ArticlePDF Available

A Review of the Clinical, Economic, and Societal Burden of Treatment-Resistant Depression: 1996-2013

Authors:
  • NeuroDrug Consulting
  • Independent Researcher

Abstract and Figures

Objective: This literature review assessed the burden of treatment-resistant depression in the United States by compiling published data about the clinical, 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 independently assessed study quality and extracted data. Results: Sixty-two articles were included (N=59,462 patients). Patients with treatment-resistant depression had 3.8±2.1 prior depressive episodes and illness duration of 4.4±3.3 years and had completed 4.7±2.7 unsuccessful drug trials involving 2.1±.3 drug classes. Response rates for treatment-resistant depression were 36%±1%. A total of 17%±6% of patients had prior suicide attempts (1.1±.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 .41±.8 and .26±.8 points lower, respectively, than for patients who experienced remission or response. Annual costs for health care and lost productivity were 5,481and5,481 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 societal cost of 2929-48 billion, pushing up the total societal costs of major depression by as much as 106106-118 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.
Content may be subject to copyright.
A Review of the Clinical, Economic,
and Societal Burden of Treatment-
Resistant Depression: 19962013
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 01, 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
patientsquality 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% (24). 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 (4,5,79). The designation
treatment resistantis used to de-
scribe patients who do not respond to
antidepressant therapy after one or
more adequate trials (911) (duration
of at least six weeks and use of
appropriate dosages [1215]). 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%
(8,1619).
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 remitis 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
Patientsbaseline 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 .87.2). On average, patients
had not responded to 4.7 drug trials
(range 110) 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
ImpressionSeverity (CGI-S) scale,
and the Quick Inventory of Depres-
sive SymptomatologyClinician 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
(15,3337). 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
(8,15,33,3944).
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
servicesutilization, or caregiversqual-
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) (8,9,17,38,4354).
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 QIDSSelf-Report16 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 recoveryat
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 (5863).
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 (5861),
.8266.065 for patients in remission
(5963), .6736.031 for patients who
responded to therapy without remission
(61,62), and .4176.126 for patients
who did not respond to therapy (6163).
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 18 013 2052 22
HAM-D-21 19.8 5.2 19.5 15.8 23.2 2 015 2364 22
HAM-D-24 27.9 4.2 27.9 21.0 33.7 4 018 2775 22
HAM-D-28 30.4 5.5 32.2 23.7 34.3 3 010 2152 23
MADRS 31.8 3.0 33.0 25.0 50.0 12 019 3560 22
CGI-S 4.6 .4 4.8 3.8 6.3 11 136724
BDI 30.9 6.6 31.7 16.5 38.2 5 018 3063 22
IDS-SR-30 41.3 2.0 40.8 38.2 43.4 3 025 3984 22
IDS-C-30 35.4 1 023 3784 22
QIDS-SR-16 15.8 2.5 15.8 14.0 17.6 2 010 1627 22
QIDS-C-16 14.4 1 010 1627 22
Other scale score
GAF 50.0 7.0 42.3 28.7 55.0 6 10061 50025
HAMA 17.8 1.1 19.6 17.5 23.3 4 017 3156 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 1631 53126 27
SF36 MCS 22.5 2.7 21.6 19.4 23.7 2 100 0 28
SF36 PCS 37.5 3.1 36.5 34.0 38.9 2 100 0 28
BAI 14.1 1 015 2663 29
MMSE 27.7 1 2430 023 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 ImpressionSeverity; 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 SymptomatologySelf-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 (7072). 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% (7478). Identifying the right
medication and dose for patients will
shorten patientstreatment 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
(8184). 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 (8184). 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 expectby 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.
References
1. Kessler RC, McGonagle KA, Zhao S, et al:
Lifetime and 12-month prevalence of
DSM-III-R psychiatric disorders in the
United States: results from the National
Comorbidity Survey. Archives of General
Psychiatry 51:819, 1994
2. Eaton WW, Martins SS, Nestadt G, et al:
The burden of mental disorders. Epide-
miologic Reviews 30:114, 2008
3. Kessler RC, Chiu WT, Demler O, et al:
Prevalence, severity, and comorbidity of
12-month DSM-IV disorders in the Na-
tional Comorbidity Survey Replication.
Archives of General Psychiatry 62:617627,
2005
4. Nemeroff CB: Prevalence and manage-
ment of treatment-resistant depression.
Journal of Clinical Psychiatry 68(suppl 8):
1725, 2007
5. Greden JF: The burden of disease for
treatment-resistant depression. Journal of
Clinical Psychiatry 62(suppl 16):2631,
2001
6. The Global Burden of Disease: 2004 Update.
Geneva, World Health Organization, 2004.
Available at www.who.int/healthinfo/global_
burden_disease/GBD_report_2004update_
full.pdf
7. Nierenberg AA, DeCecco LM: Definitions
of antidepressant treatment response, re-
mission, nonresponse, partial response,
and other relevant outcomes: a focus on
treatment-resistant depression. Journal of
Clinical Psychiatry 62(suppl 16):59, 2001
8. Fava M, Rush AJ, Wisniewski SR, et al: A
comparison of mirtazapine and nortripty-
line following two consecutive failed medi-
cation treatments for depressed outpatients:
a STAR*D report. American Journal of
Psychiatry 163:11611172, 2006
9. Bares M, Brunovsky M, Kopecek M, et al:
Early reduction in prefrontal theta QEEG
cordance value predicts response to venlafaxine
treatment in patients with resistant depres-
sive disorder. European Psychiatry 23:350355,
2008
10. Preskorn SH, Baker B, Kolluri S, et al: An
innovative design to establish proof of
concept of the antidepressant effects of
the NR2B subunit selective N-methyl-
D-aspartate antagonist, CP-101,606, in
patients with treatment-refractory major
depressive disorder. Journal of Clinical
Psychopharmacology 28:631637, 2008
11. Thase ME, Rush AJ: When at first you
dont succeed: sequential strategies for
antidepressant nonresponders. Journal of
Clinical Psychiatry 58(suppl 13):2329,
1997
12. Barbee JG, Jamhour NJ: Lamotrigine as an
augmentation agent in treatment-resistant
depression. Journal of Clinical Psychiatry
63:737741, 2002
13. Dombrovski AY, Mulsant BH, Haskett RF,
et al: Predictors of remission after elec-
troconvulsive therapy in unipolar major
depression. Journal of Clinical Psychiatry
66:10431049, 2005
14. Petersen T, Gordon JA, Kant A, et al:
Treatment resistant depression and axis I
co-morbidity. Psychological Medicine 31:
12231229, 2001
15. Souery D, Oswald P, Massat I, et al:
Clinical factors associated with treatment
resistance in major depressive disorder:
results from a European multicenter study.
