Comparison of Antidepressants in the Real-World: Retrospective Cohort Study Using Big Data
Conditions: Major Depression
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
Study information 
Title 
Comparison of Antidepressants in the Real-
World: Retrospective Cohort Study Using 
Big Data 
Protocol number 
B2061147 
Protocol version identifier 
Amendment 1 
Date 
10 February 2021 
Active substance 
DESVENLAFAXINE (N06AX23) 
Medicinal product 
Pristiq 
Research question and objectives 
Research question: What is the real-world 
data on antidepressant therapy that can be 
found in the nationwide claims database 
in Korea? 
  
Primary objectives: 
1. Explore baseline characteristics and drug 
utilization patterns of 11 commonly used 
antidepressant therapy during 90 days of 
acute treatment phase 
 
2. Explore drug utilization patterns such as 
therapy changes, medication compliance 
and recurrence relationship, and risk of 
adverse outcomes during maintenance 
phase 
 
Secondary objectives:  
1. Choice of antidepressants and drug 
utilization patterns in patients with 
various comorbidities 
 
2. The relationship of non-pharmacologic 
treatment and discontinuation, 
medication compliance 
 

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3. Choice of antidepressants by non-
psychiatric specialty 
Author 
, M.D. 
 
, Pfizer Korea 
 
  
 
, MA, PhD 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD

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1. TABLE OF CONTENTS 
1. TABLE OF CONTENTS ................................................................................................3 
2. LIST OF ABBREVIATIONS ..........................................................................................5 
3. RESPONSIBLE PARTIES..............................................................................................6 
4. ABSTRACT ...................................................................................................................7 
5. AMENDMENTS AND UPDATES ...............................................................................10 
6. MILESTONES .............................................................................................................11 
7. RATIONALE AND BACKGROUND...........................................................................11 
8. RESEARCH QUESTION AND OBJECTIVES .............................................................12 
9. RESEARCH METHODS ..............................................................................................14 
9.1. Study design .....................................................................................................14 
9.2. Setting ..............................................................................................................14 
9.2.1. Inclusion criteria ...................................................................................15 
9.2.2. Exclusion criteria ..................................................................................16 
9.3. Variables ..........................................................................................................17 
9.4. Data sources......................................................................................................24 
9.5. Study size .........................................................................................................24 
9.6. Data management..............................................................................................25 
9.7. Data analysis.....................................................................................................25 
9.8. Quality control ..................................................................................................25 
9.9. Limitations of the research methods ...................................................................26 
9.10. Other aspects...................................................................................................26 
10. PROTECTION OF HUMAN SUBJECTS....................................................................26 
10.1. Patient information ..........................................................................................26 
10.2. Patient consent ................................................................................................26 
10.3. Institutional review board (IRB)/Independent ethics committee (IEC) ...............27 
10.4. Ethical conduct of the study .............................................................................27 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ...............................................................................................................27 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS .......28 
13. REFERENCES ...........................................................................................................28 

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14. LIST OF TABLES ......................................................................................................30 
15. LIST OF FIGURES.....................................................................................................30 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS......................................................30 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS.......................................30 
ANNEX 3. ADDITIONAL INFORMATION ....................................................................30 
 
 

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2. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
HIRA 
Health Insurance and Review Assessment 
MPR 
Medication Possession Ratio 
ICD-10 
International Classification of Diseases 10th revision 
KCD-7 
Korean Standard Classification of Diseases 7th revision 
MDD 
Major Depressive Disorder 
MCI 
Mild cognitive impairment 
COPD 
Chronic Obstructive Pulmonary Disease 
CAD 
Coronary Artery Disease 
CVA 
Cerebrovascular Accident 
CBT 
Cognitive Behavioral Therapy 
SSRI 
Selective serotonin reuptake inhibitor 
SNRI 
Serotonin–norepinephrine reuptake inhibitor 
NHI 
National Health Insurance 
AD 
Antidepressants 
 
 
 
 
 
 
 
 
 
 
 

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3. RESPONSIBLE PARTIES 
Principal Investigator(s) of the Protocol 
Name, degree(s) 
Job Title 
Affiliation 
Address 
, 
M.D. 
Non-Interventional 
Study Lead 
Pfizer Korea Ltd. 
, Korea 
, 
MA, PhD 
Associate Professor 
 
 
, Korea 
PPD
PPD
PPD
PPD
PPD

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4. ABSTRACT 
Title: Comparison of Antidepressants in the Real-World: Retrospective Cohort Study Using 
Big Data 
Rationale and background 
While there are many antidepressants from which physicians can select based on efficacy and 
tolerability profile, evidence on effectiveness and safety outcomes of new antidepressants in 
real clinical practice among Korean MDD population is limited. Hence, the aim of this study 
is to investigate medication utilization pattern and risk of adverse outcomes among 
commonly used antidepressants by using nationwide claims database, in order to assess 
overall clinical benefit of antidepressant therapy in real-world practice. 
Research question and objectives 
Research question: What is the real-world data on antidepressant therapy that can be found 
in the nationwide claims database in Korea?  
 
