Journal of Affective Disorders 277 (2020) 30–38

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Research paper

Burden of Treatment Resistant Depression (TRD) in patients with major T

depressive disorder in Ontario using Institute for Clinical Evaluative
Sciences (ICES) databases: Economic burden and healthcare resource
utilization
⁎
Roger S. McIntyrea, , Brad Millsonb, G. Sarah Powerb
a
Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Mood Disorders
Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto M5T2S8, ON, Canada
b
IQVIA, Health Access and Outcomes, Kirkland, Quebec, Canada

A R T I C LE I N FO A B S T R A C T

Keywords: Introduction: The burden of treatment-resistant depression (TRD) in Canada requires empirical characterization
Major depressive disorder to better inform clinicians and policy decision-making in mental health. Towards this aim, this study utilized the
Treatment-resistant depression Institute for Clinical Evaluative Sciences (ICES) databases to quantify the economic burden and resource utili-
Burden zation of Patients with TRD in Ontario.
Healthcare resource utilization, Mental health,
Methods: TRD, Non-TRD Major Depressive Disorder (Non-TRD MDD) and Non-MDD cohorts were selected from
Public spend
the ICES databases between April 2006-March 2015 and followed-up for at least two years. TRD was defined as a
minimum of two treatment failures within one-year of the index MDD diagnosis. Non-TRD and Non-MDD pa-
tients were matched with patients with TRD to analyze costs, resource utilization, and demographic information.
Results: Out of 277 patients with TRD identified, the average age was 52 years (SD 16) and 53% were female.
Compared to Non-TRD, the patients with TRD had more all-cause visits to outpatient (38.2 vs. 24.2) and
emergency units (2.7 vs. 2.0) and more depression-related visits to GPs (3.06 vs. 1.63) and psychiatrists (5.88 vs.
1.95) (all p < 0.05). The average two-year cost for TRD patients was $20,998 (CAD).
Limitations: This study included patients with only public plan coverage; therefore, overall TRD population and
cash and private claims were not captured.
Conclusions: Patients with TRD exhibit a significantly higher demand on healthcare resources and higher overall
payments compared to Non-TRD patients. The findings suggest that there are current challenges in adequately
managing this difficult-to-treat patient group and there remains a high unmet need for new therapies.

TRD Treatment-resistant depression AP Antipsychotic

MDD Major depressive disorder DSM-IV The fourth diagnostic and statistical manual of mental dis-
ED Emergency department orders
GP/FM General practitioner/Family medicine ICD-10 The tenth revision of the International Statistical
ICES Institute for Clinical Evaluative Sciences Classification of Diseases and Related Health Problems
HCRU Healthcare resource utilization ECT Electroconvulsive therapy
ODB Ontario drug benefit rTMS Repetitive transcranial magnetic stimulation
OHIP Ontario health insurance plan CBT Cognitive behavioural therapy
DAD Discharge abstracts database SAS Statistical software suit
NACRS National ambulatory care reporting system SD Standard deviation
HCD Home care database SI Suicide ideation
OMHRS Ontario mental health reporting system SA Suicide attempt
AD Antidepressant QALY Quality-adjusted life-years

⁎
Corresponding author.
E-mail address: roger.mcintyre@uhn.ca (R.S. McIntyre).

