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A Review of the Clinical, Economic,
and Societal Burden of Treatment-
Resistant Depression: 1996–2013
David A. Mrazek, M.D.
John C. Hornberger, M.D., M.S.
C. Anthony Altar, Ph.D.
Irina Degtiar, B.A., B.S.
Objective: This literature review assessed the burden of treatment-resistant
depression in the United States by compiling published data about the clin-
ical, societal, and economic outcomes associated with failure to respond to
one or more adequate trials of drug therapy. Methods: PubMed and the Tufts
Cost-Effectiveness Analyses Registry were searched for English-language
articles published between January 1996 and August 2013 that collected
primary data about treatment-resistant depression. Two researchers in-
dependently assessed study quality and extracted data. Results: Sixty-two
articles were included (N=59,462 patients). Patients with treatment-resistant
depression had 3.862.1 prior depressive episodes and illness duration of
4.463.3 years and had completed 4.762.7 unsuccessful drug trials involving
2.16.3 drug classes. Response rates for treatment-resistant depression were
36%61%. A total of 17%66% of patients had prior suicide attempts (1.16.2
attempts per patient). Quality-of-life scores (scale of 0–1, with 0 indicating
death and 1 indicating perfect health) for patients with treatment-resistant
depression were .416.8 and .266.8 points lower, respectively, than for
patients who experienced remission or response. Annual costs for health care
and lost productivity were $5,481 and $4,048 higher, respectively, for
patients with treatment-resistant versus treatment-responsive depression.
Conclusions: Treatment-resistant depression exacts a substantial toll on
patients’quality of life. At current rates of 12%–20% among all depressed
patients, treatment-resistant depression may present an annual added soci-
etal cost of $29–$48 billion, pushing up the total societal costs of major
depression by as much as $106–$118 billion. These findings underscore the
need for research on the mechanisms of depression, new therapeutic targets,
existing and new treatment combinations, and tests to improve the efficacy of
and adherence to treatments for treatment-resistant depression. (Psychiatric
Services in Advance, May 1, 2014; doi: 10.1176/appi.ps.201300059)
Almost 50% of the U.S. pop-
ulation has experienced at
least one psychiatric disorder
in their lifetime (1). The lifetime
prevalence of major depressive disor-
der is reported to be as high as 17%,
and the 12-month prevalence is 5%2
9% (2–4). The World Health Organi-
zation ranks major depressive disor-
der among the diseases that are most
debilitating to society, in part because
of its association with increased utili-
zation of health care resources, di-
minished quality of life, and indirect
personal and societal costs (5,6).
More than 50% of patients with
major depressive disorder do not
reach remission with an initial treat-
ment; of those, 30%250% also do not
respond (4,5,7–9). The designation
“treatment resistant”is used to de-
scribe patients who do not respond to
antidepressant therapy after one or
more adequate trials (9–11) (duration
of at least six weeks and use of
appropriate dosages [12–15]). A re-
sponse to treatment is commonly
measured as a $50% decrease in
baseline scores on the Hamilton
Rating Scale for Depression (HAM-D)
(7). The Sequenced Treatment Alter-
natives to Relieve Depression (STAR*D)
trial studied the effectiveness of
different treatments for major de-
pressive disorder among patients
who did not become symptom free
after one or more treatments. Seventy-
two percent of patients did not ex-
perience remission after treatment
with citalopram, the initial medication
used in this study; with each sub-
sequent treatment, failure to remit
increased from 79% to 84% to 93%
(8,16–19).
Patients with treatment-resistant
depression contribute a disproportion-
ately high burden of illness compared
with patients who respond to treat-
ment. Several studies have documented
At the time of this research, Dr. Mrazek, who is deceased, was with the Mayo Clinic,
Rochester, Minnesota. Dr. Hornberger and Ms. Degtiar are with Cedar Associates, L.L.C.,
Menlo Park, California. Dr. Hornberger is also with the Department of Internal
Medicine, Stanford University School of Medicine, Stanford, California. Dr. Altar is with
Assurex Health, Mason, Ohio. Send correspondence to Dr. Hornberger (e-mail:
jhornberger@cedarecon.com).
PSYCHIATRIC SERVICES IN ADVANCE 1
asubsetofoutcomesrelatedto
treatment-resistant depression, such
as societal costs and effects on quality
of life, labor force participation, or
medical resource utilization, but none
has provided a comprehensive, sys-
tematic, and rigorous review of the
overall burden.