Primary objectives: 
1. Explore baseline characteristics and drug utilization patterns of 11 commonly used 
antidepressant therapy during 90 days of acute treatment phase 
2. Explore drug utilization patterns such as therapy changes, medication compliance and 
recurrence relationship, and risk of adverse outcomes during maintenance phase 
 
Secondary objectives:  
1. Choice of antidepressants and drug utilization patterns in patients with various 
comorbidities 
2. The relationship of non-pharmacologic treatment and discontinuation, medication 
compliance 
3. Choice of antidepressants by non-psychiatric specialty 
 
Study design: Retrospective cohort study 
Population:  
Subjects who newly initiated antidepressant therapies between Jan 01, 2017 to Jun 30, 
2019 in the Health Insurance and Review Assessment (HIRA) database 
*Index date is the first prescription date of study drugs, including SSRIs, SNRIs, and other 
ADs during the intake period (Jan 01, 2017 to Dec 31, 2019) 
 

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Variables – include exposures, outcomes, and key co-variates 
Exposure: The exposure to the following will be considered: 
1. SSRIs 
2. SNRIs 
3. Other ADs (including but not limited to mirtazapine, vortioxetine) 
 
Outcome variables: the following will be assessed: 
1. Outcomes related to depression 
- 
AD usage pattern (prescription proportion, dosage and length of treatment, 
switching, combination, augmentation, discontinuation), compliance, recurrence 
2. Adverse outcomes 
- 
Hyponatremia, GI bleeding, fractures, falls, risk of intracranial hemorrhage, 
attempted suicide/self-harm, myocardial infarction, epilepsy/seizures, 
stroke/transient ischemic stroke 
 
Key-Covariates: Variables, including but not limited to, will be age, sex, region, Charlson 
comorbidity index, psychiatric comorbidities, hospital admission 
 
Data sources 
HIRA database from January 01, 2016 to December 31, 2019 will be used for the analysis. It 
contains the data of universal health insurance system in Korea, wherein patient demographic 
information, inpatient and outpatient service use, and pharmacy dispensing claims can be 
obtained. 
Study size 
The study size will be determined based on the HIRA disease statistics, diagnosis code, 
inclusion and exclusion criteria, and study period. A previous study was conducted using the 
HIRA data from January 1, 2011 to December 31, 2015, during which 752,190 patients were 
identified to have been newly prescribed antidepressants with diagnosis of depressive 
disorder.  
 

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Data analysis 
Patients will be matched on demographic and clinical characteristics. All outcome variables 
will be summarized descriptively through the tabular and graphical display of mean values, 
medians, ranges and standard deviations of continuous variables of interest and frequency 
distributions of categorical variables. Safety outcomes of treatments will be estimated from 
time-to-event models. The 95% confidence intervals for the estimates will be calculated and 
p<0.05 will be considered significant. All analyses will be carried out using SAS version 9.4. 
Analysis and reporting will be compliant with Strengthening the Reporting of Observational 
Studies in Epidemiology (STROBE) recommendations. 
 

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5. AMENDMENTS AND UPDATES 
Amendment 
number 
Date 
Protocol 
section(s) 
changed 
Summary of amendment(s) 
Reason 
Ammendme
nt 1 
10Feb2021 
2. 
 
 
3. 
 
4. 
 
 
 
 
 
6. 
 
 
 
9.2 
 
 
 
9.4 
 
 
9.5 
 
 
9.6 
 
 
9.8 
 
 
9.9 
 
 
12. 
 
Figure 1. 
 
 
Table 2. 
 
 
Table 3. 
NHIS changed to HIRA. 
 
 
Name and degree of NISL changed. 
 
Population, data sources, study size 
amended to describe HIRA. Database 
selection period extended to end in 
2019. Outcome variables related to 
depression added. 
 
Planned dates for start and end of data 
collection, interim report, and final 
study report amended. 
 
Population amended to describe HIRA. 
Database selection period extended to 
end in 2019. 
 
Data sources amended to describe 
HIRA. 
 
Study size amended to describe HIRA. 
 
 
Data management amened to describe 
HIRA. 
 
Database name changed to HIRA. 
 
 
Database name changed to HIRA. 
 
 
Typo corrected. 
 
Intake and follow-up period extended 
to end in 2019. 
 
Drug Main Ingredient Codes source 
changed to HIRA. 
 
Data source changed to HIRA. 
Correction according to database 
change 
 
Correction according to NISL change 
 
Correction according to database 
change and addition of description of 
results variable 
 
 
 
Correction according to database 
change. 
 
 
Correction according to database 
change. 
 
 
Correction according to database 
change. 
 
Correction according to database 
change. 
 
Correction according to database 
change. 
 
Correction according to database 
change. 
 
Correction according to database 
change. 
 
Correction of typo 
 
Correction according to database 
change. 
 
Correction according to database 
change. 
 
Correction according to database 
change. 
 
