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The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study evaluated feasible treatment strategies to improve clinical outcomes for real-world patients with treatment-resistant depression. Although the study found no clear-cut "winner", it does provide guidance on how to start therapy and how to proceed if initial treatment fails.
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Associate Professor of Psychiatry, University of
North Carolina School of Medicine; Investigator,
Sequenced Treatment Alternatives to Relieve
Depression (STAR*D) study
University of Texas Southwestern Medical Center
at Dallas; Professor of Clinical Sciences and
Psychiatry; Principal Investigator, STAR*D study
The STAR*D study:
Treating depression in the real world
The Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) study evaluated feasible treatment strategies to
improve clinical outcomes for real-world patients with
treatment-resistant depression. Although the study found
no clear-cut “winner, it does provide guidance on how to
start therapy and how to proceed if initial treatment fails.
Remission (ie, complete relief from a depressive episode)
rather than response (merely substantial improvement)
should be the goal of treatment, as it is associated with
a better prognosis and better function.
Should the first treatment fail, either switching treatment
or augmenting the current treatment is reasonable.
For most patients, remission will require repeated trials of
sufficiently sustained, vigorously dosed antidepressant
medication. Physicians should give maximal but tolerable
doses for at least 8 weeks before deciding that an
intervention has failed.
After two well-delivered medication trials, the likelihood
of remission substantially decreases. Such patients likely
require more complicated regimens. Given the thin
existing database, these patients are best referred to
a psychiatrist for more complex treatments.
With persistent and vigorous treatment, most patients will
enter remission: about 33% after one step, 50% after two
steps, 60% after three steps, and 70% after four steps
(assuming patients stay in treatment).
can be treated successfully by
primary care physicians under “real-
world” conditions.
Furthermore, the particular drug or drugs
used are not as important as following a rational
plan: giving antidepressant medications in ade-
quate doses, monitoring the patient’s symptoms
and side effects and adjusting the regimen
accordingly, and switching drugs or adding new
drugs to the regimen only after an adequate trial.
These are among the lessons learned from
the Sequenced Treatment Alternatives to
Relieve Depression (STAR*D) study, the
largest prospective clinical trial of treatment
of major depressive disorder ever conducted. It
was funded by the National Institutes of
Health and directed by A. John Rush, MD.
Depression, a common and debilitating condi-
tion, affects approximately one in eight people
in the United States.
It is expected
to be the
second-leading cause of disability in the world
by the year 2020; today, it is the second-lead-
ing cause of disability-adjusted life years in
those 15 to 44 years old.
Nevertheless, the available evidence base
for treatment is limited, since most partici-
pants in clinical trials are recruited by adver-
tisement rather than from representative prac-
tices, and they are often selected to have few
University of Pittsburgh School of Medicine;
Associate Professor of Epidemiology; Data
Coordinating Center, STAR*D study
University of North Carolina School of Medicine;
Professor of Family Medicine; Investigator,
STAR*D study
Massachusetts General Hospital, Boston;
Professor of Psychiatry; Investigator, STAR*D
University of Texas Southwestern Medical Center
at Dallas; Professor of Psychiatry; National
Coordinating Center, STAR*D study
The authors’ disclosures of potential conflicts of interest are listed at the
end of this paper.
This project was funded by the National Institute of Mental Health,
National Institutes of Health, under Contract N01MH90003 to UT
Southwestern Medical Center at Dallas (Principal Investigator A.J. Rush).
The content of this publication does not necessarily reflect the views or
policies of the Department of Health and Human Services, nor does
mention of trade names, commercial products, or organizations imply
endorsement by the US Government.
comorbid disorders, either medical or psychi-
atric. In addition, those with chronic depres-
sion or current suicidal ideation are exclud-
These uncomplicated and “pristine” par-
ticipants are unlike typical patients seen by
primary care physicians or psychiatrists.
Similarly, the protocols used in these tri-
als do not represent usual clinic practice.
Patients in clinical trials undergo more assess-
ment and more frequent follow-up than in
real-world practice, they have no say in treat-
ment decisions, the doses are fixed, and the
patients and physicians are blinded to the
intervention. Consequently, how to translate
the results of these efficacy trials into practice
is unclear.
Further, even in relatively uncomplicated
cases, only about one-half of outpatients with
nonpsychotic major depressive disorder ini-
tially treated with a single medication or with
psychotherapy will experience a clinically sig-
nificant improvement in symptoms (ie, a
response) during the 8 to 12 weeks of acute-
phase treatment,
and only 20% to 35% of
patients will reach remission,
the aim of
The remission rates are even
lower in treatment-resistant depression.