The aim of this systematic review
was to assess the aggregate burden of
treatment-resistant depression in the
United States by compiling the data
available from published studies on
clinical, societal, and economic outcomes
associated with treatment-resistant
depression. The review assessed char-
acteristics and comorbid conditions,
costs of treatment, mortality, quality
of life, severity of symptoms, response
rates to subsequent treatments, and
adverse events among patients with
treatment-resistant depression. This re-
view also investigated factors that con-
tribute most to the societal burden of
treatment-resistant depression and iden-
tified potential areas for improvement.
Methods
We used PubMed to search MEDLINE
for articles published between Jan-
uary 1996 and May 2011 by using
terms related to treatment-resistant
depression, outcomes, economics, and
society. A supplemental search of
PubMed using additional terms was
conducted for articles published be-
tween May 2011 and August 2013.
We also conducted a search of the
Tufts Cost-Effectiveness Analysis Reg-
istry (20) for articles published from
1996 through 2013 and reviewed the
reference lists of articles identified by
the searches related to costs of treat-
ment. [A complete list of search terms
and a full description of the study
methods are available online as a data
supplement to this article.]
Two researchers screened each
abstract of the retrieved articles. The
articles were included if the abstract
referred to primary data collection as
a part of the design; if endpoints of the
study were pertinent to clinical, soci-
etal, or economic outcomes; and if the
study enrolled adults ages 18 and
older. We defined treatment resis-
tance as failure to respond to one or
more adequate trials of drug therapy.
This definition was intended to con-
form to accepted criteria of treatment
resistance while including heteroge-
neous definitions. The evidence grade
for each study was assessed by using
the quality index developed by the
Mental Disorders and Illicit Drug Use
Expert Group (21). Quality index
scores range from 0 to 17, with higher
scores indicating that more complete
reporting and higher quality methods
were used.
We included articles that reported
results from the STAR*D trial, even
though its definition of treatment
resistance as “failure to remit”is more
inclusive than the one used in this
review, which included patients who
failed to respond. However, as the
largest and longest study evaluating
depression treatment, the STAR*D
study provides valuable information
for comparing responses to treatment,
despite differences in definitions of
treatment resistance.
Summary statistics were performed
by using Stata, version 9.2, and were
weighted by sample size. Unless stated
otherwise, results are reported for the
treatment-resistant population.
Results
Literature search and
study characteristics
The original search identified 442
articles; 62 were included in this
review. [The complete list of included
articles is available in the online data
supplement.] The mean6SD study
duration was 7.7561.75 years. The
quality index score varied from 6 to 18
(mean6SD=1363). Sample sizes in
the studies varied from six to 24,415
patients (median=42; Table 1) and,
together, enrolled 59,462 patients.
Thirteen studies summarized data
on outpatients, eight on inpatients,
and six on both populations; 22 ar-
ticles did not specify a population
but likely included predominantly
outpatients.
Baseline patient characteristics
Patients’baseline characteristics var-
ied by study (Table 1). The mean age
was 46.7, and illness duration was 4.4
years. Women represented 71% and
non-Hispanic whites represented 89%
of the study populations. Patients
had 3.8 prior depressive episodes
(range .8–7.2). On average, patients
had not responded to 4.7 drug trials
(range 1–10) and 2.1 drug classes
(Table 2).
Symptom severity
The scales used to assess symptom
severity varied greatly. Commonly
used scales included the HAM-D,
the Montgomery-Asberg Depression
Scale (MADRS), the Clinical Global
Impression–Severity (CGI-S) scale,
and the Quick Inventory of Depres-
sive Symptomatology–Clinician Rated
(QIDS-C). The average scores at
baseline on the HAM-D-17, the
MADRS, the CGI-S, and the QIDS-
C indicated that symptom severity
was within or close to the scoring
range used to classify conditions as
severe or markedly ill (Table 2) (22–
32). At the end of the studies, severity
scores had improved by an average of
35%68% (improvements of 12.86
4.1, or 42%, on the HAM-D-17;
23.267.7, or 27%, on the MADRS;
and 3.061.4, or 36%, on the CGI-S).
Scores at the end of the studies were
not reported for the QIDS-C.
Comorbid conditions
Comorbid conditions were rela-
tively common among patients with
treatment-resistant depression, as in-
dicated in Table 1. Comorbid con-
ditions included joint, limb, or back
pain (73%); hypertension (67%); and
dyslipidemia (61%) (33,34). Some
psychiatric conditions, such as malaise
or fatigue, anxiety, and personality
disorder, were more prevalent among
patients with treatment-resistant ver-
sus treatment-responsive depression
(15,33–37). Suicidal ideation was
reported for 15%68% of patients
with treatment-resistant depression, 6%
of patients with treatment-responsive
depression, and 1% of the general
population (33,38,39). Approximately
17%66% of patients with treatment-
resistant depression had a history of
suicide attempt, with an average of
1.16.2 prior suicide attempts each
(8,15,33,39–44).