Journal of Clinical Psychiatry 68:10621070,
2007
16. Rush AJ, Trivedi MH, Wisniewski SR,
et al: Bupropion-SR, sertraline, or venlafaxine-
XR after failure of SSRIs for depression.
New England Journal of Medicine 354:
12311242, 2006
17. Avery DH, Isenberg KE, Sampson SM,
et al: Transcranial magnetic stimulation in
the acute treatment of major depressive
disorder: clinical response in an open-label
extension trial. Journal of Clinical Psychi-
atry 69:441451, 2008
18. Trivedi MH, Rush AJ, Wisniewski SR,
et al: Evaluation of outcomes with cital-
opram for depression using measurement-
based care in STAR*D: implications for
clinical practice. American Journal of Psy-
chiatry 163:2840, 2006
19. McGrath PJ, Stewart JW, Fava M, et al:
Tranylcypromine versus venlafaxine plus
mirtazapine following three failed antide-
pressant medication trials for depression:
aSTAR*D report. American Journal of
Psychiatry 163:15311541, 2006
20. CostEffectiveness Analysis Registry. Bos-
ton, Tufts Medical Center, 2013. Available
at research.tufts-nemc.org/cear4/. Accessed
Aug 22, 2013
21. Mental Disorders and Illicit Drug Use
Expert Group: Methodology Part 2: Sys-
tematic Review. Sydney, Australia, Univer-
sity of New South Wales, 2007. Available at
www.med.unsw.edu.au/gbdweb.nsf/resources/
MethodologyPart2/$file/GBD_Methodology_
pt2_03Nov08.pdf
22. Inventory of Depressive Symptomatology
(IDS) and Quick Inventory of Depressive
Symptomatology (QIDS). Pittsburgh, Pa,
University of Pittsburgh Epidemiology
Data Center, 2013. Available at www.ids-
qids.org
23. Bewernick BH, Hurlemann R, Matusch A,
et al: Nucleus accumbens deep brain
stimulation decreases ratings of depression
and anxiety in treatment-resistant de-
pression. Biological Psychiatry 67:110116,
2010
24. Clinical Global Impression (CGI). Rockville,
Md, US Department of Health, Education,
and Welfare, 1976
25. Diagnostic and Statistical Manual of Men-
tal Disorders, 4th ed. Washington, DC,
American Psychiatric Association, 1994
26. Hamilton M: The assessment of anxiety
states by rating. British Journal of Medical
Psychology 32:5055, 1959
27. Leucht S, Kane JM, Kissling W, et al:
Clinical implications of Brief Psychiatric Rat-
ing Scale scores. British Journal of Medical
Psychology 187:366371, 2005
28. Dumas R, Richieri R, Guedj E, et al: Im-
provement of health-related quality of life
in depression after transcranial magnetic
stimulation in a naturalistic trial is associ-
ated with decreased perfusion in pre-
cuneus. Health and Quality of Life
Outcomes 10:87, 2012
29. Grant MM: Beck Anxiety Inventory; in
Encyclopedia of Child Behavior and De-
velopment. Edited by Goldstein S, Naglieri
J. New York, Springer, 2011
30. Kukull WA, Larson EB, Teri L, et al: The
Mini-Mental State Examination score and
the clinical diagnosis of dementia. Journal
of Clinical Epidemiology 47:10611067,
1994
31. Papakostas GI, Petersen T, Denninger J,
et al: Somatic symptoms in treatment-
resistant depression. Psychiatry Research
118:3945, 2003
32. Mcnair D, Lorr M, Droppleman L: EdITS
Manual: Profile of Mood States. San Diego,
Educational and Industrial Testing Service,
1992
33. Feldman RL, Dunner DL, Muller JS, et al:
Medicare patient experience with vagus
nerve stimulation for treatment-resistant
depression. Journal of Medical Economics
16:6274, 2013
34. Lepine BA, Moreno RA, Campos RN,
et al: Treatment-resistant depression in-
creases health costs and resource utiliza-
tion. Revista Brasileira de Psiquiatria 34:
379388, 2012
35. Papakostas GI, Petersen TJ, Farabaugh
AH, et al: Psychiatric comorbidity as a
predictor of clinical response to nortriptyline
in treatment-resistant major depressive dis-
order. Journal of Clinical Psychiatry 64:
13571361, 2003
PSYCHIATRIC SERVICES IN ADVANCE 9
36.IvanovaJI,BirnbaumHG,KidoleziY,etal:
Direct and indirect costs of employees
with treatment-resistant and non-treatment-
resistant major depressive disorder. Current
Medical Research and Opinion 26:2475
2484, 2010
37. Malone DA, Jr, Dougherty DD, Rezai AR,
et al: Deep brain stimulation of the ventral
capsule/ventral striatum for treatment-
resistant depression. Biological Psychiatry
65:267275, 2009
38. Papakostas GI, Petersen T, Pava J, et al:
Hopelessness and suicidal ideation in out-
patients with treatment-resistant depression:
prevalence and impact on treatment out-
come. Journal of Nervous and Mental Dis-
ease 191:444449, 2003
39. DiazGranados N, Ibrahim LA, Brutsche
NE, et al: Rapid resolution of suicidal
ideation after a single infusion of an N-
methyl-D-aspartate antagonist in patients
with treatment-resistant major depressive
disorder. Journal of Clinical Psychiatry 71:
16051611, 2010
40. Ferrucci R, Bortolomasi M, Vergari M,
et al: Transcranial direct current stimula-
tion in severe, drug-resistant major de-
pression. Journal of Affective Disorders
118:215219, 2009