How to manage most patients—those whose
depression does not remit with the first, sec-
ond, or third step of treatment—is unclear.
Accordingly, the overall objective of
STAR*D was to develop and evaluate feasible
treatment strategies to improve clinical out-
comes for real-world patients with treatment-
resistant depression, who were identified
prospectively from a pool of patients in a cur-
rent major depressive episode.
ally, STAR*D aimed to determine prospec-
tively which of several treatments is the most
effective “next step” for patients who do not
reach remission with an initial or subsequent
treatment or who cannot tolerate the treat-
Nearly 10% of all primary care office visits are
Primary care physicians
provide nearly half the outpatient care for
depressed patients.
Indeed, primary care
physicians log approximately as many outpa-
tient visits for depression as psychiatrists do.
Medical comorbidity is especially common in
primary care settings.
When to refer to a
psychiatrist is not clear.
STAR*D involved a national consortium of
14 university-based regional centers, which
oversaw a total of 23 participating psychiatric
and 18 primary care clinics. Enrollment began
in 2000, with follow-up completed in 2004.
Entry criteria were broad and inclusive
Patients had to:
Be between 18 and 75 years of age
Have a nonpsychotic major depressive
disorder, identified by a clinician and con-
firmed with a symptom checklist based on
the Diagnostic and Statistical Manual,
fourth edition revised,
and for which
antidepressant treatment is recommended
Score at least 14 on the 17-item Hamilton
Rating Scale for Depression (HAM-
Not have a primary diagnosis of bipolar
disorder, obsessive-compulsive disorder, or
an eating disorder, which would require a
different treatment strategy, or a seizure
disorder (which would preclude bupropi-
on as a second-step treatment).
Dosing recommendations were flexible
but vigorous
Medications often were increased to maximal-
ly tolerated doses. For example, citalopram
(Celexa) was started at 20 mg/day and
increased by 20 mg every 2 to 4 weeks if the
patient was tolerating it but had not achieved
remission, to a maximum dose of 60 mg/day.
Treatment could be given for up to 14 weeks,
during which side effects
and clinical rat-
were assessed by both patients and study
Measurement-based care
We used a systematic approach to treatment
called “measurement-based care,”
involves routinely measuring symptoms
side effects
and using this information to
modify the medication doses at critical deci-
sion points. This algorithmic approach pro-
Primary care
physicians log
as many
visits for
depression as
psychiatrists do
vided flexible treatment recommendations to
ensure that the dosage and duration of antide-
pressant drug treatment were adequate.
The severity of depression was assessed by
the clinician-rated, 16-item Quick Inventory
of Depressive Symptomatology (QIDS-C16).
The QIDS-SR16 (the self-report version) can
substitute for the QIDS-C16
to make this
approach more feasible. Both tools are avail-
able at
This approach was easily worked into busy
primary care and specialty care office work-
flows (clinic physicians, most with limited
research experience, provided the treatment),
and could be translated into primary care
practice in the community as well.
Four-step protocol
The protocol had four treatment levels, each
lasting up to 14 weeks (
FIGURE 1). All patients
started at level 1; if they had not entered
remission by 14 weeks, they moved up to the
next level; if they had achieved remission,
they stayed at the same level and were fol-
lowed for up to 1 year.
A unique feature of the study design was
that the patients, in consultation with their
physicians, had some choice in the treatments
based care can
easily be used
in clinical
STAR*D algorithm: Treatment levels
Level 1 Citalopram (Celexa)
Level 2 Patients could choose one of the following:
(stop citalopram, be randomized (keep citalopram, be randomized
to receive one of the following) to also receive one of the following)
Bupropion sustained-release (Wellbutrin SR) Bupropion sustained-release
Venlafaxine extended-release (Effexor XR) Buspirone (BuSpar)
Sertaline (Zoloft) Cognitive therapy
Cognitive therapy
Level 2a SWITCH
(only for those (stop cognitive therapy, be randomized
receiving cognitive to receive one of the following)
therapy in level 2) Bupropion sustained-release or
Venlafaxine extended-release
Level 3 Patients could choose one of the following
(stop current therapy, (keep current therapy,
be randomized to receive be randomized to also receive
one of the following) one of the following)
Mirtazapine (Remeron) Lithium
Nortriptyline (Pamelor) T3 thyroid hormone (Cytomel)
Level 4 SWITCH
(stop current therapy, be randomized to receive one of the following)
Tranylcypromine (Parnate)
Mirtazapine plus venlafaxine extended-release
Patients could refuse cognitive therapy as a randomization option. All treatments were unblinded. Patients advanced to succes-
sively higher treatment levels if they failed to achieve remission with their current regimen.
