSRI

622133901

Paroxetine Tablets 10 mg “MEIJI”

Paroxetine

SSRI

622134001

Paroxetine Tablets 20 mg “MEIJI”

Paroxetine

SSRI

622137401

Paroxetine Tablets 10 mg “EE”

Paroxetine

SSRI

622137501

Paroxetine Tablets 20 mg “EE”

Paroxetine

SSRI

622138501

Paroxetine Tablets 10 mg “OHARA”

Paroxetine

SSRI

622138601

Paroxetine Tablets 20 mg “OHARA”

Paroxetine

SSRI

622140801

Paroxetine Tablets 10 mg “KN”

Paroxetine

SSRI

622140901

Paroxetine Tablets 20 mg “KN”

Paroxetine

SSRI

622141401

Paroxetine Tablets 5 mg “TOWA”

Paroxetine

66

SSRI

622141501

Paroxetine Tablets 10 mg “TOWA”

Paroxetine

SSRI

622141601

Paroxetine Tablets 20 mg “TOWA”

Paroxetine

SSRI

622141701

Paroxetine OD Tablets 10 mg “TOWA”

Paroxetine

SSRI

622141801

Paroxetine OD Tablets 20 mg “TOWA”

Paroxetine

SSRI

622144301

Paroxetine Tablets 5 mg “AMEL”

Paroxetine

SSRI

622144401

Paroxetine Tablets 10 mg “AMEL”

Paroxetine

SSRI

622144501

Paroxetine Tablets 20 mg “AMEL”

Paroxetine

SSRI

622145601

Paroxetine Tablets 5 mg “TAKATA”

Paroxetine

SSRI

622145701

Paroxetine Tablets 10 mg “TAKATA”

Paroxetine

SSRI

622145801

Paroxetine Tablets 20 mg “TAKATA”

Paroxetine

SSRI

622147801

Paroxetine Tablets 5 mg “Pfizer”

Paroxetine

SSRI

622147901

Paroxetine Tablets 10 mg “Pfizer”

Paroxetine

SSRI

622148001

Paroxetine Tablets 20 mg “Pfizer”

Paroxetine

SSRI

622150601

Paroxetine Tablets 5 mg “YD”

Paroxetine

SSRI

622150701

Paroxetine Tablets 10 mg “YD”

Paroxetine

SSRI

622150801

Paroxetine Tablets 20 mg “YD”

Paroxetine

SSRI

622152701

Paroxetine Tablets 5 mg “NISSIN”

Paroxetine

SSRI

622152801

Paroxetine Tablets 10 mg “NISSIN”

Paroxetine

SSRI

622152901

Paroxetine Tablets 20 mg “NISSIN”

Paroxetine

SSRI

622154001

Paroxetine Tablets 5 mg “FFP”

Paroxetine

SSRI

622154101

Paroxetine Tablets 10 mg “FFP”

Paroxetine

SSRI

622154201

Paroxetine Tablets 20 mg “FFP”

Paroxetine

SSRI

622154701

Paroxetine Tablets 5 mg “KOG”

Paroxetine

SSRI

622154702

Paroxetine Tablets 5 mg “NPI”

Paroxetine

SSRI

622154801

Paroxetine Tablets 10 mg “KOG”

Paroxetine

SSRI

622154802

Paroxetine Tablets 10 mg “NPI”

Paroxetine

SSRI

622154901

Paroxetine Tablets 20 mg “KOG”

Paroxetine

SSRI

622154902

Paroxetine Tablets 20 mg “NPI”

Paroxetine

SSRI

622156301

Paroxetine Tablets 5 mg “TCK”

Paroxetine

SSRI

622156401

Paroxetine Tablets 10 mg “TCK”

Paroxetine

SSRI

622156501

Paroxetine Tablets 20 mg “TCK”

Paroxetine

SSRI

622160001

Paroxetine Tablets 5 mg “AA”

Paroxetine

SSRI

622160101

Paroxetine Tablets 10 mg “AA”

Paroxetine

SSRI

622160201

Paroxetine Tablets 20 mg “AA”

Paroxetine

SSRI

622160801

Paroxetine Tablets 5 mg “TANABE”

Paroxetine

67

SSRI

622160901

Paroxetine Tablets 10 mg “TANABE”