41. Prochazka H, Sjögren M, Agren H: Oral
d-fenfluramine test in treatment-refractory
depression. Plasma prolactin response
compared in patients with and without
suicide attempts and in a healthy reference
group. Journal of Affective Disorders 57:
201208, 2000
42. Kocsis JH, Gelenberg AJ, Rothbaum B,
et al: Chronic forms of major depression
are still undertreated in the 21st century:
systematic assessment of 801 patients pre-
senting for treatment. Journal of Affective
Disorders 110:5561, 2008
43. Bewernick BH, Kayser S, Sturm V, et al:
Long-term effects of nucleus accumbens
deep brain stimulation in treatment-
resistant depression: evidence for sustained
efficacy. Neuropsychopharmacology 37:
19751985, 2012
44. Kopell BH, Halverson J, Butson CR, et al:
Epidural cortical stimulation of the left
dorsolateral prefrontal cortex for refractory
major depressive disorder. Neurosurgery
69:10151029, 2011
45. Schindler F, Anghelescu IG: Lithium ver-
sus lamotrigine augmentation in treatment
resistant unipolar depression: a random-
ized, open-label study. International Clini-
cal Psychopharmacology 22:179182, 2007
46. Dorée JP, Des Rosiers J, Lew V, et al:
Quetiapine augmentation of treatment-
resistant depression: a comparison with
lithium. Current Medical Research and
Opinion 23:333341, 2007
47. Karp JF, Whyte EM, Lenze EJ, et al:
Rescue pharmacotherapy with duloxetine
for selective serotonin reuptake inhibitor
nonresponders in late-life depression: out-
come and tolerability. Journal of Clinical
Psychiatry 69:457463, 2008
48. Mahmoud RA, Pandina GJ, Turkoz I, et al:
Risperidone for treatment-refractory major
depressive disorder: a randomized trial.
Annals of Internal Medicine 147:593602,
2007
49. Seidman SN, Miyazaki M, Roose SP: In-
tramuscular testosterone supplementation
to selective serotonin reuptake inhibitor in
treatment-resistant depressed men: ran-
domized placebo-controlled clinical trial.
Journal of Clinical Psychopharmacology
25:584588, 2005
50.InoueT,TsuchiyaK,MiuraJ,etal:
Bromocriptine treatment of tricyclic and
heterocyclic antidepressant-resistant depres-
sion. Biological Psychiatry 40:151153,
1996
51. Shelton RC, Tollefson GD, Tohen M, et al:
A novel augmentation strategy for treating
resistant major depression. American
Journal of Psychiatry 158:131134, 2001
52. Corya SA, Williamson D, Sanger TM, et al:
A randomized, double-blind comparison of
olanzapine/fluoxetine combination, ola n-
zapine, fluoxetine, and venlafaxine in
treatment-resistant depression. Depression
and Anxiety 23:364372, 2006
53. Lozano AM, Mayberg HS, Giacobbe P,
et al: Subcallosal cingulate gyrus deep
brain stimulation for treatment-resistant
depression. Biological Psychiatry 64:
461467, 2008
54. Taneja C, Papakostas GI, Jing Y, et al:
Cost-effectiveness of adjunctive therapy
with atypical antipsychotics for acute
treatment of major depressive disorder.
Annals of Pharmacotherapy 46:642649,
2012
55. Swan J, Sorrell E, MacVicar B, et al:
Coping with depression: an open study of
the efficacy of a group psychoeducational in-
tervention in chronic, treatment-refractory
depression. Journal of Affective Disorders
82:125129, 2004
56. Rush AJ, Bose A, Heydorn WE: Natural-
istic study of the early psychiatric use of
citalopram in the United States. De-
pression and Anxiety 16:121127, 2002
57. Bauer M, Bschor T, Kunz D, et al:
Double-blind, placebo-controlled trial of
the use of lithium to augment antide-
pressant medication in continuation treat-
ment of unipolar major depression. American
Journal of Psychiatry 157:14291435, 2000
58. Lenox-Smith A, Greenstreet L, Burslem K,
et al: Cost effectiveness of venlafaxine
compared with generic fluoxetine or ge-
neric amitriptyline in major depressive
disorder in the UK. Clinical Drug In-
vestigation 29:173184, 2009
59. Revicki DA, Wood M: Patient-assigned
health state utilities for depression-related
outcomes: differences by depression se-
verity and antidepressant medications.
Journal of Affective Disorders 48:2536,
1998
60. Aziz M, Mehringer AM, Mozurkewich E,
et al: Cost-utility of 2 maintenance treat-
ments for older adults with depression who
responded to a course of electroconvulsive
therapy: results from a decision analytic
model. Canadian Journal of Psychiatry 50:
389397, 2005
61. Benedict A, Arellano J, De Cock E, et al:
Economic evaluation of duloxetine ver-
sus serotonin selective reuptake inhib-
itors and venlafaxine XR in treating
major depressive disorder in Scotland.
Journal of Affective Disorders 120:94
104, 2010
62. Nuijten MJ: Assessment of clinical guide-
lines for continuation treatment in major
depression. Value in Health 4:281294,
2001
63. Sava FA, Yates BT, Lupu V, et al: Cost-
effectiveness and cost-utility of cognitive
therapy, rational emotive behavioral ther-
apy, and fluoxetine (Prozac) in treating
depression: a randomized clinical trial.