 
 
 
 
 

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6. MILESTONES 
Milestone 
Planned date 
Completion of feasibility assessment 
28 Jun 2019 
Start of data collection  
Mar 2021 
End of data collection  
Jun 2021 
Interim report 1 
Dec 2021 
Final study report 
Dec 2022 
 
7. RATIONALE AND BACKGROUND 
Major depressive disorder (MDD) is a prevalent disorder, causing great disability in 
affected individuals.1-3 Its lifetime prevalence is estimated at 6.7% in Korea, and has 
continued to increase gradually since 2006.4 The approximate economic cost of MDD in 
2005 was at $4.5 billion, with indirect cost of $2.96 billion due to loss of work 
productivity.5  
Current guidelines recommend antidepressants like selective serotonin reuptake inhibitors 
(SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SNRIs) as first-line 
pharmacotherapy for the management of MDD.6-7 The antidepressant effect not only 
reduces depressive symptoms but also contributes to patient’s overall functional 
improvement.8 Despite plenty of available evidences on antidepressant therapy, Sequenced 
Treatment Alternatives to Relieve Depression (STAR*D) study showed that only about 
30% of patients achieve remission with first-line treatment.9 In addition, those patients 
switching antidepressants compared to those initiating or maintaining first-line 
antidepressant therapy have different patient characteristics in terms of severity of 
depressive symptoms, anxiety, worse health-related quality of life, functional 
impairment.10 Non-adherence rates are high in MDD, which can lead to suboptimal 
treatment outcomes.11 
While there are many antidepressants from which physicians can select based on efficacy 
and tolerability profile, evidence on effectiveness and safety outcomes of new 

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antidepressants in real clinical practice among Korean MDD population is limited. Ahn et 
al. (2011) reported that antidepressant adherence among the Korean patients with MDD is 
less than 50% and recurrence and deterioration of MDD occurs due to the low adherence 
in Korea.12  In addition, it is uncertain how patients are being properly managed with index 
medications and the proportion of switching, combination, and augmentation therapy 
during both acute and maintenance phases. And medication adherence and persistence 
rates are clinically important as they can have a major impact on the outcomes such as 
recurrence and recovery from depressive symptoms.  
Therefore, the aim of this study is to investigate medication utilization pattern and risk of 
adverse outcomes among commonly used antidepressants by using nationwide claims 
database, in order to assess overall clinical benefit of antidepressant therapy in real-world 
practice.  
 
8. RESEARCH QUESTION AND OBJECTIVES 
Research question: What is the real-world data on antidepressant therapy that can be found 
in the nationwide claims database in Korea?  
 
Primary objectives: 
- Explore baseline characteristics and drug utilization patterns of 11 commonly used 
antidepressant therapy during 90 days of acute treatment phase 
o Top 11 commonly used antidepressants according to local market data are as 
follows: 
- 
Escitalopram, paroxetine, fluoxetine, mirtazapine, duloxetine, sertraline, 
venlafaxine, tianeptine, vortioxetine, desvenlafaxine, bupropion 
o Proportion of antidepressants prescribed by sex, age (<20, 21-64, > 65), sex and 
age combined 
o Initial doses used, average daily doses of each antidepressants 
o Average length of treatment with index medication before therapy change occurs 
(switching, combination, augmentation, discontinuation) 

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o Adherence and persistence measured by medication possession ratio during first 
90 days of treatment period 
- Explore drug utilization patterns such as therapy changes, medication compliance and 
recurrence relationship, and risk of adverse outcomes during maintenance phase 
o The choice of antidepressant, average length of new treatment maintenance, 
average number of co-administered medications (e.g., atypical antipsychotics, 
mood stabilizer, thyroid hormone, psychostimulant) when following changes 
occur from initial monotherapy: 
- Switching 
- Combination 
- Augmentation  
o Medication compliance and recurrence 
- Compliance measured as adherence and persistence  
- Recurrence 
- Relationship between recurrence and compliance 
o Risk of adverse outcomes measurement between individual ADs that are well 
known to be treatment-related (e.g., hyponatremia, GI bleeding, fractures, falls, 
risk of intracranial hemorrhage, attempted suicide/self-harm, myocardial 
infarction, epilepsy/seizures, stroke/transient ischemic stroke) 
 
Secondary objectives:  
1. Choice of antidepressants and drug utilization patterns in patients with various 
comorbidities 
o Psychiatric comorbidities 
o Mild cognitive impairment (MCI) 
2. The relationship of non-pharmacologic treatment and discontinuation, medication 
compliance 
o Non-pharmacologic treatments may include: cognitive behavioral therapy (CBT), 

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frequency of physician visit during acute and maintenance phase of treatment 
- Frequency of visit during the first 3 months of acute phase and its relationship 
to treatment maintenance at 4, 5, 6, 7, 8, 9 month time points and 
discontinuation rate 
3. Choice of antidepressants by non-psychiatric specialty 
o Rheumatology, cardiology, pulmonology, infectious diseases, nephrology, 
endocrinology and metabolism, gastroenterology, rehabilitative medicine, 
neurology, neurosurgery, urology, otorhinolaryngology, gynecology & obstetrics, 
etc. 
  