Mortality rates (deaths per 1,000
patient-years) were similar among
patients with treatment-resistant (46.2)
and treatment-responsive (46.8) de-
pression in a Medicare population and
were about 4% lower than the rate for
individuals in the general population
(48.2). (33) No articles summarized
2PSYCHIATRIC SERVICES IN ADVANCE
Table 1
Baseline characteristics of patients enrolled in studies of treatment-resistant depression
a
Treatment-resistant depression Treatment-responsive depression
N%
Median
(%)
Minimum
(%)
Maximum
(%)
Nof
studies
N%
Median
(%)
Minimum
(%)
Maximum
(%)
Nof
studiesCharacteristic M SD M SD M SD M SD
Sample size 1,239 4,756 42 6 24,415 49
Age (M6SD) 46.7 5.3 47.0 27.4 74.7 39
Age at onset (M6SD) 31.5 6.8 27.7 2.9 51.2 12
Duration of illness (M6SD years) 4.4 3.3 16.7 2.5 26.7 20
Previous episodes of depression (M6SD) 3.8 2.1 2.6 .8 7.2 16
Women 14,310 6,086 71 4 65 0 93 42
Race-ethnicity
Caucasian 3,060 1,765 89 4 91 78 97 12
African American 29 24 13 9 3 2 18 3
Other 6 3 4 3 3 0 7 3
Comorbid condition
b
Joint, limb, or back pain 3,386 73 1 5,267 70 1
Hypertension 3,095 607 67 0 40 12 68 2 5,035 903 67 9 43 17 68 2
Dyslipidemia 2,821 556 61 0 32 1 62 2 4,739 853 63 11 34 3 64 2
Cardiovascular disease 2,598 56 1 3,702 666 49 9 25 1 50 2
Malaise and fatigue 2,412 52 1 3,311 44 1
Anxiety 1,767 1,265 44 0 21 7 59 6 2,512 1,557 36 16 13 9 43 3
Anemia 3 39 1 2,633 35 1
Hypothyroidism 1,593 312 35 5 23 11 35 2 2,147 385 29 4 18 7 29 2
Chronic obstructive pulmonary disease 1,577 34 1 2,257 30 1
Diabetes 1,358 499 30 0 15 8 32 3 2,295 411 31 4 20 10 31 2
Alcohol abuse, lifetime 16 10 27 7 28 14 30 3 47 34 1
Alcohol abuse, current 231 173 6 2 5 3 8 3 180 116 3 1 2 1 3 2
Avoidant personality disorder 18 2 24 7 28 20 30 2 35 33 1
Asthma 974 21 1 1,354 18 1
Self-defeating personality disorder 11 21 1 15 14 1
Chronic pain 878 251 20 1 16 15 20 3 1,162 490 19 3 21 18 23 2
Substance use disorder, lifetime 8 4 18 12 14 7 39 3 30 22 1
Substance use disorder, current 56 42 3 1 43 1 4 2 37 2 1
Obsessive-compulsive disorder 13 2 17 4 18 15 21 2 39 37 1
Panic disorder 48 34 17 7 18 7 25 5 17 12 1
Delusions and other psychoses 774 151 17 2 13 9 17 2 444 80 6 1 4 2 6 2
Continues on next page
PSYCHIATRIC SERVICES IN ADVANCE 3
associations between treatment-resistant
depression and other outcomes, such
as crime rates, incarceration, social
services’utilization, or caregivers’qual-
ity of life.
Response and remission rates
Therapeutic options for treatment-
resistant depression consisted of deep
brain stimulation, transcranial magnetic
stimulation, transcranial direct-current
stimulation, vagus nerve stimulation,
group psychoeducation, cognitive ther-
apy, and a variety of drugs, most
commonly lamotrigine, lithium, olanza-
pine, and venlafaxine. Sixteen studies
reported rates of remission and re-
sponse (Table 3) (8,9,17,38,43–54).
Response rates for different treatment
groups varied between 0% and 80%,
for an average of 36%61%. Remission
rates varied from 8% to 80%, for an
average of 20%61%. The lowest aver-
age response and remission rates were
reported in the STAR*D trial: scores on
the QIDS–Self-Report–16 indicated
that only 15% and 10%, respectively,
had responded to treatment or were in
remission (8). One study found cogni-
tive therapy to be effective; patients
averaged a significant 9-point decline in
the Beck Depression Inventory score,
and 26% had a “sustained recovery”at
26 weeks (55).