https://doi.org/10.1016/j.jad.2020.07.045
Received 19 December 2019; Received in revised form 4 June 2020; Accepted 5 July 2020
Available online 28 July 2020
0165-0327/ © 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
R.S. McIntyre, et al.
MH Mental health
RPD Registered persons database
ODSP Ontario disability support program
CANMAT Canadian Network for Mood and Anxiety Treatments
ICER Incremental cost-effectiveness ratio
FDA Food and Drug Administration
SSRIs Selective serotonin reuptake inhibitors
SNRIs Serotonin and norepinephrine reuptake inhibitors
1. Introduction
Major Depressive Disorder (MDD) is a medical diagnosis that could
be characterized by overt negative thinking, exhaustion and lethargy,
suicidal thoughts, and inability to focus (Kennedy, 2008). Approxi-
mately 8% of adults will experience major depression at some time in
their lives (O'Donovan, 2004). Depression can have damaging effects on
health and wellbeing, and leave one at risk for social withdrawal, al-
cohol abuse, and disrupted work, family, and social life
(Kupferberg et al., 2016; Kuria et al., 2012). Major depression is well
characterized by the medical community and is treatable with a variety
of pharmacotherapies and psychotherapies. The most common and
generally accepted treatment options for patients with MDD include:
pharmacotherapy, psychotherapy, or a combination of the two.
Despite a number of approved antidepressants (ADs), a substantial
percentage of individuals with MDD have inadequate response to con-
ventional ADs alone or in various combinations (Little, 2009). A study
examining the prevalence of treatment-resistant depression (TRD)
among Canadian patients from primary care settings found that 21.7%
of patients with MDD were treatment-resistant (Rizvi et al., 2014). In-
adequate outcome in patients with TRD may account for a dispropor-
tionate amount of physician treatment time. Several studies have shown
that patients with TRD require additional healthcare resources – both
inpatient and outpatient – and incur statistically higher healthcare costs
as compared to Non-TRD MDD (Non-TRD) patients (Greden, 2001;
Greenberg et al., 2004; Johnston et al., 2019; Ontario, 2016;
Pilon et al., 2019). Much of the social and economic burden of MDD can
be attributed to TRD, which is associated with 50% increase in direct
and indirect healthcare costs compared to non-resistant MDD
(Rizvi et al., 2014). Despite the increased burden of TRD, there are few
studies comparing the therapies for TRD and Non-TRD patients that can
inform clinicians how to definitively treat refractory depression
(McIntyre et al., 2014).
There is a lack of a universal definition for TRD. In practice, phy-
sicians often use patient-centric and subjective concepts to define TRD
which limits the ability to compare outcomes across healthcare provi-
ders and studies (Brown et al., 2019). However, a recent study has
analyzed different definitions used for TRD across research and clinical
practice (Brown et al., 2019). The study reported that nearly half of the
published work defined TRD as insufficient outcome on at least 2 trials
with ADs within the same or different classes (Brown et al., 2019;
Malhi et al., 2005; McIntyre et al., 2014; Rizvi et al., 2014; Ruhe et al.,
2012). This emerging definition has now been adopted in several
clinical trials focused on developing new therapeutic options for TRD
(Daly et al., 2018; Singh et al., 2016).
Much work has been done to quantify the overall burden of de-
pression on the healthcare system globally (Lim et al., 2008). According
to the World Health Organization, mental health (MH) disorders cost $1
trillion (USD) to the global economy on an annual basis with depression
being the main cause of health and work impairment (Naveen, 2017).
In the United States, the economic burden of depression was estimated
at $210.5 billion (USD) in 2010 and in Canada, the cost of depression
was estimated at $32.3 billion (CAD) (Greenberg et al., 2015;
Southerland and Stonebridge, 2016). While the overall burden of de-
pression has been defined in Canada (Smetanin et al., 2011), little in-
formation exists describing the economic impact of TRD, especially in
the province of Ontario, which is the most populous province in Canada
31
Journal of Affective Disorders 277 (2020) 30–38
and accounts for nearly 40% of the overall Canadian population (Sta-
tistics Canada, 2019). Herein, we sought to evaluate the implications of
TRD on healthcare resource utilization (HCRU) and the associated costs
across multiple healthcare touch points for Ontario residents who had
coverage through public plans, to investigate the hypothesis that pa-
tients with TRD pose a significant burden on healthcare resources,
particularly in comparison to non-TRD patients. Information provided
would not only be of interest to practitioners, but also to healthcare
administration and persons in policy.
2. Methods
2.1. Study design
This retrospective longitudinal cohort study was implemented with
administrative data in Ontario, Canada, between April 2005 to March
2017. A one-year lookback and two-year follow-up periods were used,
and the index date for patients with MDD was defined as MDD diagnosis
associated with the first instance of either TRD or Non-TRD (where both
existed, TRD took precedence) between April 2006 and March 2015.