Paroxetine

SSRI

622161001

Paroxetine Tablets 20 mg “TANABE”

Paroxetine

SSRI

622162701

Paroxetine Tablets 5 mg “Chemiphar”

Paroxetine

SSRI

622162801

Paroxetine Tablets 10 mg “Chemiphar”

Paroxetine

SSRI

622162901

Paroxetine Tablets 20 mg “Chemiphar”

Paroxetine

SSRI

622164001

Paroxetine Tablets 5 mg “TSU”

Paroxetine

SSRI

622164101

Paroxetine Tablets 10 mg “TSU”

Paroxetine

SSRI

622164201

Paroxetine Tablets 20 mg “TSU”

Paroxetine

SSRI

622164801

Paroxetine Tablets 5 mg “NP”

Paroxetine

SSRI

622164901

Paroxetine Tablets 10 mg “NP”

Paroxetine

SSRI

622165001

Paroxetine Tablets 20 mg “NP”

Paroxetine

SSRI

622166301

Paroxetine Tablets 10 mg “JG”

Paroxetine

SSRI

622166401

Paroxetine Tablets 20 mg “JG”

Paroxetine

SSRI

622168201

Paroxetine Tablets 5 mg “SAWAI”

Paroxetine

SSRI

622168301

Paroxetine Tablets 10 mg “SAWAI”

Paroxetine

SSRI

622168401

Paroxetine Tablets 20 mg “SAWAI”

Paroxetine

SSRI

622170701

Paroxetine Tablets 5 mg “DSEP”

Paroxetine

SSRI

622170801

Paroxetine Tablets 10 mg “DSEP”

Paroxetine

SSRI

622170901

Paroxetine Tablets 20 mg “DSEP”

Paroxetine

SSRI

622172801

Paroxetine Tablets 5 mg “Nichi-Iko”

Paroxetine

SSRI

622172901

Paroxetine Tablets 10 mg “Nichi-Iko”

Paroxetine

SSRI

622173001

Paroxetine Tablets 20 mg “Nichi-Iko”

Paroxetine

SSRI

622175101

Paroxetine Tablets 5 mg “DK”

Paroxetine

SSRI

622175201

Paroxetine Tablets 10 mg “DK”

Paroxetine

SSRI

622175301

Paroxetine Tablets 20 mg “DK”

Paroxetine

SSRI

622176601

Paroxetine Tablets 5 mg “SANDOZ”

Paroxetine

SSRI

622176701

Paroxetine Tablets 10 mg “SANDOZ”

Paroxetine

SSRI

622176801

Paroxetine Tablets 20 mg “SANDOZ”

Paroxetine

SSRI

622181001

Paroxetine Tablets 10 mg “KAKEN”

Paroxetine

SSRI

622181101

Paroxetine Tablets 20 mg “KAKEN”

Paroxetine

SSRI

622182201

Paroxetine Tablets 10 mg “KO”

Paroxetine

SSRI

622182301

Paroxetine Tablets 20 mg “KO”

Paroxetine

SSRI

622205201

Paroxetine Tablets 5 mg “JG”

Paroxetine

SSRI

622221201

Paroxetine Tablets 5 mg “KAKEN”

Paroxetine

SSRI

622234601

Paroxetine Tablets 5 mg “OHARA”

Paroxetine

68

SSRI

622236101

Paroxetine OD Tablets 5 mg “TOWA”

Paroxetine

SSRI

622249401

Paroxetine Tablets 5 mg “KN”

Paroxetine

SSRI

622253001

Paroxetine Tablets 5 mg “EE”

Paroxetine

SSRI

622262701

Paroxetine Tablets 5 mg “KO”

Paroxetine

SSRI

622283401

Paroxetine Tablets 5 mg “TEVA”

Paroxetine

SSRI

622283501

Paroxetine Tablets 10 mg “TEVA”

Paroxetine

SSRI

622283601

Paroxetine Tablets 20 mg “TEVA”

Paroxetine

SSRI

622473600

Paroxetine Hydrochloride 20 mg Tablets

Paroxetine

SSRI

622473700

Paroxetine Hydrochloride 5 mg Tablets

Paroxetine

SSRI

622488601

Paroxetine Tablets 5 mg “ASPEN”

Paroxetine

SSRI

622488701

Paroxetine Tablets 10 mg “ASPEN”