Medication-related adverse events
Twenty-seven studies reported on the
incidence of adverse events among
patients with treatment-resistant de-
pression. Rush and others (56) found
that 53% of patients experienced at
least one adverse event, of which
81% were mild or moderate. The
most frequent mild or moderate drug-
related adverse events were de-
creased sexual desire (33%), orgasmic
dysfunction (26%), and blurred vi-
sion (15%). The most frequent se-
vere drug-related adverse events were
dissociative reactions (13%), ataxia
(13%), mixed states (dysphoric mania
or agitated depression) (10%), and
tremor and nausea (10%). The most
frequent procedure-related adverse
events were swollen eye (55%), head-
ache (38%), and erythema (36%); no
severe procedure-related adverse
events were reported. Only four
studies that reported adverse events
had a placebo arm. Adverse events
Table 1
Continued from previous page
Treatment-resistant depression Treatment-responsive depression
N%
Median
(%)
Minimum
(%)
Maximum
(%)
Nof
studies
N%
Median
(%)
Minimum
(%)
Maximum
(%)
Nof
studiesCharacteristic M SD M SD M SD M SD
Obesity 774 152 17 3 10 3 17 2 1,037 185 14 1 104 6 14 2
Personality disorder 728 142 16 2 11 6 16 2 296 53 4 0 43 2 4 2
Sleep disorder 694 252 16 2 13 9 16 2 978 13 1
a
SDs and minimum and maximum percentages are not reported when only one study provided results.
b
The following list reports percentages of patients with treatment-resistant vs. treatment-responsive depression and other conditions: mixed personality disorder, 14% vs. data not reported (DNR); borderline personality
disorder, 13% vs. 13%; paranoid personality disorder, 13% vs. 28%; migraine, 12% vs. 9%; social phobia, 12% vs. 35%; dependent personality disorder, 11% vs. 15%; simple phobia, 11% vs. 14%; generalized anxiety
disorder, 10% vs. 16%; agoraphobia, 10% vs. 7%; passive-aggressive personality disorder, 9% vs. 13%; physical abuse, 9% vs. DNR; posttraumatic stress disorder, 9% vs. 4%; soft tissue disorder, 7% vs. 0%; somatoform
disorder, 5% vs. 5%; antisocial personality disorder, 5% vs. 7%; eating disorder, 5% vs. 3%; narcissistic personality disorder, 4% vs. 10%; obsessive-compulsive disorder, 4% vs. 3%; acute myocardial infarction persistent,
3% vs. DNR; mood disorders, 3% vs. 1%; dysthymia, 3% vs. DNR; dementia, 2% vs. 2%; gastritis and duodenitis, 2% vs. 4%; schizoid personality disorder, 2% vs. 3%; phobic anxiety disorders, 2% vs. 3%; mild mental
retardation, 1% vs. 2%; and histrionic personality disorder, 0% vs. 3%
4PSYCHIATRIC SERVICES IN ADVANCE
that occurred in more than 5% of the
placebo groups were blood pressure
change (40%), headache (15%), dis-
sociative reaction (in a study utilizing
ketamine) (13%), and manic reaction
(13%) (10,48,54,57).
Quality of life and costs
Quality-of-life data were taken from
published models that used data
sources ranging from reviews of prior
literature to original trials (58–63).
The studies measured quality of life
with a continuous scale, with 0 in-
dicating death and 1 indicating per-
fect health. Average baseline scores
were .5526.120 for patients with
major depressive disorder (58–61),
.8266.065 for patients in remission
(59–63), .6736.031 for patients who
responded to therapy without remission
(61,62), and .4176.126 for patients
who did not respond to therapy (61–63).
Adverse events caused a further loss
of .01 to .12 quality-of-life units (59).
Five studies provided detailed in-
formation about annual per-patient
costs for treatment-resistant depres-
sion, one from Medicare and four
from databases of national employers
and private payer claims (Table 4)
(33,36,54,64,65). Annual claims for
visits to a medical facility were rela-
tively common among patients with
treatment-resistant (N=28.3 claims)
versus treatment-responsive depres-
sion (N=15.1 claims) (64). Fifty-two
percent of patients with treatment-
resistant depression were hospitalized
over their lifetimes (39).
Among private payers, the mean
annual direct health care costs per
patient for management of treatment-
resistant depression ($13,196) were
$5,481 higher than for management
of treatment-responsive depression
($7,715) (Table 4) (36,64,65). These
comparisons were from the same
studies, so observed differences were
not an artifact of sample heterogene-
ity. Annual direct medical costs for
persons in the general population
were $3,997 (64). Total costs in pro-
ductivity per patient-year were $4,048
higher among patients with treatment-
resistant depression ($6,924) than among
patients with treatment-responsive
depression ($2,876) (36,64) (Table 4).
For the general population, annual
productivity costs were $1,098 (64).