they received. In this “equipoise-stratified ran-
domized design,”
at levels 2 and 3 the
patient could choose either to switch thera-
pies (stop the current drug and be randomized
to receive one of several different treatments)
or to augment their current therapy (by
adding one of several treatments in a random-
ized fashion). Patients could decline certain
strategies as long as there were at least two
possible options to which one might be ran-
At level 2, one of the options for both
switching and augmentation was cognitive
therapy, although patients could decline that
option. Conversely, if they definitely wanted
cognitive therapy, they could choose to be
randomized to either cognitive therapy alone
or to cognitive therapy added to citalopram.
Also, anyone who received cognitive therapy
in level 2 and failed to enter remission was
additionally randomized to either bupropion
or venlafaxine (level 2a) to ensure that all
patients had failed trials on two medications
before entering level 3.
When switching to medications other than
a monoamine oxidase inhibitor (MAOI), the
clinician could choose either to stop the current
medication and immediately begin the next one,
or to decrease the current medication while
starting the new one at a low dose and then
tapering and titrating over 1 week. (Switching to
an MAOI, used only in the final level of treat-
ment, required a 7- to 10-day washout period.)
Outcomes measured
Remission (complete recovery from the
depressive episode), the primary study out-
come, was defined as a HAM-D17 score of 7
or less, as assessed by treatment-blinded raters.
A secondary remission outcome was a QIDS-
SR16 score of 5 or less. Of note, the HAM-
D17 remission rates were slightly lower than
the rates based on the QIDS-SR16, since
patients who did not have a HAM-D17 score
measured at exit were defined as not being in
remission a priori. Thus, the QIDS-SR16 rates
might have been a slightly better reflection of
actual remission rates.
Response, a secondary outcome, was
defined as a reduction of at least 50% in the
QIDS-SR16 score from baseline at the last
The patients seen in primary care clinics were
surprisingly similar to those seen in psychiatric
The two groups did not differ in
severity of depression, distribution of severity
scores, the likelihood of presenting with any of
the nine core criteria of a major depressive
episode, or the likelihood of having a con-
comitant axis I psychiatric disorder in addi-
tion to depression (about half of participants
in each setting had an anxiety disorder).
Recurrent major depressive disorders were
common in both groups, though more so in
psychiatric patients (78% vs 69%, P < .001),
while chronic depression was more common
in primary care than in psychiatric patients
(30% vs 21%, P < .001). Having either a
chronic index episode (ie, lasting > 2 years) or
a recurrent major depressive disorder was com-
mon in both groups (86% vs 83%, P = .0067).
That said, primary care patients were
older (44 years vs 39 years, P < .001), more of
them were Hispanic (18% vs 9%, P < .001),
and more of them had public insurance (23%
vs 9%, P < .001). Fewer of the primary care
patients had completed college (20% vs 28%,
P < .001), and the primary care patients tend-
ed to have greater medical comorbidity.
Psychiatric patients were more likely to have
attempted suicide in the past and to have had
their first depressive illness before age 18.
At level 1, all the patients received citalo-
pram. The mean dose was 40.6 ± 16.6 mg/day
in the primary care clinics and 42.5 ± 16.8
mg/day in the psychiatric clinics, which are
adequate, middle-range doses and higher than
the average US dose.
Approximately 30% of patients achieved
remission: 27% as measured on the HAM-
D17 and 33% on the QIDS-SR16. The
response rate (on the QIDS-SR16) was 47%.
There were no differences between primary
and psychiatric care settings in remission or
response rates.
Patients were more likely to achieve
remission if they were white, female,
The average
time needed to
remission was
almost 7 weeks
employed, more educated, or wealthier.
Longer current episodes, more concurrent psy-
chiatric disorders (especially anxiety disorders
or drug abuse), more general medical disor-
ders, and lower baseline function and quality
of life were each associated with lower remis-
sion rates.
What is an adequate trial?
Longer times than expected were needed to
reach response or remission. The average
duration required to achieve remission was
almost 7 weeks (44 days in primary care; 49
days in psychiatric care). Further, approxi-
mately one-third of those who ultimately
responded and half of those who entered
remission did so after 6 weeks.
Forty percent
of those who entered remission required 8 or
more weeks to do so.
These results suggest that longer treat-
ment durations and more vigorous medication
dosing than generally used are needed to
achieve optimal remission rates. It is impru-
dent to stop a treatment that the patient is
tolerating in a robust dose if the patient
reports only partial benefit by 6 weeks; indeed,
raising the dose, if tolerated, may help a sub-
stantial number of patients respond by 12 or
14 weeks. Instruments to monitor depression
severity (eg, self-report measures) can be use-
ful. At least 8 weeks with at least moderately
vigorous dosing is recommended.