Paroxetine

SSRI

622488801

Paroxetine Tablets 20 mg “ASPEN”

Paroxetine

SSRI

622615500

Paroxetine Hydrochloride 10 mg Tablets

Paroxetine

SSRI

622659201

Paroxetine Tablets 5 mg “FELDSENF”

Paroxetine

SSRI

622659301

Paroxetine Tablets 10 mg “FELDSENF”

Paroxetine

SSRI

622659401

Paroxetine Tablets 20 mg “FELDSENF”

Paroxetine

SSRI

620003481

JZOLOFT Tablets 25 mg

Sertraline

SSRI

620003482

JZOLOFT Tablets 50 mg

Sertraline

SSRI

622356601

JZOLOFT Tablets 100 mg

Sertraline

SSRI

622366901

JZOLOFT OD Tablets 25 mg

Sertraline

SSRI

622367001

JZOLOFT OD Tablets 50 mg

Sertraline

SSRI

622367101

JZOLOFT OD Tablets 100 mg

Sertraline

SSRI

622442801

Sertraline Tablets 25 mg “KYORIN”

Sertraline

SSRI

622442901

Sertraline Tablets 50 mg “KYORIN”

Sertraline

SSRI

622443601

Sertraline Tablets 25 mg “YD”

Sertraline

SSRI

622443701

Sertraline Tablets 50 mg “YD”

Sertraline

SSRI

622445101

Sertraline Tablets 25 mg “Chemiphar”

Sertraline

SSRI

622445201

Sertraline Tablets 50 mg “Chemiphar”

Sertraline

SSRI

622446701

Sertraline Tablets 25 mg “TANABE”

Sertraline

SSRI

622446801

Sertraline Tablets 50 mg “TANABE”

Sertraline

SSRI

622448101

Sertraline Tablets 25 mg “TOWA”

Sertraline

SSRI

622448201

Sertraline Tablets 50 mg “TOWA”

Sertraline

SSRI

622449701

Sertraline Tablets 25 mg “TAKATA”

Sertraline

SSRI

622449801

Sertraline Tablets 50 mg “TAKATA”

Sertraline

SSRI

622449901

Sertraline Tablets 100 mg “TAKATA”

Sertraline

69

SSRI

622451601

Sertraline Tablets 25 mg “TCK”

Sertraline

SSRI

622451701

Sertraline Tablets 50 mg “TCK”

Sertraline

SSRI

622453501

Sertraline Tablets 25 mg “DSEP”

Sertraline

SSRI

622453601

Sertraline Tablets 50 mg “DSEP”

Sertraline

SSRI

622454601

Sertraline Tablets 25 mg “JG”

Sertraline

SSRI

622454701

Sertraline Tablets 50 mg “JG”

Sertraline

SSRI

622457501

Sertraline Tablets 25 mg “SAWAI”

Sertraline

SSRI

622457601

Sertraline Tablets 50 mg “SAWAI”

Sertraline

SSRI

622459601

Sertraline Tablets 25 mg “MEIJI”

Sertraline

SSRI

622459701

Sertraline Tablets 50 mg “MEIJI”

Sertraline

SSRI

622459801

Sertraline Tablets 100 mg “MEIJI”

Sertraline

SSRI

622459901

Sertraline Tablets 25 mg “SANDOZ”

Sertraline

SSRI

622460001

Sertraline Tablets 50 mg “SANDOZ”

Sertraline

SSRI

622463301

Sertraline Tablets 25 mg “AMEL”

Sertraline

SSRI

622463401

Sertraline Tablets 50 mg “AMEL”

Sertraline

SSRI

622463501

Sertraline Tablets 100 mg “AMEL”

Sertraline

SSRI

622463601

Sertraline OD Tablets 25 mg “AMEL”

Sertraline

SSRI

622463701

Sertraline OD Tablets 50 mg “AMEL”

Sertraline

SSRI

622463901

Sertraline Tablets 25 mg “SANWA”

Sertraline

SSRI

622464001

Sertraline Tablets 50 mg “SANWA”

Sertraline

SSRI

622464101

Sertraline Tablets 100 mg “SANWA”

Sertraline

SSRI

622466201

Sertraline Tablets 25 mg “Nichi-Iko”

Sertraline

SSRI

622466301

Sertraline Tablets 50 mg “Nichi-Iko”