The total annual direct and indirect
costs per patient-year were $20,120
for patients with treatment-resistant
depression and $10,592 for an age-
matched population with treatment-
responsive depression (Table 4)
Table 2
Baseline measures of symptom severity among patients with treatment-resistant depression
a
Scale range
Variable M SD Median Lowest Highest N of studies
Remission
or mild
Severe or
markedly ill Reference
Failed drug trials
b
4.7 2.7 2.6 1.0 10.0 11
Failed drug classes
b
2.1 .3 2 2.0 3.0 6
Depression-specific scale score
HAM-D-17 21.9 1.7 22.6 19.2 28.4 18 0–13 20–52 22
HAM-D-21 19.8 5.2 19.5 15.8 23.2 2 0–15 23–64 22
HAM-D-24 27.9 4.2 27.9 21.0 33.7 4 0–18 27–75 22
HAM-D-28 30.4 5.5 32.2 23.7 34.3 3 0–10 21–52 23
MADRS 31.8 3.0 33.0 25.0 50.0 12 0–19 35–60 22
CGI-S 4.6 .4 4.8 3.8 6.3 11 1–36–724
BDI 30.9 6.6 31.7 16.5 38.2 5 0–18 30–63 22
IDS-SR-30 41.3 2.0 40.8 38.2 43.4 3 0–25 39–84 22
IDS-C-30 35.4 1 0–23 37–84 22
QIDS-SR-16 15.8 2.5 15.8 14.0 17.6 2 0–10 16–27 22
QIDS-C-16 14.4 1 0–10 16–27 22
Other scale score
GAF 50.0 7.0 42.3 28.7 55.0 6 100–61 50–025
HAMA 17.8 1.1 19.6 17.5 23.3 4 0–17 31–56 26
Q-LES-Q 37.4 1.2 37.3 34.6 41.0 3 100 0 26
BPRS 17.3 6.9 25.9 16.0 35.8 2 16–31 53–126 27
SF–36 MCS 22.5 2.7 21.6 19.4 23.7 2 100 0 28
SF–36 PCS 37.5 3.1 36.5 34.0 38.9 2 100 0 28
BAI 14.1 1 0–15 26–63 29
MMSE 27.7 1 24–30 0–23 30
SQ-SS 6.6 1 0 18 31
SQ-SWB 1.4 1 6 0 31
POMS 52.5 1 0 200 32
a
SDs and minimum and maximum scores are not reported when only one study provided results. HAM-D, Hamilton Rating Scale for Depression;
MADRS, Montgomery-Asberg Depression Scale; CGI-S, Clinical Global Impression–Severity; BDI, Beck Depression Inventory; IDS, Inventory of
Depressive Symptomatology; SR, Self-Report; C, Clinician Rated; QIDS, Quick Inventory of Depressive Symptomatology; GAF, Global Assessment of
Functioning; BPRS, Brief Psychiatric Rating Scale; Q-LES-Q, Quality of Life Enjoyment and Satisfaction Questionnaire; BAI, Beck Anxiety Inventory;
HAMA, Hamilton Anxiety Scale; MMSE, Mini-Mental State Examination; SF-36, Short-Form Health Survey Questionnaire; MCS, mental composite
score; PCS, physical composite score; SQ, Symptom Questionnaire; SS, somatic subscale; SWB, somatic well-being; POMS, Profile of Mood States.
b
Excluded studies that reported the number of failed drug trials and classes as ranges.