When switching to a new drug,
does it matter which one?
In level 2, if patients had not achieved
remission on citalopram alone, they had the
choice of switching: stopping citalopram and
being randomized to receive either sertraline
(Zoloft, another SSRI), venlafaxine extend-
ed-release (XR) (Effexor XR, a serotonin and
norepinephrine reuptake inhibitor), or bupro-
pion sustained-release (SR) (Wellbutrin SR, a
norepinephrine and dopamine reuptake
inhibitor). At the last visit the mean daily
doses were bupropion SR 282.7 mg/day, ser-
traline 135.5 mg/day, and venlafaxine-XR
193.6 mg/day.
The remission rate was approximately
one-fourth with all three drugs
•With bupropion SR—21.3% by HAM-
D17, 25.5% by QIDS-SR16
•With sertraline—17.6% by HAM-D17,
26.6% by QIDS-SR16
•With venlafaxine-XR—24.8% by HAM-
D17, 25.0% by QIDS-SR16. The remis-
sion rates were neither statistically nor
clinically different by either measure.
Though the types of side effects related
to specific medications may have varied, the
overall side-effect burden and the rate of
serious adverse events did not differ signifi-
When adding a new drug,
does it matter which one?
Again, no.
Instead of switching, patients in level 2
could choose to stay on citalopram and be
randomized to add either bupropion SR or
buspirone (BuSpar) to the regimen (augmen-
tation). The mean daily doses at the end of
level 2 were bupropion SR 267.5 mg and bus-
pirone 40.9 mg.
Rates of remission
•With bupropion SR—29.7% on the
HAMD-D17, 39.0% on the QIDS-SR16
•With buspirone—30.1% on the HAM-
D17, 32.9% on the QIDS-SR16.
However, the QIDS-SR16 scores declined
significantly more with bupropion SR than
with buspirone (25.3% vs 17.1%, P < .04).
The mean total QIDS-SR16 score at the last
visit was lower with bupropion SR (8.0) than
with buspirone (9.1, P < .02), and augmenta-
tion with bupropion SR was better tolerated
(the dropout rate due to intolerance was
12.5% with bupropion-SR vs 20.6% with bu-
spirone 20.6%; P < .009).
Can we directly compare the benefits
of switching vs augmenting?
Patients could choose whether to switch
from citalopram to another drug or to add
another drug at the second treatment level.
Consequently, we could not ensure that the
patient groups were equivalent at the point of
randomization at the beginning of level 2,
and, indeed, they were not.
STAR*D cannot
tell us if adding
another drug is
better than
Those who benefitted more from citalo-
pram treatment and who better tolerated it
preferred augmentation, while those who ben-
efitted little or who could not tolerate it pre-
ferred to switch. Consequently, those in the
augmentation group at level 2 were somewhat
less depressed than those who switched.
Whether augmentation is better even if the
initial treatment is minimally effective could
not be evaluated in STAR*D.
What about cognitive therapy?
There was no difference between cognitive
therapy (either as a switch or as augmenta-
tion) and medication (as a switch or as aug-
Adding another drug was more
rapidly effective than adding cognitive thera-
py. Switching to cognitive therapy was better
tolerated than switching to a different antide-
Of note, fewer patients accepted cogni-
tive therapy as a randomization option than
we expected, so the sample sizes were small.
Possible reasons were that all patients had
to receive a medication at study entry
(which may have biased selection towards
those preferring medication), and cognitive
therapy entailed additional copayments and
visiting still another provider at another
After two levels of treatment,
how many patients reach remission?
About 30% of patients in level 1 achieved
remission, and of those progressing to level 2,
another 30% achieved remission. Together,
this adds up to about 50% of patients achiev-
ing remission if they remained in treatment
(30% in level 1 plus 30% of the roughly 70%
remaining in level 2).
If switching again to another drug,
does it matter which one?
In level 3, patients could choose to stop
the drug they had been taking and be ran-
domized to receive either mirtazapine
(Remeron) or nortriptyline (Pamelor).
Switching medications was not as effec-
tive as a third step as it was as a second step.
Remission rates:
•With mirtazapine—12.3% on the HAM-
D17, 8.0% on the QIDS-SR16
•With nortriptyline—19.8% on the HAM-
D17, 12.4% on the QIDS-SR16.