Journal of Clinical Psychology 65:3652,
2009
64. Corey-Lisle PK, Birnbaum HG, Green-
berg PE, et al: Identification of a claims
data signatureand economic conse-
quences for treatment-resistant depres-
sion. Journal of Clinical Psychiatry 63:
717726, 2002
65. Olchanski N, McInnis Myers M, Halseth
M, et al: The economic burden of treatment-
resistant depression. Clinical Therapeutics
35:512522, 2013
66. Cancer Facts and Figures 2011. Atlanta,
Ga, American Cancer Society, 2011
67. American Diabetes Association: Economic
costs of diabetes in the US in 2007. Di-
abetes Care 31:596615, 2008
68. Gillum LA, Gouveia C, Dorsey ER, et al:
NIH disease funding levels and burden of
disease. PLoS ONE 6:e16837, 2011
69. Pukrop R, Schlaak V, Möller-Leimkühler
AM, et al: Reliability and validity of quality
of life assessed by the Short-Form 36 and
the Modular System for Quality of Life in
patients with schizophrenia and patients
with depression. Psychiatry Research 119:
6379, 2003
70. Birmaher B, Ryan ND, Williamson DE,
et al: Childhood and adolescent de-
pression: a review of the past 10 years: part
I. Journal of the American Academy of Child
and Adolescent Psychiatry 35:14271439,
1996
71. Vanheusden K, Mulder CL, van der Ende
J, et al: Young adults face major barriers to
seeking help from mental health services.
Patient Education and Counseling 73:
97104, 2008
72. Fleury MJ, Grenier G, Bamvita JM, et al:
Comprehensive determinants of health
service utilisation for mental health reasons
in a Canadian catchment area. Inter-
national Journal for Equity in Health 11:
20, 2012
73. Brent DA, Emslie GJ, Clarke GN, et al:
Predictors of spontaneous and systemat-
ically assessed suicidal adverse events
in the treatment of SSRI-resistant de-
pression in adolescents (TORDIA) study.
American Journal of Psychiatry 166:
418426, 2009
74. Wilke RA, Dolan ME: Genetics and vari-
able drug response. JAMA 306:306307,
2011
10 PSYCHIATRIC SERVICES IN ADVANCE
75. Winner J, Allen JD, Altar CA, et al: Psy-
chiatric pharmacogenomics predicts health
resource utilization of outpatients with anx-
iety and depression. Translational Psychiatry
3:e242, 2013
76. Hall-Flavin DK, Winner JG, Allen JD,
et al: Using a pharmacogenomic algorithm
to guide the treatment of depression.
Translational Psychiatry 2:e172, 2012
77. Hall-Flavin DK, Winner JG, Allen JD,
et al: Utility of integrated pharmacoge-
nomic testing to support the treatment of
major depressive disorder in a psychiatric
outpatient setting. Pharmacogenetics and
Genomics 23:535548, 2013
78. Altar CA, Hornberger J, Shewade A, et al:
Clinical validity of cytochrome P450 me-
tabolism and serotonin gene variants in
psychiatric pharmacotherapy. International
Review of Psychiatry 25:509533, 2013
79. Mrazek DA, Lerman C: Facilitating clinical
implementation of pharmacogenomics.
JAMA 306:304305, 2011
80. Simon GE, Perlis RH: Personalized medi-
cine for depression: can we match patients
with treatments? American Journal of
Psychiatry 167:14451455, 2010
81. Alegría M, Chatterji P, Wells K, et al:
Disparity in depression treatment among
racial and ethnic minority populations in
the United States. Psychiatric Services 59:
12641272, 2008
82. Berry JG, Bloom S, Foley S, et al: Health
inequity in children and youth with chronic
health conditions. Pediatrics 126(suppl 3):
S111S119, 2010
83. Williams DR, González HM, Neighbors H,
et al: Prevalence and distribution of major
depressive disorder in African Americans,
Caribbean blacks, and non-Hispanic whites:
results from the National Survey of American
Life. Archives of General Psychiatry 64:
305315, 2007
84. Surault P: Mental health and social deter-
minants [in French]. LEncéphale 36(suppl):
2732, 2010
PSYCHIATRIC SERVICES IN ADVANCE 11
... РД связана с повышенным риском СП vs. поддающимся лечению ДР (нДР) [15,17]. Треть пациентов с РД совершают ≥ 1 попытки в течение жизни [18], вдвое чаще, чем при нДР при контроле тяжести депрессии и психиатрической коморбидности. Суициды. ...
... TRD is associated with an increased risk of SB compared to treatable DD (tDD) [15,17]. One third of patients with TRD make ≥ 1 attempt during their lifetime [18], twice as often as with tDD when controlling for depression severity and psychiatric comorbidity. Suicides. ...
... Пациенты с РД перенесли 4±2 эпизодов продолжительностью 4±3 года, завершив 5±3 безуспешных курсов ≥ 2-х классов АД [18]. На участках ПНД (определяющего тяжесть выборки) у ≥ 60% больных ДР [25] и РД [12] дисгармоничные (апато -адинамические, астенические) состояния. ...
Article
Full-text available
Treatment-resistant depression (TRD) is associated with a higher risk of suicidal behavior (SB) than in depressive disorder prone to treatment, and SB should be considered as its separate outcome. Risk factors for SB in TRD are similar to those in the general population and serve as risk factors and/or contribute to the socioeconomic burden of TRD. Keywords: treatment-resistant depression, suicidal behavior, prevalence, risk factors, burden
... Depression is one of the leading causes of the global burden of disease [1] and a major risk factor for suicide deaths [2][3][4]. Aside from its long-term impact on the functioning and quality of life of affected individuals and their families and peers [5,6], the longitudinal course of depression also inflicts considerable burdens on the healthcare system and economy, particularly if untreated or not fully treated [7][8][9]. The importance of timely intervention targeting those with subclinical depressive symptoms in the community is critical [10]. ...