PSYCHIATRIC SERVICES IN ADVANCE 5
Table 3
Rates of response and remission among patients with treatment-resistant depression, by study
a
Study
Rating
scale
b
Length
of study
(weeks)
Nof
patients
Treatment with lowest
rate of response or remission
Treatment with highest rate
of response or remission
Response (%) Remission (%)
Average Lowest Highest Average Lowest Highest
Inoue et al., 1996 (50) HAM-D-17 6 6 Bromocriptine 67
Shelton et al., 2001 (51) MADRS 8 34 Olanzapine Olanzapine and fluoxetine 25 0 60
Papakostas et al., 2003 (35) HAM-D-17 6 92 Nortriptyline; patients with
comorbid avoidant
personality disorder
Nortriptyline; patients without
comorbid avoidant personality
disorder
42 17 49
Seidman et al., 2005 (49) HAM-D-17 6 23 Placebo Testosterone —23 54
Corya et al., 2006 (52) MADRS 7 483 Olanzapine Venlafaxine (response); olanzapine
and fluoxetine combination
(remission)
38 25 50 23 14 30
Fava et al., 2006 (8) QIDS-SR-16 14 235 Mirtazapine Nortriptyline 15 13 17 10 8 12
Fava et al., 2006 (8) HAM-D-17 14 235 Mirtazapine Nortriptyline 16 12 20
Doree et al., 2007 (46) HAM-D-17 8 20 Lithium Quetiapine 65 50 80 60 40 80
Doree et al., 2007 (46) MADRS 8 20 Lithium Quetiapine 65 50 80 55 30 80
Mahmoud et al., 2007 (48) HAM-D-17 6 258 Placebo Risperidone —30 46 25 11 25
Schindler and Anghelescu,
2007 (45) HAM-D-17 8 34 Lithium Lamotrigine 47 41 53 21 18 23
Avery et al., 2008 (17) MADRS 9 158 Sham, then transcranial
magnetic stimulation (TMS)
Extended TMS 40 34 45 25 18 31
Avery et al., 2008 (17) MADRS 6 158 Sham, then TMS Extended TMS 35 26 42 16 11 20
Avery et al., 2008 (17) HAM-D-24 6 158 Sham, then TMS Extended TMS 37 32 42 22 16 27
Avery et al., 2008 (17) HAM-D-24 9 158 Sham, then TMS Extended TMS 39 32 46 29 19 37
Bares et al., 2008 (9) MADRS 4 25 Venlafaxine 48
Karp et al., 2008 (47) HAM-D-17 6.9 20 Duloxetine 50
Lozano et al., 2008 (53) HAM-D-17 26 20 Deep brain stimulation 60
Lozano et al., 2008 (53) HAM-D-17 52 20 Deep brain stimulation 55 35
Bewernick et al., 2010 (23) HAM-D-28 52 11 Deep brain stimulation 46 9
Kopell et al., 2011 (44) HAM-D-28 91 11 Epidural cortical stimulation 46 36
Taneja et al., 2012 (54) MADRS 6 1,034 Meta-analysis: antidepressant 30 20 39
Taneja et al., 2012 (54) MADRS 6 540 Meta-analysis: aripiprazole
with antidepressant
49 41 60
Taneja et al., 2012 (54) MADRS 6 309 Meta-analysis: quetiapine
150 mg with antidepressant
34 28 40
Taneja et al., 2012 (54) MADRS 6 312 Meta-analysis: quetiapine
300 mg with antidepressant
38 32 44
Taneja et al., 2012 (54) MADRS 6 200 Meta-analysis: olanzapine
and fluoxetine
45 32 64
Average6SD (weighted)
c
6620 1766234 366126614561206113612561
a
For studies that assessed only one treatment, the treatment is listed under lowest response or remission rate, and results are listed under average response or remission rates.
b
HAM-D, Hamilton Rating Scale for Depression; MADRS, Montgomery-Asberg Depression Scale; QIDS-SR, Quick Inventory of Depressive Symptomatology–Self-Report
c
Weighted by inverse-variance method. Excludes patients on placebo
6PSYCHIATRIC SERVICES IN ADVANCE
(36,64,65). These costs were $5,095 in
the general population (64).
Annual direct medical costs among
Medicare patients were $20,736 for
patients with treatment-resistant de-
pression, $14,098 for patients with
treatment-responsive depression, and
$10,380 in the general population of
Medicare patients (33). These differ-
ences in cost in the Medicare popula-
tion reinforce the considerable health
care benefit that could be obtained
from more effectively treating major
depressive disorder.
Discussion
Our review of literature shows that
among the many burdens of patients
with treatment-resistant depression,
they experience only a 20% probabil-
ity of achieving remission in the
course of treatment, a 17% preva-
lence of prior suicide attempts, sub-
stantially lower quality-of-life scores
than patients whose depression
remits, and direct and indirect annual
costs among private payers that are
$9,529 higher than those of patients
with treatment-responsive depression.
Patients with treatment-resistant de-
pression had 28.3 annual general
medical visits, more than three times
as many as the general population
average of 8.7, whereas patients with
treatment-responsive depression had
less than twice as many annual gen-
eral medical visits as the general
population (64).
Although response and remission
rates for patients with treatment-
resistant depression varied widely
among studies, average improvements
on the CGI-S (36%), the HAM-D-17
(42%), and the MADRS (27%) were
similar. The STAR*D study found par-
ticularly low rates of response (15%)
and remission (10%), possibly be-
cause this study consisted of patients
who did not respond to up to three
well-monitored treatments, whereas
many other studies used nonresponse
to just one or two naturalistic treat-
ments as their criterion for treatment
resistance.
Among adults in the United States,
the 12-month prevalence of major
depressive disorder in 2012 was 6.7%
(3), or 16 million individuals. Assum-
ing that 12% of these patients had
treatment-resistant depression, which
was the lowest estimate reported by
studies in this review (64), a total of
1.9 million adults in the United States
had treatment-resistant depression in
2012. If annual costs of treatment per
patient-year for private payers totaled
$20,120, as estimated, the total costs
for treatment of this population in
2012 was $38 billion. Adding in the
annual cost of treatment of the 14
million patients with treatment-
responsive depression ($10,592 each;
$148 billion total), the societal burden
of major depressive disorder for the
United States in 2012 was $188
billion. By comparison, the societal
cost for cancer was $131 billion (66),
and in 2007, the societal cost for
diabetes in 2012 dollars was $173
billion (67).
