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Excess deaths in treatment-resistant depression
Philip Brenner, Johan Reutfors, Michel Nijs, and Therese M-L Andersson
Therapeutic Advances in Psychopharmacology 2021 10.1177/20451253211006508
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Excess deaths in treatment-resistant depression
Philip Brenner, Johan Reutfors, Michel Nijs, and Therese M-L Andersson
Therapeutic Advances in Psychopharmacology 2021 10.1177/20451253211006508
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EXCESS DEATHS IN TREATMENT-RESISTANT DEPRESSION
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Philip Brenner
Philip Brenner
Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska
Institutet, 171 77 Stockholm, Sweden
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, Johan Reutfors
Johan Reutfors
Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska
Institutet, Stockholm, Sweden
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, Michel Nijs
Michel Nijs
Janssen Global Services, Titusville, NJ, USA
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Therese M-L Andersson
Therese M-L Andersson
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,
Stockholm, Sweden
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...
First Published April 12, 2021 Research Article Find in PubMed
https://doi.org/10.1177/20451253211006508
https://doi.org/10.1177/20451253211006508
Article information
ARTICLE INFORMATION
Volume: 11
Article first published online: April 12, 2021; Issue published: January 1, 2021
Received: October 12, 2020; Accepted: March 01, 2021
Philip Brenner
Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska
Institutet, 171 77 Stockholm, Sweden
Johan Reutfors
Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska
Institutet, Stockholm, Sweden
Michel Nijs
Janssen Global Services, Titusville, NJ, USA
Therese M-L Andersson
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,
Stockholm, Sweden
Corresponding Author:
philip.brenner@ki.se
https://creativecommons.org/licenses/by/4.0/This article is distributed under
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PMID: 33912340
* Abstract
* Full Text
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ABSTRACT
BACKGROUND:
Patients with treatment-resistant depression (TRD) have an increased mortality
risk compared with other patients with depression, but it is not known how this
translates into absolute numbers of excess deaths.
METHODS:
Swedish national registers were used to identify a cohort of 118,774
antidepressant initiators 18–69 years old with a depression diagnosis. Patients
who initiated a third consecutive treatment trial were classified as having TRD.
Flexible parametric survival models were used to estimate the mortality risk due
to all causes and external causes (suicides and accidents), comparing TRD
patients with patients with other depression while adjusting for clinical and
sociodemographic covariates and including interactions with TRD, age, and
Charlson comorbidity index (CCI) for a number of somatic comorbidities.
Standardized survival was estimated, as were numbers of excess deaths among TRD
patients within each age and comorbidity category.
RESULTS:
Compared with the mortality risk of other depressed patients, patients with TRD
experienced excess deaths in most age and comorbidity categories in the range of
7–16 deaths per 1000 patients during 5 years. Highest numbers for all-cause
excess deaths were found among patients 18–29 years old with CCI 1, where 16
[95% confidence interval 5–28] of the expected 37 [25–48] deaths per 1000
patients were excess deaths. The majority of the excess deaths were due to
external causes.
CONCLUSION:
Patients with TRD experience significant numbers of excess deaths compared with
other patients with depression.
Keywords
depression, epidemiology, major depressive disorder, mortality, suicide,
treatment-resistant
BACKGROUND
Several definitions of treatment-resistant depression (TRD) have been proposed,
most of which are based on the concept of not achieving adequate response
despite two separate, adequate treatment trials.1,2 TRD is common, with rates
among patients initiating treatment for depression estimated at up to 50% in
clinical cohorts,3,4 and in register based studies from 7% to 29%, depending on
the method and definition used.5,6
Compared with other patients with depression, those with TRD may experience a
greater risk of negative outcomes, including somatic and psychiatric
comorbidities, poorer social outcomes, and lower quality of life.7,8 We recently
found that patients fulfilling a pharmacoepidemiological definition of TRD had
an increased mortality rate compared with other patients with depression, with a
hazard ratio (HR) of 1.35, while the HR was 1.97 when only counting mortality
from external causes, i.e., suicides and accidents.9
Measures of relative risks, such as HRs and incidence rate ratios, are commonly
used for comparisons between groups. However, they are not always translatable
to absolute numbers, and they seldom communicate an intuitive message of the
actual impact that a condition, or preventive measure, may have on mortality. In
our previous study, HRs comparing mortality among the TRD group with other
depressed patients were higher in younger age groups and in groups without
comorbidities.9 However, a high relative effect may not necessarily mean that
the absolute effect is highest in these groups.