... The implementation of JoyAge has expanded from four districts in 2016-2019 (Phase I) to all 18 districts in 2020-2023 (Phase II), involving 47 district-based elderly community centres and community-based mental wellness centres. All local residents aged 60 years and above, with mild-to-moderate levels of depressive symptoms (PHQ-9 score of [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], and with no known history of schizophrenia spectrum disorder, bipolar disorder, autism spectrum disorder, intellectual disability, Parkinson's disease, or major neurocognitive disorders were eligible. Those with significant suicidal risk (determined using items concerning any present suicidal thoughts, plan, or attempt, respectively, item nine of the PHQ-9 concerning self-harm and suicidal thoughts, as well as via clinical assessment) were excluded and referred to local hospital psychiatric services or provided with additional support following standard risk management protocols. ...
Article
Full-text available
Background Depression is among the leading causes of the global burden of disease and is associated with substantial morbidity in old age. The importance of providing timely intervention, particularly those with subclinical symptoms, has thus increasingly been emphasised. Despite their overall effectiveness, a small but notable subgroup tends to be less responsive to interventions. Identifying predictors of non-remission and non-response is critical to inform future strategies for optimising intervention outcomes. Methods A total of 4153 older adults aged 60 years and above with subclinical depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] = 5–19) were recruited from JC JoyAge, a large-scale collaborative stepped-care intervention service across Hong Kong. A wide range of clinical and modifiable risk and protective factors at baseline were assessed, including depressive symptoms, anxiety symptoms, loneliness, suicidal ideation, cognitive capacity, multimorbidity, chronic pain, need for informal care due to mental health reasons, history of abuse, and sociodemographic characteristics. Separate multivariable logistic regression models were applied to identify predictors of non-remission (PHQ-9 ≥ 5) and non-response (< 50% reduction in PHQ-9) following intervention. Results The rates of non-remission and non-response were 18.9% (n = 784) and 23.0% (n = 956), respectively. Comorbid anxiety symptoms (adjusted odds ratio [aOR] = 2.08, CI = 1.72–2.51; 1.28, 1.05–1.57), loneliness (2.00, 1.66–2.42; 1.67, 1.38–2.01), need for informal care (1.86, 1.49–2.33; 1.48, 1.18–1.85), lower cognitive capacity (0.95, 0.93–0.97; 0.94, 0.92–0.96), and absence of chronic pain (0.59, 0.48–0.72; 0.76, 0.64–0.91) predicted both non-remission and non-response. Meanwhile, moderate-to-severe depressive symptoms predicted higher odds of non-remission (1.41, 1.18–1.69) and lower odds of non-response (0.28, 0.23–0.34), respectively. Subgroup analyses conducted separately in older adults with mild and moderate-to-severe depressive symptoms at baseline revealed that comorbid anxiety, loneliness, need for informal care, and absence of chronic pain were consistent predictors of non-remission. Those with non-remission and non-response showed more depression-related functional impairments and poorer health-related quality of life post-intervention. Conclusions Older adults with subclinical depressive symptoms showing comorbid anxiety, higher loneliness, need for informal care, and chronic pain may be offered more targeted interventions in future services. A personalised risk-stratification approach may be helpful. Trial registration ClinicalTrials.gov identifiers: NCT03593889 (registered 29 May 2018), NCT04863300 (registered 23 April 2021).
... Despite significant advancements in treatment options, a substantial proportion of patients do not respond to conventional therapy, leading to a condition known as treatment-resistant depression (TRD). TRD not only exacerbates the suffering of individuals but also imposes a significant economic and social burden (Li et al., 2020;Mrazek et al., 2014). ...
Article
Full-text available
Treatment-resistant depression (TRD) represents a significant challenge in psychiatric care, affecting a substantial portion of patients who do not respond to conventional treatment modalities. This qualitative study aims to explore the lived experiences of individuals diagnosed with TRD to better understand the personal, social, and systemic factors that contribute to treatment resistance and identify potential avenues for more effective interventions. The study utilized a qualitative design, conducting semi-structured interviews with 33 participants diagnosed with TRD. Data collection continued until theoretical saturation was achieved. Interviews were transcribed and analyzed using NVivo software to facilitate thematic analysis and ensure comprehensive data exploration and theme identification. Four main themes were identified: Personal Experiences with Depression, Interactions with the Healthcare System, Treatment Efficacy and Options, and Psychological and Social Insights. These themes encompassed subthemes such as emotional impact, coping mechanisms, quality of care, medication efficacy, alternative treatments, stigma, and the role of support networks. Each category provided deep insights into the challenges faced by individuals with TRD and the factors influencing their treatment outcomes. The study highlights the complex nature of TRD and underscores the need for a more personalized, empathetic approach in treating this condition. Insights gained suggest that enhancing patient-provider communication, increasing access to alternative treatment options, and addressing societal stigma could improve treatment outcomes for individuals with TRD.
... Our patient had recurrent depressive disorder with poor outcomes despite conventional empirical treatment. A 2012 review study showed that patients who failed to respond adequately to antidepressant medications had healthcare-related expenditures that were approximately $10,000 more per year than those who responded effectively [14]. Although metabolic phenotype is an important factor in guiding antidepressant selection, patient response to antidepressants is not entirely dependent on metabolic rate. ...