2.2. Data source
Administrative health service records for publicly insured in-
dividuals in Ontario were extracted from multiple linked datasets held
by the Institute for Clinical Evaluative Sciences (ICES). These datasets
are coded, extracted at record-level, and include health service records
relating to Ontario's universal health coverage from 1986 onwards
(ICES Data, 2020). The datasets utilized in this study were physician
billing from the Ontario health insurance plan (OHIP), hospital data-
bases including Discharge Abstract Database (DAD) and National Am-
bulatory Care Reporting System (NACRS), Home Care Database (HCD),
Ontario Mental Health Reporting System (OMHRS), Ontario Drug
Benefit prescription claims (ODB), and demographic information from
Registered Persons Database (RPD). Patients’ encrypted OHIP card
numbers were used to follow the patients through each healthcare
touchpoint. All data sources were linked at the patient level to allow for
patient-specific, longitudinal analysis.
2.3. Inclusion and exclusion criteria
All patients included in this study were adults (aged ≥ 18 years)
with at least one year of ODB and OHIP eligibility prior to index, at
least one year of ODB eligibility after index and at least two years of
OHIP eligibility after index. Persons in Ontario are considered eligible
for ODB when they turn 65 years of age or may qualify for ODB before
this age based on the following conditions: patients living in a long-
term care home or a home for special care, or enrolled in Home Care,
Ontario Works, Ontario Disability Support Program (ODSP), or Trillium
Drug Program. Residents of Ontario are eligible for OHIP coverage and
have access to emergency and preventive care free of charge
(Ministry Programs, 2015).
Patients were excluded from the study if: they had claims for lithium
or antipsychotic (AP) medications (Table S2) during the one-year
lookback period or an AD (Table S1) during the 30 days to one year
prior to the index date; were diagnosed with one of the following
conditions during the one-year lookback period: alcohol abuse, anxiety,
schizophrenia and psychosis, compulsive disorder, dementia, drug de-
pendence, involuntary assessment, personality disorder, nervous system
and intellectual disorders, post-traumatic stress disorder or suicide
ideation (SI) and suicide attempts (SA), substance or alcohol abuse; had
history of ketamine use, electroconvulsive therapy (ECT) use during the
one-year lookback period, or repetitive transcranial magnetic stimula-
tion (rTMS) use during the one-year lookback period; or were diag-
nosed with mania or bipolar disorder at any time (Table S3).
With the exception of the final exclusion criteria pertaining to a
R.S. McIntyre, et al.
diagnosis of mania or bipolar disorder at any time, all other exclusion
criteria were applied solely to the one-year lookback period. If any of
the above therapies or diagnoses occurred after the index date, the
patient was still included in the cohort.
2.4. Matched cohorts
Three cohorts were identified: TRD cohort, which was defined as
MDD patients with at least one AD claim within ( ± ) 30 days of a MDD
diagnosis date, who failed to respond to at least 2 lines of AD therapies
with adequate daily dose (Table S1) in the year post index date; Non-
TRD MDD (Non-TRD) cohort, which was defined as MDD patients with
at least one AD claim within ( ± ) 30 days of a MDD diagnosis date,
who failed to respond to fewer than 2 lines of AD therapy with adequate
daily dose (Table S1) during the year post index; and Non-MDD cohort,
which was defined as patients with no evidence of MDD, where the
index date was randomly assigned between April 2006 and March
2015. MDD was defined using diagnostic codes from OHIP, the fourth
edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV) (American Psychiatric Association, 2000), and the tenth re-
vision of the International Statistical Classification of Diseases and
Related Health Problems (ICD-10) (WHO, 1993) (Table S4). A liberal
definition of MDD that also included patients with adjustment disorder,
dysthymic disorder, depression not otherwise specified (NOS), and
history of one or more depressive episodes was applied in order to
capture all potential MDD patients, including those who may not have
received a properly coded MDD diagnosis. AD failure was defined as
any of the following three scenarios: a prescription of a second AD
(Table S1) or AP (Table S2) less than or equal to 28 days after the
prescription of the first AD or AP, provided the first AD or AP was not
refilled within 60 days of its initial prescription; a prescription of a
second AD more than 28 days after the prescription of the first AD; a
prescription of an AP more than 28 days after the prescription of an AD
where the first AD was refilled within 60 days of its initial prescription
(Supplementary Figure 1). In each of the three scenarios, at least one of
the AD prescriptions had to have an adequate daily dose (Table S1).
Additionally, the patient's first line of treatment had to be an AD.
Patients could not be present in more than one cohort. If their
longitudinal data allowed them to be eligible for more than one cohort
they were assigned in the following hierarchy: TRD, Non-TRD and Non-
MDD. Patients with TRD were matched to both Non-TRD and Non-MDD