An alternative way of illustrating mortality differences is the number of deaths
that count as excess deaths within a specific time period (e.g., 5 years) in a
group of patients, compared with that group if it were to experience the same
mortality as a comparison group. This may also be a relevant measure for
patients as well as for clinicians and decision makers.10 Attempts to quantify
the excess mortality from depression as number of deaths have been made, for
example, in a recent study where 3.5% of deaths in the general population in the
United States (US) were deemed attributable to anxiety and depression11;
however, this measure does not convey excess deaths within the depressed
population and does not take excess deaths in treatment-resistant patients into
account.
Building on our previous investigation of the relative mortality risk associated
with TRD, the purpose of this study was to estimate the absolute effect, that
is, numbers of excess deaths among patients with TRD compared with other
patients with depression, by using a cohort of patients with depression
identified in nationwide Swedish registers. This is presented by age- and
comorbidity groups.
MATERIAL AND METHODS
DATA SOURCES AND STUDY POPULATION
As previously described,9 we used a combination of Swedish national registers to
identify the study cohort, covariates, and outcomes. All patients 18–69 years
old who filled a prescription for an antidepressant drug (any drug with an
ATC-code starting with N06A) in Sweden between 1 July 2006 and 31 December 2014,
without any previous antidepressant prescription for 180 days, were identified
through The Prescribed Drug Register (PDR),12 which contains data on all
prescribed and dispensed prescriptions in Sweden since 1 July 2005. Among these,
patients who had a diagnosis of depression (ICD-10 F32, F33, or F34) in the
National Patient Register (NPR) within a time interval of 30 days before, and up
to 365 days after, the filled prescription were included in the depression
cohort.13 The NPR contains data on all diagnoses and procedures during
in-patient care and specialized out-patient care – excluding primary care –
according to the International Statistical Classification of Diagnoses, 7th–10th
editions (ICD 7–10) with complete national coverage for in-patient care since
1987, and for out-patient care since 2001. Exclusion criteria were fills of
lithium (N05AN01), antipsychotics (N05A, except for lithium), and the
anticonvulsants valproate (N03AG01), lamotrigine (N03AX09), and carbamazepine
(N03AF01) during 180 days before the first antidepressant prescription, and also
those with procedure codes for electroconvulsive therapy (ECT; DA006, DA024-25)
or repetitive transcranial magnetic stimulation (rTMS; DA022, DU050). Patients
with a previous history of psychosis (ICD-10 F20–F29), mania (F30), bipolar
disorder (F31), or dementia (F00–F03) were also excluded, as were patients who
were not residents in Sweden for the full 180 days according to the Total
Population Register before the first antidepressant prescription filling.14 The
index date was defined as the date when both the criteria of a prescription and
a diagnosis were fulfilled. Patients could enter the study at any time during
the study period when inclusion criteria were met.
DEFINITION OF TRD
Patients were classified with TRD from the starting date of a third treatment
trial for depression after having undergone two adequate trials. An adequate
treatment trial was defined as lasting for at least 28 days. Subsequent
treatment trials after the first dispensed antidepressant trial had to include
at least one fill of a different antidepressant (as monotherapy or in
combination with the previous one), add-on medication to the antidepressant
(antipsychotics or anticonvulsants), or administration of ECT or rTMS. Durations
of trials were estimated by semi-manually reading prescription dosage texts and
taking into account the number of tablets dispensed at each fill, and by action
codes for ECT/rTMS in the NPR. Treatment gaps of >28 days were not allowed in
order to emulate consecutive treatment trials. Distribution of
medication/treatments used for the third treatment trial is shown in
Supplemental Table S1.