Article
Full-text available
Background Few new psychiatric drugs have entered the market in recent decades; in contrast, the number of drugs carrying pharmacogenomic labels continues to increase. For the foreseeable future, the advancement of psychiatry and drug therapy may hinge on personalized treatment. Currently, antipsychotic or antidepressant choices rely heavily on the clinical experience of psychiatrists and potentially lengthy iterative trials. During these trials, the clinical response to treatment in acutely depressed patients can be assessed only after several weeks of exposure to the drug. Although pharmacogenomic testing has been used in clinical care for several years, most Chinese clinicians struggle to utilize the information accurately, resulting in expensive tests that provide little real benefit to patients. Here, we demonstrate how to combine the results of pharmacogenomic testing to develop an individualized treatment plan. Our goal is to find the optimal medication regimen and dosage for the patient in the shortest possible time, control symptoms as soon as possible, and predict adverse drug reactions. This approach aims to offer a practical therapeutic idea for clinical practice. Case presentation We present the case of a 27-year-old female patient experiencing a relapse of depression. Despite previous attempts with empiric medication, her symptoms remained uncontrolled, leading to exacerbation and drug withdrawal reactions. Utilizing the results of pharmacogenetic testing, we crafted an individualized treatment plan, resulting in rapid remission without any adverse drug reactions. Conclusion Recognizing the complexity of antidepressant response, our patients aim to improve their understanding, as well as that of other healthcare providers, by undergoing pharmacogenomics testing. This enhances the credibility of their medication choices. While pharmacogenomics is just one aspect considered in selecting a treatment regimen for depression, it remains a valuable tool for increasing credibility and mitigating potential adverse events.
... A recent reanalysis of the STAR*D trial indicates a cumulative remission rate of 35.0% after up to four antidepressant treatment trials [4]. Treatmentresistant depression is associated with more somatic comorbidity, substance abuse, and excess mortality, including death by suicide [5,6]. Given the high individual and societal disease burden, there is a strong incentive to identify alternative or augmentative treatments. ...
Article
Full-text available
Introduction: Major depressive disorder (MDD) significantly impacts millions worldwide, with limited success in achieving remission for many patients, leading to high disease burden and increased suicide risk. Psychotherapy and antidepressants, although effective, do not provide relief for all, prompting the search for alternative treatments. Ketogenic diets have demonstrated positive effects on brain health. Our study aims to investigate the efficacy of the ketogenic diet in alleviating MDD symptoms, filling a critical gap in psychiatric treatment options and offering a novel dietary approach with potential to mitigate disease burden and enhance mental well-being. Methods: This phase 2 randomized controlled trial will evaluate the efficacy of a 10-week program of dietitian counseling and ketogenic meal provision versus an intervention with similar dietetic contact promoting a healthy, insulin-lowering, non-ketogenic diet. The primary outcome is the change in the Patient Health Questionnaire nine-item depression score. Secondary outcomes include cognitive and affective mindfulness, self-efficacy, sleep, cognitive function, work and social adjustment, and various immunological, metabolic, and microbiome markers at weeks 6 and 10. Conclusion: This study addresses a critical gap in depression treatment by exploring the ketogenic diet’s potential as a metabolic mood enhancing intervention. Given the global impact of depression and limitations of current therapies, this research is valuable for exploring previously underappreciated neuroprotective and metabolic mechanisms and clinical benefits.
... It has been estimated that ADRs occur in over 25% of patients taking antidepressants (Mishra et al., 2013). Consequently, difficulties inherent in prescribing antidepressants often result in longer duration of symptoms, more side effects and increased healthcare costs (Mrazek et al., 2014). ...
Article
Full-text available
Introduction Pharmacogenetics (PGx) holds promise for optimizing psychotropic medication use, with CYP2D6 and CYP2C19 identified as key genes in antidepressant treatment. However, few studies have explored the genetic variants of these genes in real-world settings for patients experiencing ineffectiveness or adverse drug reactions (ADRs) to antidepressants. Methods This case series includes 40 patients who underwent PGx testing due to antidepressant ineffectiveness or ADRs between June 2020 and April 2022. We describe the patients' demographic, clinical, and genetic characteristics and assess the value of PGx testing based on feedback from their psychiatrists. Results The most common diagnoses were major depressive disorder (60.0%) and post-traumatic stress disorder (30.0%). Ineffectiveness was reported in 65.0% of patients, ADRs in 2.5%, and both in 32.5%. The antidepressants involved included SSRIs (45.0%), SNRIs (27.5%), atypical antidepressants (20.0%), and tricyclics (17.5%). Only 17.5% of patients had normal CYP2D6 and CYP2C19 metabolic activity. Actionable genetic variants were identified in 22.0% of CYP2D6/CYP2C19-antidepressant-response pairs. PGx recommendations were followed in 92.7% of cases, with significant improvement in ADRs reported in 71.4% of patients and efficacy improvement in 79.5%. Discussion Our findings suggest that PGx testing can guide prescribing decisions for patients with antidepressant ineffectiveness or ADRs. The relatively high prevalence of genetic variants affecting pharmacokinetics supports the broader adoption of PGx testing in psychiatric practice.
Article
A BSTRACT Background Depression is a common illness that affects about 3.8% of the population worldwide. Patients with major depression respond to antidepressant treatment, but 10%–20% of them do not improve or show a partial response. It is coupled with functional impairment, poor quality of life, suicide ideation and attempts, self-injurious behavior, and a high relapse rate. Treatment-resistant depression (TRD) is a challenge to clinicians because of its increased loss of functionality and the increased rate of suicide among people diagnosed with the illness. Studies are evolving to combine various treatment options to reduce morbidity and mortality in people suffering from the illness. This study aims at comparing the efficacy of electroconvulsive therapy (ECT) and ketamine transfusion in treating TRD. It hopes to prove that ketamine provides rapid relief for people suffering from TRD. Materials and Methods A prospective, parallel randomized controlled, open label, noninferiority/superiority trial to compare the efficacy of ECT and ketamine was done. Ninety-six persons suffering from TRD were selected for the study through proportionate stratified random sampling and 46 persons received 6 ECT treatment and 50 persons received six doses of ketamine. Treatment response was measured using Hamilton depression ratings scale (HAM-D) using baseline, mid assessment, and postassessment scores. The scores were used to determine the effectiveness of ECT and ketamine in the treatment of TRD. Results Ketamine was proven to have the same antidepressant effect in participants as that of ECT. Ketamine was observed to have rapid reduction in depressive symptoms when compared to ECT. Conclusion This study highlights that ketamine can be considered as an effective alternative to ECT in those with TRD.