patients in a 1:4 ratio using propensity score matching (Rosenbaum and
Rubin, 1983) for age (continuous), sex (male, female), Charlson Co-
morbidity Index (Charlson et al., 1987) (CCI, missing, 0, ≥1), income
quintile, Local Health Integration Network (LHIN), type of ODB cov-
erage (long-term or specialty care, home care, Ontario Works, ODSP,
Trillium Drug Program, over 65 years of age), and fiscal year of index
date. Caliper matching with a width of 0.2 standard deviations of the
logit of propensity score was used to choose matches.
2.5. Study variables
All demographic data was assessed at baseline. Using census data,
median income in each dissemination area was calculated and each
neighborhood was divided into income quintiles, with quintiles 1 and 5
having the lowest and highest median incomes, respectively
(Kapral et al., 2012).
All-cause and depression-related HCRU were assessed for each of
the following healthcare touchpoints: GP/FM (General practitioner/
Family medicine) visits, psychiatry visits, emergency department (ED)
visits, acute care visits, and MH hospitalization (i.e. a dedicated mental
health bed) over a patient's follow-up period (and for each year within
the follow-up period). Depression related HCRU (e.g. GP/FM, psy-
chiatrist, ED, acute care and mental health visits) included visits for
MDD (Table S4) and suicide ideation and attempt diagnosis (Table S3).
The costs associated with outpatient visits (split into GP visits,
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Journal of Affective Disorders 277 (2020) 30–38
psychiatrist visits and other outpatient visits), ED visits, hospitalization
(including those to a dedicated mental health bed), and specialty care
(home care and inpatient rehabilitation) were calculated for each pa-
tient over their follow-up period and standardized to 2016/2017. The
total costs were defined using an algorithm developed by ICES. These
costs were reported for all-cause and depression-related HCRU, where
depression-related included GP and psychiatrist visits for substance
abuse, ED visits and hospitalization for MDD as well as ED visits and
hospitalization attended by a psychiatrist (Table S6).
2.6. Data analysis
Descriptive statistics were applied to summarize patient demo-
graphic characteristics for TRD, matched and unmatched Non-TRD, and
matched and unmatched Non-MDD cohorts’ populations. Standardized
differences were reported for both matched cohorts comparing the full
cohort and those included as a result of propensity score matching.
Mean (standard deviation (SD)) number of HCRU visits and costs
were reported, along with the number and percentage of patients with
any HCRU. Unadjusted negative binomial regression model was used to
compare number of HCRU visits, unadjusted conditional logistic re-
gression was used to compare binary HCRU use and unadjusted gamma
regression model was used to compare costs between the TRD cohort,
matched Non-TRD and matched Non-MDD cohorts (Kellar et al., 2014;
Nolen, 1994; Rizvi et al., 2014). P-values less than 0.05 were con-
sidered significant; no adjustment was made for multiple comparisons.
Results based on less than six patients were suppressed in accordance
with ICES policies. All analyses were performed using statistical soft-
ware suit (SAS) Enterprise Guide, 7.12.
2.7. Ethics
ICES is authorized to collect personal health information without
consent for the purpose of management, evaluation and monitoring of
the health system (Privacy at ICES, 2020) as it is a prescribed entity
under Section 45 of Ontario's Personal Health Information Protection
Act. This project was approved by ICES's Privacy and Compliance Of-
ficer and received ethics approval from the Institutional Review Board
Services (Advarra, Approval# Pro00024460) in Toronto, Canada.
3. Results
3.1. Patient demographics and clinical characteristics
A total of 1,652,828 patients were identified within ICES databases
between April 2006 and March 2015 who were diagnosed with MDD.
Of those patients, 344,573 met the inclusion criteria and did not have a
diagnosis of mania or bipolar at any time (Fig. 1). After applying further
exclusion criteria, 277 patients belonged to the treatment-resistant
depression (TRD) cohort and 68,861 patients to the cohort with no TRD
(Non-TRD cohort), all of whom were covered by public plans (Table 1).
Additionally, after applying inclusion and exclusion criteria, the total
number of eligible patients identified between April 2006 and March
2015 with no MDD diagnosis (Non-MDD cohort) was 1,470,071 (Sup-
plementary Fig. 2). The 277 patients with TRD were matched to 1,108
Non-TRD and 1,108 Non-MDD patients.
The average age of patients with TRD and with public plan coverage
was 52 years with 53% being female. Out of 277 patients with TRD
identified, 34% were in the lowest income quintile. Nearly half of the
patients with TRD were receiving support through the ODSP. Among
different types of providers, patients with TRD were more commonly
diagnosed for MDD by a GP/FM (58%).
After matching, patients in the TRD group had similar demo-
graphics, ODB coverage, and geographies as patients within the Non-
TRD and Non-MDD cohorts. The patient demographics and baseline
characteristics are summarized in Table 1. With the exception of the
R.S. McIntyre, et al. Journal of Affective Disorders 277 (2020) 30–38