9. RESEARCH METHODS  
9.1. Study design  
Using a retrospective cohort design, this study will evaluate treatment utilization pattern, 
medication compliance, incidence of recurrence, risk of adverse outcomes of antidepressant 
therapy, choice of therapy in various comorbidities, and choice of therapy in other specialty 
that are recorded in national health insurance database. 
 
 
 
 
 
 
 
 
 
Figure 1. Study design scheme 
 
9.2. Setting 
Population 
Subjects who newly initiated antidepressant therapies between Jan 01, 2017 to Jun 30, 2019 
in the HIRA database 
Discontinuation, switching 
Intake period (Jan 01, 2017 – Jun 30, 2019) 
Outcomes 
No events 
Follow-up period (Index date – Dec 31, 2019) 
Pre-Index period 
From 1 yr prior to the 
day before index date  
Index date (1st Rx of study drugs) 
 

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* Index date is the first prescription date of study drugs, including SSRIs, SNRIs, and other 
ADs during the intake period (Jan 01, 2017 to Dec 31, 2019). 
9.2.1. Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study: 
1. Patients aged 18 years or older on the index date 
2. Patients who had at least one inpatient claim or two outpatient claims in the intake period 
with any of the following diagnosis codes 
Table 1. Diagnosis codes for inclusion 
KCD-7 Code1) 
Description 
F06.3 
F32* 
F33* 
F34.1 
F38.1 
F41.2 
Organic mood[affective] disorders 
Depressive episode 
Recurrent depressive disorder 
Neurotic depression 
Other recurrent mood[affective] disorders 
Mixed anxiety and depressive disorder 
1) KCD-7 = Korean version of ICD-10 
3. Patients prescribed any of the following antidepressant during intake period (from 
January 1, 2017 to June 30, 2019) 
Table 2. Study Drug List 
Active 
Ingredient 
Dosage 
HIRA Drug Main Ingredient Codes 
Escitalopram 
5mg 
10mg 
20mg 
15mg 
10mg 
20mg 
474801ATB 
474802ATB 
474803ATB 
474804ATB 
521101ATD 
521102ATD 
Paroxetine 
10mg 
20mg 
12.5mg 
25mg 
209301ATB 
209302ATB 
209304ATR 
209305ATR 
Fluoxetine 
10mg 
10mg 
20mg 
20mg 
20mg 
161501ACH 
161501ATB 
161502ACH 
161502ATB 
161502ATD 

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Mirtazapine 
15mg 
15mg 
30mg 
30mg 
7.5mg 
7.5mg 
196201ATB 
196201ATD 
196202ATB 
196202ATD 
196204ATB 
196204ATD 
Duloxetine 
30mg 
30mg 
60mg 
60mg 
495501ACE 
495501ATE 
495502ACE 
495502ATE 
Sertraline 
50mg 
0.1g 
227001ATB 
227002ATB 
Venlafaxine 
75mg 
37.5mg 
247502ACR 
247504ACR 
Tianeptine 
12.5mg 
229601ATB 
Vortioxetine 
5mg 
10mg 
15mg 
20mg 
628501ATB 
628502ATB 
628503ATB 
628504ATB 
Desvenlafaxine 
50mg 
100mg 
626401ATR 
626402ATR 
Bupropion 
0.1g 
0.15g 
0.3g 
428101ATB 
428102ATR 
428103ATR 
 
9.2.2. Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
1. Patients with a claim of diagnosis codes in Table 1 during the 12 month pre-index period 
2. Patients with a claim of prescription in Table 2 during the 12 month pre-index period 
3. Patient who had a claim as a beneficiary of Medical Aid program (Korean Medicaid 
program with free or minimum copay) 
4. Patients who are hospitalized at the index date 
5. Patients who are under hospice care (procedure codes WG*-WO*) 
 

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9.3. Variables 
Table 3. List of Variable Categories 
Variable 
Role 
Data Source 
Operational Definition 
SSRIs 
Exposure 
HIRA 
Database 
Prescription claims with a HIRA 
Drug Main Ingredient code for the 
following drugs defined in Table 2 
will be used individually for each 
drug: 
 
Escitalopram, paroxetine, 
fluoxetine, sertraline  
SNRIs 
Exposure 
HIRA 
Database 
Prescription claims with a HIRA 
Drug Main Ingredient code for the 
following drugs defined in Table 2 
will be used individually for each 
drug: 
 
Duloxetine, venlafaxine, 
desvenlafaxine 
Other ADs 
Exposure 
HIRA 
Database 
Prescription claims with a HIRA 
Drug Main Ingredient code for the 
following drugs defined in Table 2 
will be used individually for each 
drug: 
 
Mirtazapine, tianeptine, 
vortioxetine, bupropion 
Proportion of 
Antidepressants 
Primary 
outcome 
HIRA 
Database 
For each of 11 study drugs, the 
following proportions will be 
calculated 
1) Proportion out of total 
prescriptions in the first 90 
days from the index date 
(acute treatment phase) 
2) Proportion out of each 
gender in the first 90 days 
from the index date (acute 
treatment phase) 
3) Proportion out of three age 
groups (≤20, 21-64, ≥65) 
in the first 90 days from 
the index date (acute 