Article
Full-text available
In the present work, we performed a computational study on hydroxamic acid containing compounds as acid sphingomyelinase (ASM) inhibitors. The study starts from the development of 3D‐QSAR and pharmacophore models, which were further taken as a source for the enumeration and virtual screening study. The 3D‐QSAR results showed the best statistical model with Q², R², and R² scrambling values of 0.7175, 0.9019, and 0.7128, respectively. The pharmacophore hypothesis generated one of the best hypotheses including five features such as 2 aromatic rings, 2 hydrogen bond donors, and 1 hydrogen bond acceptor. The enumeration study paved the path in the discovery of novel compounds where pharmacophore hypothesis and 3D QSAR study data was used for the identification of novel compounds. Compound 9f_20 showed good docking score −11.399 and binding interactions with amino acids HIP317, ASN316, GLH386, Zn701, Zn702, HIP317, and HIP280 required for ASM inhibitory activity. The virtual screening study was performed on the basis of developed pharmacophore ADDRR_1 where ZINC000013941849 showed good binding interactions with receptor including amino acids Zn701, Zn702, HIP280, LYS103, HIP317, ASN316, and ILE487. ZINC000013941849 with docking score −13.101. The screened compounds may be taken for the further development of novel antidepressant agents.
Article
Full-text available
Abstract Adverse events, response failures and medication non-compliance are common in patients receiving medications for the treatment of mental illnesses. A systematic literature review assessed whether pharmacokinetic (PK) or pharmacodynamic (PD) responses to 26 commonly prescribed antipsychotic and antidepressant medications, including efficacy or side effects, are associated with nucleotide polymorphisms in eight commonly studied genes in psychiatric pharmacotherapy: CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, HTR2C, HTR2A, and SLC6A4. Of the 294 publications included in this review, 168 (57%) showed significant associations between gene variants and PK or PD outcomes. Other studies that showed no association often had insufficient control for confounding variables, such as co-medication use, or analysis of medications not substrates of the target gene. The strongest gene-outcome associations were for the PK profiles of CYP2C19 and CYP2D6 (93% and 90%, respectively), for the PD associations between HTR2C and weight gain (57%), and for SLC6A4 and clinical response (54%), with stronger SLC6A4 response associations for specific drug classes (60-83%). The preponderance of evidence supports the validity of analyzing nucleotide polymorphisms in CYP and pharmacodynamic genes to predict the metabolism, safety, or therapeutic efficacy of psychotropic medications commonly used for the treatment of depression, schizophrenia, and bipolar illness.
Article
Full-text available
The objective was to evaluate the potential benefit of an integrated, five-gene pharmacogenomic test and interpretive report (GeneSight) for the management of psychotropic medications used to treat major depression in an outpatient psychiatric practice. The open-label study was divided into two groups. In the first (unguided) group (n=113), pharmacogenomic information was not shared until all participants completed the study. In the second (guided) group (n=114), the pharmacogenomic report was provided to physicians for clinical use. Three depression ratings, the 17-item Hamilton Rating Scale for Depression (HAMD-17), the Quick Inventory of Depressive Symptomatology - Clinician Rated (QIDS-C16), and the Patient Health Questionnaire (PHQ-9), were collected at baseline, and at 2, 4, and 8 weeks. The guided group experienced greater percent improvement in depression scores from baseline on all three depression instruments (HAMD-17, P<0.0001; QIDS-C16, P<0.0001; PHQ-9, P<0.0001) compared with the unguided group. Eight-week response rates were higher in the guided group than in the unguided group on all three measurements (HAMD-17, P=0.03; QIDS-C16, P=0.005; PHQ-9, P=0.01). Eight-week QIDS-C16 remission rates were higher in the guided group (P=0.03). Participants in the unguided group who at baseline were prescribed a medication that was most discordant with their genotype experienced the least improvement compared with other unguided participants (HAMD-17, P=0.007). Participants in the guided group and on a baseline medication most discordant with their genotype showed the greatest improvement compared with the unguided cohort participants (HAMD-17, P=0.01). These findings replicate previous studies and demonstrate significantly improved depression outcomes with use of GeneSight, an integrated, multigenetic pharmacogenomic testing platform.
Article
Objective: Few controlled studies have addressed the issue of which antidepressant medications should be recommended for outpatients who have not responded to multiple treatment trials. This study compared the efficacy of switching to mirtazapine to that of switching to a tricyclic antidepressant (nortriptyline) following two prospective, consecutive, unsuccessful medication treatments for non-psychotic major depressive disorder. Method: Following lack of remission or an inability to tolerate an initial trial of citalopram for up to 12 weeks (first step) and a second trial with either monotherapy involving another antidepressant or augmentation of citalopram with bupropion or buspirone (second step), adult outpatients (N=235) with nonpsychotic major depressive disorder were randomly assigned to 14 weeks of treatment with mirtazapine (up to 60 mg/day) (N=114) or nortriptyline (up to 200 mg/day) (N=121). The primary outcome, symptom remission, was defined a priori as a total exit score of ≤7 on the 17-item Hamilton Rating Scale for Depression. The 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16), obtained at treatment visits, provided secondary outcomes of remission (score ≤5 at exit) and response (≥50% reduction in score from baseline). Results: For mirtazapine, remission rates were 12.3% and 8.0% per the Hamilton and QIDS-SR16 scores, respectively. For nortriptyline, remission rates were 19.8% and 12.4%, respectively. QIDS-SR16 response rates were 13.4% for mirtazapine and 16.5% for nortriptyline. Neither response nor remission rates statistically differed by treatment, nor did these two treatments differ in tolerability or adverse events. Conclusions: Switching to a third antidepressant monotherapy regimen after two consecutive unsuccessful antidepressant trials resulted in low remission rates (<20%) among patients with major depressive disorder.