Fig. 1. TRD patient selection Inclusion and exclusion criteria were applied on a total number of 1,652,828 patients who were identified between April 2006 and
March 2015 and were diagnosed with MDD. Excluded records represent the total number of patients who met the exclusion criteria at each step.

fiscal year as a parameter, the standardized difference between mat-
ched and unmatched patients for the Non-TRD and Non-MDD cohorts
never exceeded 0.08 across all demographics reported; fiscal year
ranged from 0.02 to 0.21.
3.2. Healthcare Resource Utilization (HCRU)
Over the two-year follow-up period, patients with TRD and with
public plan coverage had a significantly greater number of all-cause
outpatient visits (38.2 vs. 24.2; p < 0.001) and ED visits (2.7 vs. 2;
p < 0.05) compared to the matched Non-TRD patients (Fig. 2). Within
the outpatient visits, the main drivers of all-cause HCRU for the TRD
cohort were due to GP/FM visits (21 vs. 15; p < 0.0001) and psychiatry
visits (10 vs. 3; p < 0.0001) compared to the Non-TRD cohort (Fig. 2).
Furthermore, we also calculated the two-year mean number of de-
pression-related visits between all three cohorts who were covered by
public plans. Within hospitals, the average number of ED visits for MDD
was greater for patients with TRD (0.24 vs. 0.06; p < 0.0001), as was
the average number of MH hospitalizations for MDD (0.22 vs. 0.02;
p < 0.0001), compared to matched Non-TRD. Outside of the hospital
system, patients with TRD had significantly higher number of visits to
GP/FMs for MDD (3.06 vs. 1.63; p < 0.0001) and psychiatry practices
for MDD (5.88 vs. 1.95; p < 0.0001) compared to Non-TRD (Fig. 3).
3.3. Healthcare costs
The average two-year healthcare costs for the TRD cohort with
public insurance were reported to be $20,998 (CAD). These patients