OUTCOMES
The main outcomes were all-cause mortality and death from external causes
(including suicides and accidents; ICD codes V01–Y98) as registered in the Cause
of Death Register.15
COVARIATES
The following covariates were added to the patients in the cohort: sex, age,
history of depression before or within the last 5 years, self-harm (ICD-10:
X60–X84 and Y10–Y34), substance use disorders [ICD-10: F10–16 and F18–19, or
prescriptions of sublingual buprenorphine (ATC: N07BC01/ N07BC51), methadone
(ATC: N07BC02), disulfiram (ATC: N07BB01), acamprosate (ATC: N07BB03),
naltrexone (ATC: N07BB04), or nalmefen (ATC: N07BB05)], and 5-year history of
other psychiatric comorbidity (anxiety disorder, attention deficit hyperactivity
disorder, autism spectrum disorder, eating disorder, personality disorder;
ICD-10: F40–F42, F50, F60–F61, F84.0–1, F84.5, and F90). A Charlson comorbidity
index (CCI) was constructed from diagnoses in the NPR categorized as 17 major
comorbidity groups adjusted for ICD-10 diagnostic coding.16,17 The CCI is a
method of categorizing comorbidities of patients based on ICD diagnosis codes,
and weighs comorbidities based on a predefined adjusted risk of mortality or
resource use.16
ESTIMATION OF HAZARD RATES AND HRS
Flexible parametric models (FPM) were used to model mortality in the
cohort.18,19 A FPM can be used to estimate HRs, similarly to Cox regression,
but, unlike the Cox model, it also estimates the baseline hazard rate using
restricted cubic splines. Two FPMs were fitted first with all deaths considered
as events, and secondly with death from external causes (ICD codes V01–Y98) as
events, censoring at other deaths. Patients were followed from the index date
until death and censored at emigration, end of study, or if any of the exclusion
criteria were fulfilled. The exposure of interest, TRD, was treated as a
time-varying covariate where a patient moved to the TRD group (i.e., from
unexposed to exposed group) when the criteria for TRD were fulfilled. The two
FPMs also adjusted for age at index date (using splines), sex, previous
self-harm, previous substance use disorder, previous depression, other
psychiatric comorbidity, and CCI (categorized as 0, 1, ⩾2 in the model for death
due to external causes), and all of these were allowed to have time-varying
effects (non-proportional hazards). Interactions between TRD and age (in
categories 18–29, 30–49, 50–69), as well as TRD and CCI were included, since
those were the interaction effects shown to be important in the previous study.9
Both FPMs had four degrees of freedom for modelling the baseline and two for
time-varying effects.
ESTIMATION OF STANDARDIZED SURVIVAL AND EXCESS DEATHS
Based on a fitted FPM, the survival probability at a certain point in time can
be estimated for each patient, given the values of all variables included in the
model for that specific patient. By taking the average of the estimated survival
probabilities across all patients, a marginal survival probability is estimated,
internally standardized to the covariate distribution within the cohort.
Marginal all-cause 5-year survival was estimated for the group that developed
TRD, separately for each combination of age group and CCI category. Within the
cohort, TRD is a time-varying exposure; however, in the estimation of marginal
survival, TRD-status was assumed to be fixed, so the survival was estimated as
if everyone was TRD from start of and throughout 5 years of follow up. In the
actual cohort, not all patients had 5 years of potential follow up, and even
those who did, might not have 5 years of potential follow up as TRD exposed
since TRD varies over time.
When interest lies in comparing survival between groups, while adjusting for
other covariates, standardized survival can be used, by standardizing over the
same covariate distribution for all groups. The average 5-year survival was
therefore also estimated for non-TRD, separately for each combination of age
group and CCI category, but standardized to the covariate distribution of the
TRD patients. Since the only difference between the two standardized estimates
within each age group and CCI category is the value set for the exposure of
interest, the standardized survival estimates are comparable in terms of the
confounder variables included in the model, and can be viewed as adjusted
survival estimates.