Corey-Lisle and colleagues (64) stat-
ed that treatment resistance among
patients with depression might actu-
ally be as high as 20%. When this
higher estimate was used, the esti-
mated societal burden of major de-
pressive disorder in the United States
reaches $200 billion per year and the
burden of treatment-resistant depres-
sion alone reaches $64 billion per
year. A prior study estimated that the
societal cost of major depressive
disorder was $124 billion per year, in
2012 dollars (2). This estimate may be
lower than our estimate of $188–$200
billion because of temporal changes in
unit service costs, for example, increas-
ing wages, and the possible exclusion
of costs for patient visits that were
not reported as being primarily for
depression (36,64).
The burden of major depression
can also be calculated as an increase
in costs above those of the general
population. If 12% of patients with
depression are resistant to therapy,
the costs of depression above general
population costs are $29 billion for
patients with treatment-resistant de-
pression, $77 billion for patients with
treatment-responsive depression, and
$106 billion for all major depression.
If 20% of depressed patients are
resistant to therapy, the estimated
costs are $48 billion for patients with
treatment-resistant depression, $70
billion for patients with treatment-
responsive depression, and $118 billion
for all major depression. Conversely,
if 70% more patients respond to
antidepressant therapy, the costs for
the 3.6% of patients who remain
treatment resistant would decrease
to $8.6 billion, and costs for patients
with treatment-responsive depression
would be $84.3 billion. The aggregate
$93 billion annual cost of major
depression above general population
costs would save $13 billion, a 12%
reduction in the annual cost of treat-
ing all patients with major depressive
disorder.
Gillum and colleagues (68) recently
compared 29 common conditions
and diseases in terms of incidence,
prevalence, and disability-adjusted
life years. Depression ranked first in
populationwide burden by disability-
adjusted life years. The next four most
impactful conditions or disorders
were injuries, ischemic heart disease,
alcohol abuse, and chronic obstructive
pulmonary disorder. The low quality-
of-life scores (.417 on a scale of 0 to 1)
reported by patients with treatment-
resistant depression who did not re-
spond to therapy fell within the range
of scores reported for metastatic
cancer, chronic moderate-to-severe
pain, or acquired blindness (20).
Although these quality-of-life mea-
sures may be confounded by patients’
current mood and depressive symp-
toms (69), the estimates amount to
one million quality-adjusted years lost
due to treatment-resistant depression
in the United States. Treatment-
responsive depression accounts for
an additional loss of more than 1.5
million quality-adjusted years.
The small numbers and heteroge-
neity that characterized the study
populations and treatments described
in the articles summarized here may
limit the general applicability of some
findings. For example, only a few
studies included information about
comorbid disorders and adverse events.
Our summaries of the five studies that
reported costs per patient-year for
depression treatment and our extrap-
olation of the data to determine na-
tionwide costs can be combined with
results of future studies to more accu-
rately calculate the monetary impact
of treatment-resistant depression.
Other limitations of this analysis in-
cluded the heterogeneity of methods
and the degree to which complete
findings were reported, the relatively
PSYCHIATRIC SERVICES IN ADVANCE 7
short periods of patient follow-up, and
a focus primarily on clinical endpoints
during follow-up.
The burden of treatment-resistant
depression was likely underestimated
because there is limited published
research, or none at all, on the
incidence of crime rates, incarcera-
tion, and use of social services among
persons with depression and on costs
and quality-of-life burden for family
members and caregivers. The burden
might also have been underestimated
because we excluded studies with
adolescent populations, which have
similar prevalence rates for depres-
sion as adults but lower treatment
rates (70–72). Among patients with
treatment-resistant depression, ado-
lescents experienced a greater burden
with regard to suicide attempts com-
pared with adults, and their rate of
substance use disorders (54%) was
higher than the current (3%) and
lifetime (18%) rates for adults (73).
In response to these challenges,
personalized medicine technologies
are finding increasing application in
reducing the burden of major depres-
sion. One such approach, pharmacoge-
nomics, matches the pharmacokinetic
and pharmacodynamic properties of
antidepressant medications to the
genetic profile of individual patients.