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treatment phase) 
4) Proportion out of 6 
subgroups generated by 2 
genders and 3 age groups 
in the first 90 days from 
the index date (acute 
treatment phase) 
Dosage 
Primary 
outcome 
HIRA 
Database 
For each of 11 study drugs, the 
following dosages will be 
calculated 
1) Initial dosage at the index 
date 
2) The average dosage during 
the first 90 day period 
from the index date (acute 
treatment phase) 
Persistence 
Primary 
outcome 
HIRA 
Database 
For each of 11 study drugs, the 
average length of treatment on the 
index drug (allowing 14 day 
permissible gap) will be calculated 
- Switching, combination, 
augmentation, discontinuation 
will terminate the persistent 
period 
Discontinuation 
Primary 
outcome 
HIRA 
Database 
For each of 11 study drugs chosen 
as index drug, the percentage of 
discontinuation in the first 90 days 
from the index date (acute 
treatment phase) will be measured 
(allowing 14 day permissible gap) 
Adherence 
Primary 
outcome 
HIRA 
Database 
For each of 11 study drugs chosen 
as index drug, adherence will be 
measured by MPR during the first 
90 days from the index date (acute 
treatment phase) 
* MPR = (Days of medication 
possession from the prescriptions 
filled in the 90 days) / (90 days + 
extra days of drug supply from the 
last prescription fill during the 90 
days) 
** For those period with any 
identified adverse outcome such as 
GI bleeding will be considered as 

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non-adherent period 
Drug utilization 
pattern in acute 
phase 
Secondary 
outcome 
HIRA 
Database 
During the first 90 day period 
starting from the index date, the 
following types of drug utilization 
pattern is recorded 
- monotherapy (kept on the 
index medication) 
- switching (switched to other 
antidepressant) 
- combination (adding other 
antidepressant) 
- augmentation (adding other 
non-AD drug such as 
antipsychotic) 
Drug utilization 
pattern in 
maintenance phase 
Secondary 
outcome 
HIRA 
Database 
During the second 90 day period 
(91 ~ 180 days) starting from the 
index date, the following types of 
drug utilization pattern is recorded 
- choice of antidepressant 
- monotherapy (kept on the same 
medication) 
- switching (switched to other 
antidepressant) 
- combination (adding other 
antidepressant) 
- augmentation (adding other 
non-AD drug such as 
antipsychotic) 
Recurrence 
Primary 
outcome 
HIRA 
Database 
Recurrence was operationally 
defined as either one of the 
following was satisfied: 
1) inpatient episode with a 
diagnosis code in Table 1 
2) emergency room visit with 
a diagnosis code in Table 
1 
3) suicide attempt identified 
by the following KCD-7 
codes: 
T40 Poisoning by narcotics and 
psychodysleptics [hallucinogens] 
T41 Poisoning by anaesthetics and 

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therapeutic gases 
T42 Poisoning by antiepileptic, 
sedative-hypnotic and 
antiparkinsonism drugs 
T43 Poisoning by psychotropic 
drugs, not elsewhere classified 
T54 Toxic effect of corrosive 
substances 
T60 Toxic effect of pesticides 
X60-X84 intentional self harm 
Adverse outcomes 
Primary 
outcome 
HIRA 
Database 
The following known treatmwent 
related outcomes will be 
operationally defined by KCD-7 
diagnosis codes and/or NHI 
procedure codes in medical claims 
- GI bleeding 
I850, I983, K2211, K226, K228, 
K250, K252, K254, K256, K260, 
K262, K264, K266, K270, K272, 
K274, K276, K280, K282, K284, 
K286, K290, K3181, K5521, K625, 
K920, K921, K922 
- Fractures 
S02, S12, S22, S32, S42, S52, S62, 
S72, S82, S92, T02, T08, T10, T12, 
T14.2 
- Falls 
W00-W19 
- Intracranial hemorrhage 
I60, I61, I62, I690, I691, I692, S064, 
S065, S066, S068 
- Suicide attempt, self-harm 
T40 Poisoning by narcotics and 
psychodysleptics [hallucinogens] 
T41 Poisoning by anaesthetics and 
therapeutic gases 
T42 Poisoning by antiepileptic, 
sedative-hypnotic and 
antiparkinsonism drugs 
T43 Poisoning by psychotropic 
drugs, not elsewhere classified 
T54 Toxic effect of corrosive 
substances 
T60 Toxic effect of pesticides 
X60-X84 intentional self-harm 
- Myocardial infarction 
I21.9, I21.4, I21.0, I21.1, I21.2, I21.3, 
I22.0A, I22.0B, I22.0C, I22.8A, 