Sertraline

SSRI

622467501

Sertraline Tablets 25 mg “TSURUHARA”

Sertraline

SSRI

622467601

Sertraline Tablets 50 mg “TSURUHARA”

Sertraline

SSRI

622467701

Sertraline Tablets 100 mg “TSURUHARA”

Sertraline

SSRI

622469001

Sertraline Tablets 25 mg “KAKEN”

Sertraline

SSRI

622469101

Sertraline Tablets 25 mg “NIPRO”

Sertraline

SSRI

622469201

Sertraline Tablets 50 mg “KAKEN”

Sertraline

SSRI

622469301

Sertraline Tablets 50 mg “NIPRO”

Sertraline

SSRI

622479401

Sertraline OD Tablets 25 mg “TOWA”

Sertraline

SSRI

622479501

Sertraline OD Tablets 50 mg “TOWA”

Sertraline

SSRI

622480601

Sertraline Tablets 100 mg “DSEP”

Sertraline

SSRI

622481601

Sertraline Tablets 100 mg “TCK”

Sertraline

SSRI

622481901

Sertraline Tablets 100 mg “Chemiphar”

Sertraline

70

SSRI

622484201

Sertraline Tablets 100 mg “KYORIN”

Sertraline

SSRI

622491301

Sertraline Tablets 100 mg “JG”

Sertraline

SSRI

622496401

Sertraline Tablets 100 mg “SANDOZ”

Sertraline

SSRI

622497701

Sertraline Tablets 100 mg “SAWAI”

Sertraline

SSRI

622504401

Sertraline Tablets 100 mg “TANABE”

Sertraline

SSRI

622505701

Sertraline Tablets 100 mg “KAKEN”

Sertraline

SSRI

622507001

Sertraline Tablets 100 mg “NIPRO”

Sertraline

SSRI

622510601

Sertraline Tablets 100 mg “YD”

Sertraline

SSRI

622513301

Sertraline OD Tablets 100 mg “TOWA”

Sertraline

SSRI

622513401

Sertraline Tablets 100 mg “TOWA”

Sertraline

SSRI

622528801

Sertraline Tablets 100 mg “Nichi-Iko”

Sertraline

SSRI

622610900

Sertraline Hydrochloride 25 mg Tablets (1)Sertraline

SSRI

622611000

Sertraline Hydrochloride 50 mg Tablets (1)Sertraline

SSRI

622611100

Sertraline Hydrochloride 100 mg Tablets

Sertraline

SSRI

622689800

Sertraline Hydrochloride 25 mg Tablets (2)Sertraline

SSRI

622689900

Sertraline Hydrochloride 50 mg Tablets (2)Sertraline

SSRI

622069502

LEXAPRO Tablets 10 mg

Escitalopram

SSRI

622675901

LEXAPRO Tablets 20 mg

Escitalopram

SNRI

620008497

Toledomin Tablets 12.5 mg

Milnacipran

SNRI

620008498

Toledomin Tablets 50 mg

Milnacipran

SNRI

620009123

Toledomin Tablets 15 mg

Milnacipran

SNRI

620009124

Toledomin Tablets 25 mg

Milnacipran

SNRI

620008086

Milnacipran Hydrochloride Tablets 15 mg “AMEL”

Milnacipran

SNRI

620008087

Milnacipran Hydrochloride Tablets 15 mg “AFP”

Milnacipran

SNRI

620008089

Milnacipran Hydrochloride Tablets 15 mg “NP”

Milnacipran

SNRI

620008090

Milnacipran Hydrochloride Tablets 15 mg “SAWAI”

Milnacipran

SNRI

620008091

Milnacipran Hydrochloride Tablets 15 mg “JG”

Milnacipran

SNRI

620008092

Milnacipran Hydrochloride Tablets 15 mg “TAIYO”

Milnacipran

SNRI

620008093

Milnacipran Hydrochloride Tablets 15 mg “TYK”

Milnacipran

SNRI

620008094

Milnacipran Hydrochloride Tablets 15 mg “TOWA”

Milnacipran

SNRI

620008095

Milnacipran Hydrochloride Tablets 15 mg “Nichi-Iko”

Milnacipran

SNRI

620008096

Milnacipran Hydrochloride Tablets 25 mg “AMEL”