Based on the 5-year standardized survival estimates, the expected number of
deaths within 5 years was estimated, within each age group and CCI category. We
then estimated the difference in number of expected deaths within 5 years for
each age and CCI group combination, from the two standardized survival
estimates. This can be interpreted as the number of deaths that could be avoided
within 5 years among TRD patients, if they had the same mortality rate as
patients with other depression (given their covariate distribution), within that
specific age and CCI group. To aid comparison across age and CCI groups, we also
estimated the number of expected deaths within 5 years for 1000 patients of each
group. However, for each age and CCI group, the marginal/standardized survival
was estimated given the distribution of other covariates within each of the
groups. Differences in the number of expected deaths, between age and CCI
groups, can therefore be due, to some extent, to differences in the distribution
of all other factors taken into account in the analysis. The comparison between
TRD and non-TRD is, however, due to the standardization, adjusted for all
covariates. Standardized survival and number of excess deaths were also
estimated for deaths due to external causes, using the same approach as
described above.
ETHICAL PERMISSION
The study was approved by the regional ethical review board in Stockholm (no.
2017/1236-31/2).
RESULTS
The depression cohort included 118,774 patients with a mean age of 37 (±14)
years (58.2% women). Of these, 15,013 patients (13%) were classified as having
TRD during the study period, with a mean age of 39 (±14) years (57.6% women).
Characteristics of the population of patients with depression and TRD are shown
in Table 1.
Table 1. Characteristics of the study cohort with depression and the subset of
patients with TRD.
Table 1. Characteristics of the study cohort with depression and the subset of
patients with TRD.
View larger version
Total follow-up time was 489,488 person years (mean 4.12 years). The amount of
follow-up time as TRD was 54,697 years (mean 3.64 years) and with other
depression 434,792 years (mean 3.78 years). The number of deaths during
TRD-exposed follow-up time was 432, with 2295 during other depression follow-up
time. During TRD follow-up time, 214 deaths (50%) were due to external causes
(including 143 suicides), while during follow-up time with other depression, 849
(37%) deaths were due to external causes (including 550 suicides).
The number of TRD patients in each age- and CCI group is presented in Table 2,
which also shows HRs for all-cause mortality in TRD compared with other
depression, standardized/marginal 5-year survival, expected number of deaths,
and numbers of estimated excess deaths. The HRs were highest for the youngest
age group and the group with no comorbidities, which were the groups with
highest survival. The marginal 5-year survival in TRD ranged from 98.0% (95% CI
97.6; 98.5), for the youngest group without comorbidities, to 74.4% (95% CI
69.6; 79.5) for the oldest group with a CCI of 2 or above, respectively. If the
TRD patients had the same mortality rate as patients with other depression
(otherwise given the same covariate distribution), this range for 5-year
survival was found to be slightly higher: 99.1 (95% CI 99.0; 99.2) to 72.8 (95%
CI 70.9; 74.7).
Table 2. HRs for all-cause mortality, expected number of deaths, and excess
deaths for patients with TRD compared with other patients with depression.
Table 2. HRs for all-cause mortality, expected number of deaths, and excess
deaths for patients with TRD compared with other patients with depression.
View larger version
Patients with TRD displayed excess deaths in all age and comorbidity categories
where numbers were large enough for statistical significance. The largest number
of expected all-cause excess deaths within 5 years was found among patients
18–29 years old with CCI 0, where 45 (95% CI 24; 67) of a total of 87 (95% CI
66; 108) TRD deaths were deemed excess deaths. Translating these numbers into
excess deaths within 5 years per 1000 patients showed point estimates ranging
from 7 to 16 in the age- and comorbidity groups with statistical significance.
The highest significant point estimate was found in the age group 18–29 years
with CCI 1, with 16 (95% CI 5; 28) of the expected 37 (95% CI 25; 48) TRD deaths
per 1000 patients being excess deaths. There were non-significant estimates in
the number of expected all-cause deaths in the age groups of 18–29 and
30–49 years with CCI 2 and above, and for the 50–69 age group with CCI 1 or 2
and above.