Pharmacogenomic test results can
identify variability in psychiatric drug
response and, when applied clinically,
can increase antidepressant responses
by 70% (74–78). Identifying the right
medication and dose for patients will
shorten patients’treatment odyssey,
thereby decreasing the proportion
that become treatment resistant. The
resulting savings would diminish an-
nual health expenditures and increase
productivity. Psychiatric pharmacoge-
nomics and other innovations may
also improve the classification of
major depressive disorder subtypes;
define more individualized and earlier,
potentially prodromal treatments; and
reduce adverse event rates (79,80).
Conclusions
The studies reviewed here reveal that
the personal and societal burdens of
depression are disproportionately
greater among patients who do not
respond to antidepressant therapies.
Contributory factors to this extra
burden include more unsuccessful
drug trials; more comorbid disorders,
such as malaise, fatigue, and anxiety;
and increases in suicidal ideation. The
far greater personal financial burden
of treatment resistance is likely to
compound anxiety, depression, and
comorbid disorders as financial hard-
ships mount.
Despite multiple treatment options
available to clinicians, treatment re-
sistance remains highly prevalent and
exacts a substantial toll on patients’
quality of life and on society. The
burden of treatment-resistant depres-
sion is on a par with or is greater than
that of other chronic conditions such
as cancer and diabetes, yet depression
ranks only 15th among conditions or
disorders that receive National Insti-
tutes of Health research funds (68).
Improvements in technology are
likely to diminish treatment resistance
and mitigate its extra costs. These
include pharmacogenomic tests that
incorporate additional DNA variants
and DNA methylation status; new
medications that are based on non-
monoaminergic approaches, such as
N-methyl-D-aspartate receptor an-
tagonism; and refinements in trans-
cranial magnetic stimulation.
Disparities in care also need to be
addressed so that innovations can
achieve a broad societal impact. Certain
racial or ethnic groups and unemploy-
ment are associated with underdetec-
tion of mental illness and inadequate
mental health care access or quality
(81–84). Solutions include more social
programs, better patient education,
quality improvement programs, and
Table 4
Costs per patient-year for patients with treatment-resistant and treatment-
responsive depression, by resource category
a
Category M SD
b
Median Lowest Highest
Nof
studies
Treatment-resistant depression
Health care (direct costs)
Depression drugs 2,667 1,026 3,736 1,346 7,568 4
Nondepression drugs 2,556 141 2,580 2,216 2,963 3
Hospitalizations
Emergency care 392 —— — — 1
Nonpsychiatric medical care 2,508 786 2,986 2,253 3,719 2
Psychiatric visits 593 324 790 488 1,092 2
Physician visits 4,829 2,431 3,351 1,085 5,618 2
Psychotherapy 978 344 770 449 1,090 2
Total
c
13,196 219 13,402 13,152 14,417 3
Productivity (indirect costs)
Absenteeism 2,625 987 2,025 1,105 2,945 2
Disability 4,299 815 3,804 3,044 4,564 2
Total 6,924 1,801 5,829 4,149 7,509 2
Total direct and indirect costs 20,120
Treatment-responsive depression
Health care (direct costs)
Depression drugs 898 162 561 385 939 3
Nondepression drugs 1,407 75 1,369 1,094 1,422 3
Hospitalizations
Emergency care 224 —— — — 1
Nonpsychiatric medical care 1,438 119 1,418 1,332 1,505 2
Psychiatric visits 99 23 95 79 112 2
Physician visits 1,708 1,864 2,021 666 3,376 2
Psychotherapy 255 176 284 156 412 2
Total
c
7,715 456 6,902 6,375 7,832 3
Productivity (indirect costs)
Absenteeism 1,125 849 1,268 651 1,885 2
Productivity 1,751 464 1,829 1,492 2,166 2
Total 2,876 1,312 3,096 2,142 4,050 2
Total direct and indirect costs 10,592
a
Costs are for private payers and are reported in 2012 dollars.
b
An SD and other data were not reported when only one study provided results.
c
May include other costs that are not listed
8PSYCHIATRIC SERVICES IN ADVANCE
increased resources for indigent care
clinics (81–84). Consistent processes
for assessing regulatory and reim-
bursement implications of new ther-
apeutic and diagnostic practices are
also needed (79). Expanded treat-
ment alternatives, augmented with
pharmacogenomic decision support,
have the potential to improve out-
comes and help patients retain pro-
ductive lives. Along with decreases in
health care costs and increased global
productivity, there is much to achieve—
and expect—by decreasing the individual
and societal burdens of treatment-
resistant depression.
Acknowledgments and disclosures
This study was supported by Assurex Health
through a research contract with Cedar
Associates.
Dr. Mrazek developed intellectual property
that was licensed by Assurex Health and
received research funding from Assurex Health
to create and maintain a bibliographic system
designed to regularly curate scientific liter-
ature. The other authors report no competing
interests.
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