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I22.8B, I22.8C, I22.8D, I22.8E,  
I22.8F, I22.8G, I22.8H, I22.8I,  
I22.8, I22.9, I22.1A, I22.1B, I22.1C 
- Epilepsy/seizures  
G40.XX 
- Stroke 
- Transient ischemic attack  
 G459, I63, I693 
- Hemorrhagic stroke 
I60, I61, I62, I690, I691, I692 
- Ischemic stroke 
I63 
[NOTE] Hospitalization and CT 
or MRI codes such as brain CT 
or MRI procedure code for 
ischemic stroke and 
hemorrhagic stroke, or any CT 
or MRI for systemic embolism 
are also required for 
identification. 
* Brain CT 
HA441, HA451, HA461, HA471, 
HA851 
* Brain MRI 
HE101, HE102, HE135, HE201, 
HE202, HE235, HE301, HE302, 
HE401, HE402, HE501, HE502, 
HE535 
* Any CT or MRI or CT 
HA401-HA416, HA424, HA425, 
HA434, HA435, HA443-HA449, 
HA453, HA456-HA459, HA463-
HA469, HA473-HA479, HA496, 
HA497, HA801, HA805, HA809, 
HA813, HA834, HA835, HA853, 
HA856, HA857-HA859, S852 
* MRI 
HE103-HE142, HE203-HE234, 
HE236-HE241, HE303-HE334, 
HE403-HE434, HE430-HE434, 
HE503-HE534, HE536-HE541, 
HF101, HF102, HF104-HF107, 
HF201, HF202, HF305, HF306 
 
- Hyponatremia  
- will be identified by 

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prescription codes for 
vasopressin receptor 
antagonists such as 
tolvaptan (drug 
code=616501ATB) 
Comorbidities 
Covariates 
HIRA 
Database 
The following comorbidities 
which may affect the drug 
utilization patterns of 
antidepressants will be 
operationally defined using KCD-
7 diagnosis codes in medical 
claims 
- Psychiatric comorbidities: panic 
disorder (F41.0), bipolar 
disorder (F31), PTSD (F43.1),  
acute stress (F43.0), personality 
disorder (F60-69), GAD 
(generalized anxiety disorder) 
(F41.1), adjustment disorder 
(F43.2), sleep disorder ((F51), 
g470, f108), dementia (F00-F03, 
G30), OCD (obsessive 
compulsive disorder) ((F42), 
F429, F605, F428)), substance 
related disorders (F10-19), 
schizophrenia (F20-29), eating 
disorder (F50), sexual 
dysfuntion (F52), mental 
retardation (F70-F79), 
developmental disorder (F80-
F89), somatoform disorder F45, 
eating disorder F50 
- Mild cognitive impairment 
(MCI):  diagnosis code F06.7 
along with a procedure code for 
neurocognitive function test 
FB001-FB060* 
- Charlson Comorbidity Index 
(CCI) 
Non-pharmacologic 
treatments 
Covariates 
HIRA 
Database 
The following non-pharmacologic 
treatments which may affect 
antidepressant adherence and 
persistence/discontinuation will be 

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defined using NHI procedure 
codes* in medical claims 
- Individual psychotherapy** 
NN012 intensive analytic 
NN013 intensive 
- Group psychotherapy 
NN021 general 
NN022 analytic 
NN023 psychodrama 
- Family psychotherapy 
NN031 individual 
NN032 group 
NN040 occupational or recreation 
therapy 
NN050 narcosynthesis 
- Electroconvulsive therapy 
NN071 simple ETC 
NN072 modified ETC 
- Continuous sleep treatment 
NN081 electro sleep treatment 
NN082 drug induced sleep treatment 
NN083 sleep treatment with 
anesthesia 
NN090 psychiatric rehabilitation 
NN100 psychiatric emergency 
treatment 
- Psychiatric social work 
NN111 individual history taking 
NN112 social work guidance 
NN113 social investigation 
NN114 home visiting 
 
* Since January 2018, new code 
system was employed for 
psychotherapy and expert advisor 
consensus will be used to align the 
new codes to the codes above 
NN001-NN005 individual 
psychotherapy 
NN061 Cognitive Behavioral 
Therapy-Individual 
NN062 Cognitive Behavioral 
Therapy-Group 
** NN011 supportive was 
excluded since it is more of a 
routine code used for majority of 
patients according to Ahn et al. 

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(2012)13 
Patient 
demographics and 
provider 
characteristics 
Covariates 
HIRA 
Database 
The following patient 
demographics and provider 
characteristics will be definced 
using medical claims  
- Age 
- Gender 
- Region of provider 
- Specialty of provider 
- Class of clinic/hospital 
Number of visits 
Covariates 
HIRA 
Database 
Number of provider visits will be 
calculated from medical claims 
- Inpatients visits 
- Outpatient visits 
- Emergenccy room visits 
 
 
9.4. Data sources  
The Korean HIRA claims data covers 97% of Korean population (about 50 million people) in 
NHI and 3% of Korean population in Medical Aid program. Patients in Medical Aid program 
are excluded from analysis because the estimated drug compliance may be different from 
those patients covered by NHI due to the fact that patients in Medical Aid program make no 
self-payment or very little payment for medical services (Ahn et al, 2011).   
HIRA database from January 01, 2016 to December 31, 2019 will be used for the analysis. It 
contains the data of universal health insurance system in Korea, wherein patient demographic 
information, inpatient and outpatient service use, and pharmacy dispensing claims can be 
obtained. 
The main limitation of HIRA data is lack of clinical lab data and other clinical marekrs since 
it is a data collected for claims for reimbursement purpose. 
 