33
R.S. McIntyre, et al. Journal of Affective Disorders 277 (2020) 30–38

Table 1
Summary of baseline characteristics.
Characteristics TRD Non-TRD Matched Non-TRD Overall Non-MDD Matched Non-MDD Overall
Patient Count, n
277 1,108 68,861 1,108 1,470,071
Age
Mean ± SD 51.82 ± 15.92 51.43 ± 18.41 62.72 ± 18.52 51.86 ± 19.11 68.92 ± 14.21
Median (IQR) 52 (40-65) 52 (38-65) 67 (51-77) 54 (37-66) 71 (66-78)
Sex, n (%)
Female 147 (53.1%) 606 (54.7%) 43,437 (63.1%) 596 (53.8%) 772,938 (52.6%)
Male 130 (46.9%) 502 (45.3%) 25,424 (36.9%) 512 (46.2%) 697,133 (47.4%)
Index Fiscal Year, n (%)
2006 23 (8.3%) 120 (10.8%) 7,583 (11.0%) 121 (10.9%) 141,550 (9.6%)
2007 22 (7.9%) 99 (8.9%) 7,022 (10.2%) 136 (12.3%) 145,771 (9.9%)
2008 28 (10.1%) 105 (9.5%) 6,952 (10.1%) 107 (9.7%) 150,956 (10.3%)
2009 45 (16.2%) 104 (9.4%) 7,305 (10.6%) 127 (11.5%) 156,594 (10.7%)
2010 38 (13.7%) 112 (10.1%) 7,337 (10.7%) 108 (9.7%) 161,681 (11.0%)
2011 38 (13.7%) 117 (10.6%) 7,850 (11.4%) 112 (10.1%) 168,153 (11.4%)
2012 21 (7.6%) 154 (13.9%) 7,898 (11.5%) 128 (11.6%) 175,382 (11.9%)
2013 39 (14.1%) 158 (14.3%) 8,289 (12.0%) 134 (12.1%) 181,436 (12.3%)
2014 23 (8.3%) 139 (12.5%) 8,625 (12.5%) 135 (12.2%) 188,548 (12.8%)
Type of OBD Coverage, n (%)
Home Care 6 (2.2%) 28 (2.5%) 1,887 (2.7%) 20 (1.8%) 41,037 (2.8%)
Long Term or special Care 8 (2.9%) 31 (2.8%) 1,740 (2.5%) 28 (2.5%) 12,893 (0.9%)
Ontario Disability Support Program 127 (45.8%) 508 (45.8%) 15,139 (22.0%) 518 (46.8%) 120,684 (8.2%)
Ontario Works 22 (7.9%) 94 (8.5%) 3,653 (5.3%) 82 (7.4%) 31,326 (2.1%)
Seniors 60 (21.7%) 233 (21.0%) 39,590 (57.5%) 245 (22.1%) 1,161,862 (79.0%)
Trillium 54 (19.5%) 214 (19.3%) 6,852 (10.0%) 215 (19.4%) 102,269 (7.0%)
Neighbourhood Income Quintile, n (%)
Missing *1 - 5 15 (1.4%) 222 (0.3%) *12–16 4,808 (0.3%)
1 94 (33.9%) 367 (33.1%) 18,571 (27.0%) 365 (32.9%) 309,634 (21.1%)
2 55 (19.9%) 223 (20.1%) 14,712 (21.4%) 230 (20.8%) 303,183 (20.6%)
3 50 (18.1%) 193 (17.4%) 12,728 (18.5%) 201 (18.1%) 283,654 (19.3%)
4 39 (14.1%) 152 (13.7%) 11,714 (17.0%) 161 (14.5%) 285,739 (19.4%)
5 *34 - 38 158 (14.3%) 10,914 (15.8%) *135–139 283,053 (19.3%)
Most Common Indexing Physicians, n (%)
General Practice/Family medicine (GP/FM) 162 (58%) 774 (70%) 51,101 (74%)
Psychiatry 96 (35%) 266 (24%) 12,771 (19%)
Emergency 11 (4%) 23 (2%) 1,722 (3%)
Internal Medicine (IM) *1 - 5 (1%) 15 (1%) 1,233 (2%)
Neurology *1 - 5 (1%)
Geriatrics *1 - 5 (0.3%) 500 (1%)
LHIN, n (%)⁎⁎
Erie St. Clair 25 (9.0%) 104 (9.4%) 4,831 (7.0%) 95 (8.6%) 80,264 (5.5%)
South West 29 (10.5%) 99 (8.9%) 6,384 (9.3%) 139 (12.5%) 113,426 (7.7%)
Waterloo Wellington 15 (5.4%) 58 (5.2%) 2,463 (3.6%) 67 (6.0%) 72,863 (5.0%)
Hamilton Niagara Haldimand Brant 34 (12.3%) 128 (11.6%) 9,316 (13.5%) 122 (11.0%) 172,448 (11.7%)
Central West 9 (3.2%) 44 (4.0%) 2,856 (4.1%) 40 (3.6%) 76,044 (5.2%)
Mississauga Halton 14 (5.1%) 55 (5.0%) 3,526 (5.1%) 54 (4.9%) 105,537 (7.2%)
Toronto Central 24 (8.7%) 124 (11.2%) 5,391 (7.8%) 97 (8.8%) 125,987 (8.6%)
Central 24 (8.7%) 89 (8.0%) 8,162 (11.9%) 93 (8.4%) 182,720 (12.4%)
Central East 38 (13.7%) 144 (13.0%) 8,308 (12.1%) 142 (12.8%) 185,000 (12.6%)
South East 17 (6.1%) 79 (7.1%) 3,273 (4.8%) 73 (6.6%) 68,204 (4.6%)
Champlain 25 (9.0%) 93 (8.4%) 7,593 (11.0%) 99 (8.9%) 126,448 (8.6%)
North Simcoe Muskoka 7 (2.5%) 27 (2.4%) 2,264 (3.3%) 22 (2.0%) 55,765 (3.8%)
North East 10 (3.6%) 43 (3.9%) 3,367 (4.9%) 39 (3.5%) 78,437 (5.3%)
North West 6 (2.2%) 21 (1.9%) 1,127 (1.6%) 26 (2.3%) 26,928 (1.8%)

⁎
Exact counts suppressed for privacy reason
⁎⁎
LHIN is the geographic partition of Ontario into healthcare regions, where each region has its own set of healthcare providers and administration to coordinate
care and distribute funds.