In Table 3, the same estimates as above are presented for deaths from external
causes only. Again, the highest HRs and absolute numbers of estimated deaths
were seen in the numerically largest patient categories. Numbers of estimated
excess deaths from external causes were similar to estimates for all-cause
deaths among younger and physically healthy patients – for instance, the same
estimate, 10 deaths (95% CI 5; 15) per 1000 patients within 5 years was found
among patients 18–29 years old with CCI 0 in both analyses – suggesting that the
absolute majority of all expected deaths among these patients were from external
causes. When estimating the numbers of excess deaths from external causes, the
numbers of significant excess deaths were of a similar magnitude as for
all-cause deaths, ranging from 9 to 15 per 1000 patients with TRD survival
within 5 years. The largest number was estimated at 15 (95% CI 2; 28) of a total
of 34 (95% CI 22; 47) expected TRD deaths in the age group 50–69 with CCI 1. For
patients with CCI 2 and above, the point estimates for excess deaths were lower,
but statistically non-significant.
Table 3. HRs for mortality due to external causesa, expected number of deaths,
and excess deaths for patients with TRD compared with other patients with
depression.
Table 3. HRs for mortality due to external causesa, expected number of deaths,
and excess deaths for patients with TRD compared with other patients with
depression.
View larger version
DISCUSSION
This is the first study to translate the increased mortality in TRD compared
with other depression into estimated numbers of excess deaths. Excess deaths
were found in most age and comorbidity categories, ranging from 7 to 16 deaths
per 1000 patients with TRD during 5 years. Numbers of excess deaths from
external causes, i.e., suicides or accidents, were similar to numbers of excess
all-cause deaths, implying that the majority of excess deaths in TRD are due to
external causes. The results illustrate how excess deaths can be used to expand
and complement the previously reported increased HRs for mortality, standardized
mortality ratios, and excess mortality rate ratios among patients with
TRD.9,20,21
INTERPRETATION
The interactions of mortality with age and physical comorbidity were
investigated specifically in this study. Within each age category, most point
estimates for all-cause excess deaths were somewhat higher among patients with
comorbidities (CCI ⩾1) compared with patients without comorbidities. This higher
number of excess deaths could, if accurate, be attributed to several factors.
First, patients with somatic comorbidity may be at higher risk for developing
TRD compared with other patients, although evidence in the literature for this
association is conflicting.22 It is also possible that TRD itself may have a
negative impact on the course of somatic disease, and therefore contribute to
the excess deaths among these patients. Studies have reported an increased
mortality after acute myocardial infarction among patients with TRD compared
with other depression,23 and persistent depressive symptoms may increase
mortality after somatic hospitalization.24 Also, the construction of the CCI
means that patients with different severity of the same somatic disease are
classified with an equal score.16 This may leave residual confounding as
severely ill patients with depression may be at higher risk for both TRD and
death.22
In the analysis including only deaths from external causes, no clear pattern
regarding somatic comorbidity could be seen, apart from lower point estimates
for excess deaths among patient with major comorbidities (CC1 ⩾2). This may be
due to suicide and somatic disease being competing risks of death for these
patients. Regarding the interaction with age, however, both suicide risk and
actual numbers of suicide are known to increase with age in the general
population.10 In the present study, there were also slightly higher – albeit
non-significant – numbers of excess deaths from external causes in 5 years per
1000 patients in the oldest age segment. However, as this was also the smallest
group in numbers, absolute numbers of excess deaths were higher in the two
younger age categories. Together, the investigation of these interactions
emphasizes the importance of applying different measures of mortality in a
population and identifying subgroups at risk, as patients who are in higher risk
categories may not impact the overall numbers if numerically small.
IMPLICATIONS
Previous research has established that the all-cause mortality among patients
with depression is markedly higher than in the general population, and that this
is even more pronounced for suicide.25 The results of the present study
regarding excess deaths in TRD may be of both clinical and societal importance.