9.5. Study size 
Determined based on the HIRA disease statistics, diagnosis code, inclusion and exclusion 
criteria, and study period. A previous study was conducted using the HIRA data from 
January 1, 2011 to December 31, 2015, during which 752,190 patients were identified to 
have been newly prescribed antidepressants with diagnosis of depressive disorder. 

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9.6. Data management  
Ewha Womans University (EWU) team will submit the data request to the HIRA big data 
division. After HIRA prior consultation procedure and data release committee review and 
approval, the requested data will be uploaded only to the HIRA internal server which can be 
accessed from HIRA analysis room available in Wonju or remotely. Even if the data can be 
remotely accessed, copying and moving of data to personal computer is blocked and data 
provision will be suspended in the situation of screen capture, handwriting, or photography, 
all of which are subject to sactions. EWU team hopes to analyze the data in remote access, 
however HIRA has a policy that does not allow remote access to industry-related users, and 
so the data provision method for this study cannot be predicted. Among the analyzed data, 
only summary data such as tables and graphs can be requested to send out to the research 
team. HIRA big data division checks the export requests for patient privacy protection and 
will email the summary file to EWU team. 
Data protection is guaranteed by the HIRA data providing server which is disconnected from 
any outside access and only final anonymized form of tables and figures are allowed to be 
delivered to researcher computers. Before releasing these final output, HIRA Big Data 
Division checks for privacy protection again and makes approval of data export. Hence, there 
will be no violation of privacy of research subjects. 
 
9.7. Data analysis  
The proportions and drug utilization patterns comparisons of 11 study drugs will use all the 
patients satisfying inclusion and exclusion criteria (raw data). Adherence, persistence, 
discontinuation, recurrence, and adverse outcomes comparison of 11 study drugs will use 
both raw data and matched data where patients will be matched on demographic and clinical 
characteristics. All outcome variables will be summarized descriptively through the tabular 
and graphical display of mean values, medians, ranges and standard deviations of continuous 
variables of interest and frequency distributions of categorical variables. Safety outcomes of 
treatments will be estimated from time-to-event models. The 95% confidence intervals for 
the estimates will be calculated and p<0.05 will be considered significant. All analyses will 
be carried out using SAS version 9.4 which is installed on HIRA server. Analysis and 
reporting will be compliant with Strengthening the Reporting of Observational Studies in 
Epidemiology (STROBE) recommendations. 
 
9.8. Quality control 
HIRA claims data files are large and complex. The study analysis will be thoroughly 
evaluated and assessed for quality in twofolds: 1) EWU professors with 30+ years of claims 
data analysis will guide analysts to perform data analyses accurately and efficiently; and 2) 

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clinical expert advisors who are leading clinicains in mental health in Korea will evaluate the 
summary statistics of all levels of data and results and will guide correct interpretation. 
SAS programs used in the data analysis will be checked and stored to ensure integrity and 
quality of analysis.  
 
9.9. Limitations of the research methods 
Even though HIRA claims data is from the whole population of Korea, the data is not 
collected for research purpose. Its original purpose was to claim reimbursement. There might 
be intentional or unintentional miscoding of services performed and diagnosis. These errors 
are generally undetectable but the dominant majority of data is valid according to the 
previous studies on the feasibility of Korean NHI claims data. 
To reduce chances of including antidepressants use for a disease other than major deressive 
disorders, operational definitions of at least two outpatient claims or one inpatient claims 
with diagnosis codes in Table 1 is used. However, it is not 100% accurate since proviers are 
afraid of denial of reimbursement from the HIRA which is empowered with reimbursement 
review and denial of payment. Hence, in some cases, diagnosis code is put strategically to 
minimize a chance of denial. For this reason, this study focuses on antidepressants prescribed 
by a specialist in mental health and only analyze antidepressant prescritions from other 
specialists as secondary analysis to identify antidepressant practice patterns from other 
specialties. 
 
9.10. Other aspects 
Not applicable. 
 
10. PROTECTION OF HUMAN SUBJECTS 
10.1. Patient information  
This study involves data that exist in anonymized structured format and contain no patient 
personal information.  
 
10.2. Patient consent 
As this study involves anonymized structured data, which according to applicable legal 
requirements do not contain data subject to privacy laws, obtaining informed consent from 
patients by Pfizer is not required.  An exemption of informed consent will be sought from the 
EWU IRB and the approval will be forwarded to Pfizer. 