incurred an incremental cost of $3,047 (CAD) compared to the matched
Non-TRD cohort, which represented the economic burden of TRD
(Fig. 4). Compared to the Non-TRD cohort, the main drivers of incre-
mental costs for the TRD cohort over the two-year follow-up period
were MDD hospitalizations ($2,756 vs. $445 (CAD); p < 0.0001) and
psychiatry visits ($1,016 vs. $247 (CAD); p < 0.002) (Fig. 5).
4. Discussion
The objective of this retrospective, longitudinal cohort study was to
capture the true costs of TRD to the healthcare system. As such, we
eliminated the impact of confounding comorbidities, such as bipolar
disorders, on the healthcare costs and did not set out to measure the
prevalence of TRD in our study. Therefore, our small sample size of 277
TRD patients identified here is not representative of the high prevalence
of TRD mentioned in previous studies (Rizvi et al., 2014).
Our results demonstrated an increase in the all-cause resource uti-
lization and healthcare cost attributable to TRD patients with public
insurance as compared to matched patients with no TRD (Non-TRD)
and with no MDD (Non-MDD). As this study looked at equally sick
cohorts, any difference in healthcare costs between patients with TRD
and their Non-TRD or Non-MDD matches should be due to TRD. Our
findings showed that patients with TRD used significantly more
healthcare resources compared to the other two cohorts. The average
number of all-cause outpatient visits increased by 58% among patients
with TRD compared to Non-TRD patients. Additionally, the TRD patient

34
R.S. McIntyre, et al.
Fig. 2. Two-year TRD all-cause resource utilization ED= Emergency Department; GP/FM= General Practitioner/Family Medicine; *p < 0.05 using conditional
logistic regression for percent comparisons and negative binomial regression for average number comparisons
population identified in this study had more than three times the
average number of all-cause and depression-related psychiatry visits
compared to the Non-TRD cohort. During the two-year follow-up
period, publicly insured patients with TRD incurred an incremental cost
of $3,047 (CAD) to the healthcare system compared to Non-TRD pa-
tients, and an incremental cost of $9,932 (CAD) compared to Non-MDD
patients. The key drivers of this economic burden were associated with
ED and psychiatry visits and hospitalization.
Several studies have used administrative claim databases to assess
the economic burden of TRD in the United States (Amos et al., 2018;
Corey-Lisle et al., 2002; Crown et al., 2002; Gibson et al., 2010;
Greenberg et al., 2004; Ivanova et al., 2010; Kubitz et al., 2013;
Lepine et al., 2012; Olchanski et al., 2013; Olfson et al., 2018;
Russell et al., 2004; Sussman et al., 2019). However, to our knowledge,
this is the first study to analyze the resource utilization and costs of TRD
in the Canadian province of Ontario. Similar to previously conducted
studies in other jurisdictions, our results indicated a significant eco-
nomic burden attributable to TRD compared to Non-TRD patients in
Ontario with public plans coverage (Sussman et al., 2019). Sussman
et al. published a study to evaluate the economic burden of TRD on the
U.S. healthcare system and, similar to our study in the Canadian setting,
reported higher healthcare costs associated with the TRD cohort com-
pared to Non-TRD cohort — ($9,890 USD vs. $6,848 USD over a one-
year period, relative to $20,998 CAD vs. $17,951 CAD over a two-year
period in our study) (Sussman et al., 2019). While there are known
differences in access to care between the two healthcare systems, and
there may be differences in the epidemiology of MDD between the U.S.
35
Journal of Affective Disorders 277 (2020) 30–38
and Canada, both populations studied were required to have insurance
coverage. Therefore, reimbursement should not be a barrier to treat-
ment in either instance and as such the results are comparable.
There are several alternative therapies available for Non-TRD pa-
tients including pharmacotherapy options, ECT and rTMS. ECT is in-
dicated in Non-TRD patients if the severity of the disorder requires it.
However, in daily practice, ECT is usually applied as a second line
treatment in Non-TRD, being the most effective treatment for TRD.
Non-pharmacological approaches recommended or supported by
Canadian Network for Mood and Anxiety Treatments (CANMAT) for
TRD include adjunctive cognitive behavioural therapy (CBT) and ECT,
second line (Parikh et al., 2016; Milev et al., 2016). rTMS is a first-line
recommendation for MDD patients who have failed to respond to at
least one AD (Milev et al., 2016). However, the evidence cited for ad-
junctive CBT and ECT is not specific to MDD patients with inadequate
response to ≥ 2 ADs, and the single meta-analysis referenced for rTMS
in this population concludes that rTMS is more likely than sham to
produce remission, based on “evidence of moderate strength”
(Milev et al., 2016; Parikh et al., 2016).
A recent study evaluating the cost-effectiveness of rTMS in patients
with TRD found that rTMS has an incremental cost-effectiveness ratio
(ICER) of $37,640.66 per quality-adjusted life-years (QALY) gained
compared to ECT, and $98,242.37 per QALY gained when compared to
pharmacotherapy (Health Quality Ontario, 2016). Although patients
with TRD may benefit from these alternative therapies such as rTMS,
which is approved by both Health Canada and Food and Drug Admin-
istration (FDA), they bring a considerable cost to the healthcare system
R.S. McIntyre, et al. Journal of Affective Disorders 277 (2020) 30–38