Milnacipran

SNRI

620008097

Milnacipran Hydrochloride Tablets 25 mg “AFP”

Milnacipran

SNRI

620008099

Milnacipran Hydrochloride Tablets 25 mg “NP”

Milnacipran

SNRI

620008100

Milnacipran Hydrochloride Tablets 25 mg “SAWAI”

Milnacipran

71

SNRI

620008101

Milnacipran Hydrochloride Tablets 25 mg “JG”

Milnacipran

SNRI

620008102

Milnacipran Hydrochloride Tablets 25 mg “TAIYO”

Milnacipran

SNRI

620008103

Milnacipran Hydrochloride Tablets 25 mg “TYK”

Milnacipran

SNRI

620008104

Milnacipran Hydrochloride Tablets 25 mg “TOWA”

Milnacipran

SNRI

620008105

Milnacipran Hydrochloride Tablets 25 mg “Nichi-Iko”

Milnacipran

SNRI

621965101

Milnacipran Hydrochloride Tablets 50 mg “SAWAI”

Milnacipran

SNRI

621980301

Milnacipran Hydrochloride Tablets 12.5 mg “AMEL”

Milnacipran

SNRI

621980401

Milnacipran Hydrochloride Tablets 50 mg “AMEL”

Milnacipran

SNRI

621982501

Milnacipran Hydrochloride Tablets 50 mg “AFP”

Milnacipran

SNRI

621986801

Milnacipran Hydrochloride Tablets 12.5 mg “Nichi-Iko”

Milnacipran

SNRI

621986901

Milnacipran Hydrochloride Tablets 50 mg “Nichi-Iko”

Milnacipran

SNRI

621993401

Milnacipran Hydrochloride Tablets 12.5 mg “SAWAI”

Milnacipran

SNRI

621993501

Milnacipran Hydrochloride Tablets 50 mg “TYK”

Milnacipran

SNRI

622021601

Milnacipran Hydrochloride Tablets 12.5 mg “AFP”

Milnacipran

SNRI

622022601

Milnacipran Hydrochloride Tablets 12.5 mg “JG”

Milnacipran

SNRI

622029201

Milnacipran Hydrochloride Tablets 12.5 mg “TYK”

Milnacipran

SNRI

622055301

Milnacipran Hydrochloride Tablets 12.5 mg “TOWA”

Milnacipran

SNRI

622055401

Milnacipran Hydrochloride Tablets 50 mg “TOWA”

Milnacipran

SNRI

622058301

Milnacipran Hydrochloride Tablets 12.5 mg “TAIYO”

Milnacipran

SNRI

622058401

Milnacipran Hydrochloride Tablets 50 mg “TAIYO”

Milnacipran

SNRI

622070701

Milnacipran Hydrochloride Tablets 50 mg “JG”

Milnacipran

SNRI

622078701

Milnacipran Hydrochloride Tablets 12.5 mg “NP”

Milnacipran

SNRI

622078801

Milnacipran Hydrochloride Tablets 50 mg “NP”

Milnacipran

SNRI

621978201

Cymbalta Capsules 20 mg

Duloxetine

SNRI

621978301

Cymbalta Capsules 30 mg

Duloxetine

SNRI

622449501

EFFEXOR SR CAPSULES 37.5 mg

Venlafaxine

SNRI

622449601

EFFEXOR SR CAPSULES 75 mg

Venlafaxine

NaSSA

621932101

REFLEX TABLETS 15 mg

Mirtazapine

NaSSA

622497001

REFLEX TABLETS 30 mg

Mirtazapine

NaSSA

621929501

REMERON Tablets 15 mg

Mirtazapine

NaSSA

622482601

REMERON Tablets 30 mg

Mirtazapine

NaSSA

622647601

Mirtazapine Tablets 15 mg “Chemiphar”

Mirtazapine

NaSSA

622647701

Mirtazapine Tablets 30 mg “Chemiphar”

Mirtazapine

NaSSA

622648101

Mirtazapine Tablets 15 mg “YD”

Mirtazapine

NaSSA

622648201

Mirtazapine Tablets 30 mg “YD”

Mirtazapine

72

NaSSA

622648801

Mirtazapine Tablets 15 mg “Pfizer”

Mirtazapine

NaSSA

622648901

Mirtazapine Tablets 30 mg “Pfizer”