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10.3. Institutional review board (IRB)/Independent ethics committee (IEC) 
An exemption of IRB review will be sought from the EWU IRB and the approval will be 
forwarded to Pfizer.. 
10.4. Ethical conduct of the study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) Good Practices for 
Outcomes Research issued by the International Society forPharmacoeconomics and 
Outcomes Research (ISPOR), Good practices for real-world data studies of treatment and/or 
comparative effectiveness:Recommendations from the joint ISPOR-ISPE Special Task Force 
on real-world evidence in health care decision making, International Ethical Guidelines for 
Epidemiological Studies issued by the Council forInternational Organizations of Medical 
Sciences (CIOMS), European Medicines Agency (EMA) European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on Methodological 
Standards in Pharmacoepidemiology, The ENCePP Code of Conduct for scientific 
independence and transparency in the conduct of pharmacoepidemiological and 
pharmacovigilance studies, Food and Drug Administration (FDA) Guidance for Industry: 
Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, FDA Guidance 
for Industry and FDA Staff: Best Practices for Conducting and Reporting 
Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data and FDA Guidance 
for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims. 
 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
This study involves data that exist as structured data by the time of study start or a 
combination of existing structured data and unstructured data, which will be converted to 
structured form during the implementation of the protocol solely by a computer using 
automated/algorithmic methods, such as natural language processing. 
 
In these data sources, individual patient data are not retrieved or validated, and it is not 
possible to link (i.e., identify a potential association between) a particular product and 
medical event for any individual.  Thus, the minimum criteria for reporting an adverse event 
(AE) (i.e., identifiable patient, identifiable reporter, a suspect product, and event) cannot be 
met. 

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12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
The results of this research will be submitted for publication in scientific peer-reviewed 
journals and for presentation at appropriate research conferences in either poster or podium 
presentation, 
Authorship of any publications resulting from this study will be determined on the basis of 
the International Committee of Medical Journal Editors (ICJME) Recommendations for 
Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals: 
- Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data (2) drafting the 
article or revising it critically for important intellectual contgent; (3) final approval of 
the version to be published and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved. Authors should meet conditions 1, 2, 
3 and 4. 
All publications based on this study must be submitted to Pfizer for corporate review. The 
vender agreement will detail the procedures for, and timing of, Pfizers review of publications. 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
competent authority in any area of the world, or if the party responsible for collecting data 
from the participant is aware of any new information which might influence the evaluation of 
the benefits and risks of a Pfizer product, Pfizer should be informed immediately.  
 
13. REFERENCES 
1. Global Burden of Disease Study 2013 Collaborators, 2013. Global, regional, and 
national incidence, prevalence, and years lived with disability for 301 acute and 
chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the 
global burden of disease study 2013. Lancet 386, 743–800. 
2. World Health Organization, 2017. Depression and Other Common Mental Disorders: 
Global Health Estimates. World Health Organization, Geneva, Switzerland (Technical 
report). 
3. Vigo D, Thornicroft G, Atun R, 2016. Estimating the true global burden of mental 
illness. Lancet Psychiatry 3, 171-178. 

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4. Jeon H, 2012. Epidemiologic studies on depression and suicide. J Korean Med Assoc 
55 (4), 322-328. 
5. Chang S, Hong J, Cho M, 2012. Economic burden of depression in South Korea. Soc 
Psychiatry Psychiatr Epidemiol 47 (5), 683-689. 
6. Kennedy SH, Lam RW, McIntyre RS, et al. Canadian Network for Mood and Anxiety 
Treatments (CANMAT) 2016 clinical guidelines for the management of adults with 
major depressive disorder. III. Pharmacological treatments. The Canadian J Psychiatry 
61(9), 540-560. 
7. Galenberg AJ, Freeman MP, Markowitz JC, 2010. Treatment of patients with major 
depressive disorder (Technical report), American Psychiatric Association.  
8. Trivedi MH, Rush AJ, Wisniewski SR, 2013. Increase in work productivity of 
depressed individuals with improvement in depressive symptom severity. AM J 
Psychiatry 170, 633-641. 
9. Trivedi MH, Morris DW, Wisniewski SR, 2006. STAR*D Study Team, Evaluation of 
outcomes with citalopram for depression using measurement-based care in STAR*D: 
implications for clinical practice. AM J Psychiatry 163, 28-40. 
10. Haro JM, Lamy FX, Jonsson B, 2018. Characteristics of patients with depression 
initiating or switching antidepressant treatment: baseline analyses of the PERFORM 
cohort study. BMC Psychiatry 18:80. 
11. DiMatteo MR, Lepper HS, Croghan TW, 2000. Depression is a risk factor for 
noncompliance with medical treatment: meta-analysis of the effects of anxiety and 
depression on patient adherence. Arch Intern Med 160(14):2101-2107. 
12. Ahn J et al., 2011. Economic evaluation and analysis of factors influencing 
antidepressant adherence. NECA research report. 
13. Ahn J et al., 2012. Korean research status on mental disorders and sucides from 

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depression. NECA research report. 
 
14. LIST OF TABLES  
Table 1. Diagnosis codes for inclusion...............................................................................15 
Table 2. Study Drug List ...................................................................................................15 
Table 3. List of Variable Categories ..................................................................................17 
 
15. LIST OF FIGURES 
Figure 1. Study design scheme ..........................................................................................14 
 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
None  
 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Not applicable 
 
ANNEX 3. ADDITIONAL INFORMATION 
Not applicable