Rates of TRD among patients initiating treatment for depression have been
estimated to be 6%–29% in administrative data studies,5,6 and as high as 30%–50%
in clinical studies.3,4 Considering that life-time risk for depression in the
general population has been estimated at 15%–20%,26 the number of excess deaths
in TRD is likely to be numerically impactful when transferring these rates to
larger populations. According to the estimates in this study, TRD patients may
experience up to twice as many deaths than if they had the survival of other
patients with depression. Especially worrisome may be the estimated excess
deaths among young, somatically healthy, patients, of which the large majority
was due to external causes.
The patients with TRD in this study have all been administered several treatment
trials for depression, as a proxy for depression that have not responded
adequately to treatment, which may be a contributing factor to the excess deaths
reported in this study. However, the group classified with TRD may be
heterogeneous, as a substantial number of patients who present with TRD may have
been misdiagnosed with depression and/or suffer from other undiagnosed
psychiatric comorbidities,27,28 which could lead to worse antidepressant
treatment results and may contribute to the excess deaths seen here. The TRD
rate of 13% found in this cohort is substantially lower than the 30%–50% found
in clinical studies,3,4 but is similar to other epidemiological studies in
countries with comparable national databases (Denmark 14%, Taiwan 21%),29,30 and
also to using other algorithms for defining TRD in Swedish data (9%–19%).31 The
lower number of patients with TRD identified in observational studies compared
with clinical studies may represent a lower tendency in real-life practice to
administer more than two treatment trials, and some evidence points to the view
that the smaller the proportion of patients identified with TRD, the higher the
morbidity and poorer outcomes among patients.31
Regardless of the underlying mechanism, TRD as defined in this study – starting
a third treatment trial for depression – seems to increase the risk for
mortality and the number of deaths.
STRENGTHS AND WEAKNESSES
Strengths of this study include the cohort design with use of nationwide
registers of high quality and virtually no loss of follow up, allowing for the
calculation of survival rates in a large population for estimation of excess
deaths. Among the limitations of this study is the use of a
pharmacoepidemiological model for identifying TRD without access to clinical
data aside from registered diagnoses. This lack of information includes unknown
reasons for continuation, discontinuation or change of treatment trials (e.g.,
efficacy, non-efficacy, side effects, or lack of adherence). Patients over
70 years of age were not included due to hypothized competing risks between
age-related deaths and deaths from sickness and external causes, and also due to
likely differences in antidepressant treatment patterns compared with younger
patients. Also, due to diagnoses registered in Swedish primary care not being
included in the NPR, only patients seeking specialized psychiatric care were
included. This may have attenuated the risk differences in the group comparison,
for example, not including patients with milder or easily treated forms of
depression. Finally, the PDR contains data from July 2005 onwards, which means
that patients with TRD status before this date may have died before or during
follow up without study inclusion.
CONCLUSION
Patients with TRD experience all-cause excess deaths in the range of 7–16 deaths
per 1000 patients during 5 years compared with if they had similar mortality as
other patients with depression. More knowledge is needed regarding to what
extent more effective treatments for depression may lower the number of excess
deaths.
Conflict of interest statement
PB and JR are affiliated with/employed at the Centre for Pharmacoepidemiology at
Karolinska Institutet, which receives grants from several entities
(pharmaceutical companies, regulatory authorities, contract research
organizations) for the performance of drug safety and drug utilization studies.
MN is an employee and stockholder of Janssen Inc. and contributed to
conceptualization of the study and manuscript writing.
Data availability
The data used for this study may not, according to the ethical permission
granted for its use, be shared by the authors to a third party. It is accessible
by application to the Swedish authorities (The National Board of Health and
Welfare and Statistics Sweden).
Funding
The authors disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: This project was
funded through grants from the Söderström-König Foundation (grant no.
SLS-759771) and the Thuring Foundation (grant no. 2017-00302), as well as
through the public–private real-world evidence collaboration between Karolinska
Institutet and Janssen Pharmaceuticals (contract: 5-63/2015).
ORCID iD
Philip Brenner https://orcid.org/0000-0001-5266-6144
Supplemental material
Supplemental material for this article is available online.
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