Fig. 3. Two-year TRD depression-related resource utilization ED = Emergency Department; SI/A = Suicide Ideation / Attempt; MH = Mental Health; *p < 0.05
using conditional logistic regression for percent comparisons and negative binomial regression for average number comparisons

Fig. 4. Average Two-year direct cost of TRD to the Ontario healthcare system compared to Non-TRD and Non-MDD SD=Standard Deviation; Costs are represented as
Mean (SD); * p < 0.05 using Gamma regression

that must be weighed against the burden associated with the disease
(Health Quality Ontario, 2016).
Given the limitations of existing therapies, physicians continue to
struggle with the challenge of managing patients with TRD effectively.
Analyzing the use of HCRU and economic burden for patients with TRD
may add value for healthcare decision makers to better inform the
evaluation of future therapeutic options. Future research could focus on
better understanding the patient perspective including limitations of
current therapies, impact on quality of life, and productivity loss.
5. Limitations
This study utilized administrative public healthcare databases to
determine resource utilization and costs of TRD. Only those patients
who were eligible for coverage through the public plan (OHIP and ODB)
were included in this study. Patients that paid in cash or via private
drug plans were not included in this study. In Ontario, up to 60% of
patients under 65 are covered under private drug plans and outpatient
counselling is typically not covered under the public schema (Allin and
Hurley, 2009). As a result, the patient sample in this study may not be
representative of the overall population of MDD and patients with TRD,

36
R.S. McIntyre, et al.
Fig. 5. Key drivers of incremental economic burden of TRD, stratified by healthcare touchpoints within hospitals and outside hospitals SD=Standard Deviation;
ED = Emergency Department; Psych = Psychiatry consultation; GP= General Practitioner; Costs are represented as mean (SD); *p < 0.05 using Gamma regression
and the stakeholder burden and costs are likely underrepresented.
TRD was defined as ≥ 2 switches of different AD prescription with
adequate duration between AD prescriptions. The administrative da-
tabases included in this analysis did not include treatment outcomes
about tolerability, clinical symptom reduction, patient-reported out-
comes, or reasons for medication changes. As a result, this study may
not have accurately classified all of the included patients.
Finally, diagnosis codes recorded in the database are for the purpose
of physician billing. These codes typically reflect the primary reason for
the patient visit as deemed by the physician. Therefore, the accuracy of
diagnosis recorded in the database could be an issue especially in the
case of patients having multiple depression-related comorbidities and
the stigma associated with MH. To address the possibility of mis-
classification, diagnosis codes of MDD were required at the same event
of therapy initiation, ensuring a more accurate, albeit conservative
cohort.
6. Conclusions
Our findings from this population-based study demonstrated that
TRD was associated with an increased economic burden to the health-
care system. HCRU and costs were found to be higher in patients with
MDD who failed to respond to at least 2 AD treatments of adequate
duration. With the therapeutic options currently available, the in-
creased healthcare burden of TRD patients highlights the challenges in
treating this subpopulation of patients with depression. Additionally,
there is a need to develop cost-effective treatments specifically tested
and shown to be effective in patients with TRD. Further research is
37
Journal of Affective Disorders 277 (2020) 30–38
needed to understand the full societal burden and costs for these pa-
tients, including patient reported outcomes, productivity loss, and
caregiver costs as well as the burden of TRD accompanied with other
related comorbidities (i.e. bipolar disorders).
Contributors
Brad Millson, Sarah Power, and Roger S. McIntyre contributed to
the study design and preparation and review of the study protocol. In
addition, Sarah Power contributed to the statistical analysis. All authors
contributed to the interpretation of data and were involved in the re-
view and approval of the finalized manuscript.
Author disclosure
This work was conducted by Brad Millson and Sarah Power who are
employees of IQVIA and have provided consulting services to Janssen
Inc. Dr. Roger S. McIntyre received consultation fees from Janssen Inc.
for this study.
Acknowledgements
Mozhgan Naeini, from IQVIA, contributed to the writing of this
article. Arash Akaberi, from IQVIA, provided statistical support during
the preparation of this paper. Oliver Sang, from IQVIA, provided sup-
port for the coding of the TRD treatment algorithms. Aren Fischer and
Dorian Murariu, from IQVIA, assisted with the overall study design and
management. ICES data and analytical services contributed to the data
R.S. McIntyre, et al.
collection and outputs used for this study.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.jad.2020.07.045.
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