Article
Errors in Byline, Author Affiliations, and Acknowledgment. In the Original Article titled “Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in the National Comorbidity Survey Replication,” published in the June issue of the ARCHIVES (2005;62:617-627), an author’s name was inadvertently omitted from the byline on page 617. The byline should have appeared as follows: “Ronald C. Kessler, PhD; Wai Tat Chiu, AM; Olga Demler, MA, MS; Kathleen R. Merikangas, PhD; Ellen E. Walters, MS.” Also on that page, the affiliations paragraph should have appeared as follows: Department of Health Care Policy, Harvard Medical School, Boston, Mass (Drs Kessler, Chiu, Demler, and Walters); Section on Developmental Genetic Epidemiology, National Institute of Mental Health, Bethesda, Md (Dr Merikangas). On page 626, the acknowledgment paragraph should have appeared as follows: We thank Jerry Garcia, BA, Sara Belopavlovich, BA, Eric Bourke, BA, and Todd Strauss, MAT, for assistance with manuscript preparation and the staff of the WMH Data Collection and Data Analysis Coordination Centres for assistance with instrumentation, fieldwork, and consultation on the data analysis. We appreciate the helpful comments of William Eaton, PhD, Michael Von Korff, ScD, and Hans-Ulrich Wittchen, PhD, on earlier manuscripts. Online versions of this article on the Archives of General Psychiatry Web site were corrected on June 10, 2005.
Article
Background: Major depressive disorder has high prevalence, morbidity, and mortality. Inadequate results with antidepressants have prompts addition of a nonstandard treatment (augmentation therapy). Objective: To assess whether augmentation therapy with risperidone reduces symptoms and increases response to antidepressant therapy and remission of depression in adults. Design: Multicenter, double-blind, placebo-controlled, randomized trial conducted from 19 October 2004 to 17 November 2005. Setting: 75 primary care and psychiatric centers. Patients: 274 outpatient adults with major depressive disorder that was suboptimally responsive to antidepressant therapy. Intervention: After a 4-week run-in period to ensure insufficient response to standard antidepressants, patients were randomly assigned to receive risperidone, 1 mg/d, or placebo for 6 weeks. After 4 weeks, the dosage of risperidone was increased to 2 mg/d in some cases. Measurements: Symptoms were measured by using the 17-item Hamilton Rating Scale for Depression (HRSD-17). Other outcomes were response to therapy, remission of depression, and various clinician- and patient-rated assessments. Results: Of the intention-to-treat population (268 patients), 81 % (111 of 137) who received risperidone and 87.8% (115 of 131) who received placebo completed 6 weeks of double-blind treatment. Mean (±SE) HRSD-17 scores improved more in the risperidone augmentation group than in the placebo group (13.4 ± 0.54 vs. 16.2 ± 0.53; difference, -2.8 ± 0.72 [95% Cl, -4.2 to -1.4]; P <0.001). More risperidone recipients than placebo recipients experienced remission of depression (24.5% [26 of 106] vs. 10.7% [12 of 112]; P = 0.004) and had a response (46.2% [49 of 106] vs. 29.5% [33 of 112]; P = 0.004). Headache (8.8% of risperidone recipients vs. 14.5% of placebo recipients), somnolence (5.1% vs. 1.5%), and dry mouth (5.1% vs. 0.8%) were the most frequently reported adverse events. Limitations: Patients were receiving many different antidepressants, and the duration of augmentation therapy was limited. Conclusion: Risperidone augmentation produced a statistically significant mean reduction in depression symptoms, substantially increased remission and response, and improved other patient- and clinician-rated measures.
Article
IntroductionSocial disparities in health is becoming a topic of major importance. Recent studies presents data on social differences in morbidity on various diseases. This paper shows how mental health disorders prevalences are strongly linked to sociological variables. It is based on the data of the research-action entitled « Mental Health in General Population: images and realities (MHGP) » carried out by the World Health Organisation Collaborative Centre (Lille, France) and the Direction of research, studies, assessment and statistics (Drees) of the French Ministry of Health, in a sample of 36 000 French subjects over 18 years old, between 1999 and 2003.
Article
Background: Fenfluramine (d-FEN) has been used as a serotonin challenge agent to assess central serotonin availability. Blunted serum prolactin (PRL) response to d-FEN has been reported in depressed patients, in suicide-prone patients, and in patients with aggression and personality disorders. We have analyzed suicidality in relation to central serotonergic events by comparing the PRL response to d-FEN in chronically depressed patients with and without suicide attempts and in healthy volunteers. Methods: In 56 inpatients (10 patients with and 46 without suicide attempts) with at least 2 years of treatment-refractory depression (TRD) (DSM-IV) and a reference group of 30 healthy adults, the PRL response after an oral dose of 30 mg d-FEN was followed for 5 h. Results: Controlling for group differences in age, sex, and weight, the PRL response to d-FEN did not differ significantly between the three groups. Far from confirming the hypothesis of a blunted PRL response in depressed patients, our results suggest: (1) that duration and treatment resistance of depression may affect the PRL secretion, and (2) that TRD and major depression may differ in biological relationship to suicidal behavior. Limitations: The findings require corroboration in larger and more closely matched study populations. The fenfluramine concentration was not analyzed in blood. Conclusions: PRL responses to d-FEN challenge did not differ between TRD patients with and without suicidality and the healthy reference group. Chronicity/treatment refractoriness per se may be related to a serotonergic mechanism.