Mirtazapine

NaSSA

622650201

Mirtazapine OD Tablets 15 mg “DSEP”

Mirtazapine

NaSSA

622650301

Mirtazapine OD Tablets 30 mg “DSEP”

Mirtazapine

NaSSA

622650701

Mirtazapine Tablets 15 mg “TCK”

Mirtazapine

NaSSA

622650801

Mirtazapine Tablets 30 mg “TCK”

Mirtazapine

NaSSA

622652401

Mirtazapine Tablets 15 mg “EE”

Mirtazapine

NaSSA

622652501

Mirtazapine Tablets 15 mg “Nichi-Iko”

Mirtazapine

NaSSA

622652601

Mirtazapine Tablets 30 mg “EE”

Mirtazapine

NaSSA

622652701

Mirtazapine Tablets 30 mg “Nichi-Iko”

Mirtazapine

NaSSA

622654201

Mirtazapine OD Tablets 15 mg “AMEL”

Mirtazapine

NaSSA

622654301

Mirtazapine OD Tablets 30 mg “AMEL”

Mirtazapine

NaSSA

622655801

Mirtazapine OD Tablets 15 mg “SAWAI”

Mirtazapine

NaSSA

622655901

Mirtazapine OD Tablets 30 mg “SAWAI”

Mirtazapine

NaSSA

622656001

Mirtazapine Tablets 15 mg “SAWAI”

Mirtazapine

NaSSA

622656101

Mirtazapine Tablets 30 mg “SAWAI”

Mirtazapine

NaSSA

622657501

Mirtazapine Tablets 15 mg “TOWA”

Mirtazapine

NaSSA

622657601

Mirtazapine Tablets 30 mg “TOWA”

Mirtazapine

NaSSA

622657701

Mirtazapine OD Tablets 15 mg “TOWA”

Mirtazapine

NaSSA

622657801

Mirtazapine OD Tablets 30 mg “TOWA”

Mirtazapine

NaSSA

622658701

Mirtazapine Tablets 15 mg “NISSIN”

Mirtazapine

NaSSA

622658801

Mirtazapine Tablets 30 mg “NISSIN”

Mirtazapine

NaSSA

622659501

Mirtazapine Tablets 15 mg “FELDSENF”

Mirtazapine

NaSSA

622659601

Mirtazapine Tablets 30 mg “FELDSENF”

Mirtazapine

NaSSA

622660301

Mirtazapine Tablets 15 mg “KYOSOMIRAI”

Mirtazapine

NaSSA

622660401

Mirtazapine Tablets 30 mg “KYOSOMIRAI”

Mirtazapine

NaSSA

622661801

Mirtazapine Tablets 15 mg “KYORIN”

Mirtazapine

NaSSA

622661901

Mirtazapine Tablets 30 mg “KYORIN”

Mirtazapine

NaSSA

622662901

Mirtazapine Tablets 15 mg “TAKEDA TEVA”

Mirtazapine

NaSSA

622663001

Mirtazapine Tablets 30 mg “TAKEDA TEVA”

Mirtazapine

NaSSA

622663201

Mirtazapine Tablets 15 mg “AMEL”

Mirtazapine

NaSSA

622663301

Mirtazapine Tablets 30 mg “AMEL”

Mirtazapine

NaSSA

622664401

Mirtazapine Tablets 15 mg “JG”

Mirtazapine

NaSSA

622664501

Mirtazapine Tablets 30 mg “JG”

Mirtazapine

NaSSA

622666401

Mirtazapine OD Tablets 15 mg “NIPRO”

Mirtazapine

73

NaSSA

622666501

Mirtazapine OD Tablets 30 mg “NIPRO”

Mirtazapine

NaSSA

622666601

Mirtazapine Tablets 15 mg “NIPRO”

Mirtazapine

NaSSA

622666701

Mirtazapine Tablets 30 mg “NIPRO”

Mirtazapine

NaSSA

622667801

Mirtazapine Tablets 15 mg “MEIJI”

Mirtazapine

NaSSA

622667901

Mirtazapine Tablets 30 mg “MEIJI”

Mirtazapine

Other622699301

Trintellix Tablets 10 mg

Vortioxetine

Other622699401

Trintellix Tablets 20 mg

Vortioxetine

74