Response rates were 13.4% with mirtaza-
pine and 16.5% with nortriptyline. Statistically,
neither the response nor the remission rates dif-
fered by treatment, nor did these two treat-
ments differ in tolerability or side-effect burden.
Does choice of augmentation agent matter:
Lithium vs T3?
Similarly, after two failed medication treat-
ments, medication augmentation was less
effective than it was at the second step.
two augmentation options tested, lithium and
T3 thyroid hormone (Cytomel), are common-
ly considered by psychiatrists but less com-
monly used by primary care doctors.
Lithium is believed to increase serotoner-
gic function, which may have a synergistic
effect on the mechanism of action of antide-
pressants; a meta-analysis of placebo-con-
trolled studies supports lithium’s effectiveness
as adjunctive treatment.
Its side effects,
however, must be closely monitored.
primary monitoring concern is the small dif-
ference between the therapeutic blood level
(0.6–1.2 mEq/L) and potentially toxic blood
levels (> 1.5 mEq/L).
Lithium was started at 450 mg/day, and at
week 2 it was increased to the recommended
dose of 900 mg/day (a dose below the target
dose for bipolar disorder). If patients could not
tolerate 450 mg/day, the initial dose was 225
mg/day for 1 week before being increased to
450 mg/day, still with the target dose of 900
mg/day. The mean exit dose was 859.9 mg/day,
and the median blood level was 0.6 mEq/L.
Thyroid hormone augmentation using T3
is believed to work through both direct and
indirect effects on the hypothalamic-pituitary-
thyroid axis, which has a strong relationship
with depression. The efficacy of T3 augmenta-
tion is supported by a meta-analysis of eight
and T3 is effective whether or not
thyroid abnormalities are present.
In STAR*D, T3 was started at 25 µg/day
for 1 week, than increased to the recommend-
ed dose of 50 µg/day. The mean exit dose was
45.2 µg/day.
Fewer patients
therapy as a
option than we
Remission rates:
•With lithium augmentation—15.9% by
the HAM-D17, 13.2% by the QIDS-
•With T3 augmentation—24.7% by both
Response rates were 16.2% with lithium
augmentation and 23.3% with T3 augmenta-
While neither response nor remission
rates were statistically significantly different
by treatment, lithium was more frequently
associated with side effects (P = .045), and
more participants in the lithium group left
treatment because of side effects (23.2% vs
9.6%; P = .027). These results suggest that in
cases in which a clinician is considering an
augmentation trial, T3 has slight advantages
over lithium in effectiveness and tolerability.
T3 also offers the advantages of being easy to
use and not necessitating blood level moni-
toring. These latter benefits are especially rel-
evant to the primary care physician. However,
T3’s potential for long-term side effects (eg,
osteoporosis, cardiovascular effects) were not
examined, and it is not clear when to discon-
tinue it.
Switch to mirtazapine plus venlafaxine XR
or tranylcypromine?
Patients who reached level 4 were considered
to have a highly treatment-resistant depressive
illness, so treatments at this level were, by
design, more aggressive. Accordingly, at level 4
we investigated treatments that might be con-
sidered more demanding than those a primary
care physician would use. Approximately 40%
of patients in each treatment group were from
primary care settings.
Remission rates
•With the combination of mirtazapine
(mean dose 35.7 mg/day) and venlafaxine
XR (mean dose 210.3 mg/day)—13.7% by
the HAM-D17 and 15.7% by the QIDS-
•With the MAOI tranylcypromine (Parnate,
mean dose 36.9 mg/day)—6.9% by the
HAM-D17 and 13.8% by the QIDS-SR16.
Response rates were 23.5% with the com-
bination and 12.1% with tranylcypromine.
Neither remission nor response rates differed
However, the percentage reduction in
QIDS-SR16 score between baseline and exit
was greater with the combination than with
tranylcypromine. Further, more patients
dropped out of treatment with tranyl-
cypromine because of side effects (P < .03).
Tranylcypromine also has the disadvantage
of necessitating dietary restrictions.
A significant limitation of this compari-
son is that patients were less likely to get an
adequate trial of tranylcypromine, an MAOI,
than of the combination. When the 2-week
washout period (required before switching to
an MAOI) is subtracted from the total time in
treatment, approximately 30% of participants
in the tranylcypromine group had less than 2
weeks of treatment, and nearly half had less
than 6 weeks of treatment.
Therefore, even though the remission and
response rates were similar between groups,
the combination of venlafaxine-XR plus mir-
tazapine therapy might have some advantages
over tranylcypromine. These results provided
the first evidence of tolerability and at least
modest efficacy of this combination for treat-
ment-resistant cases.
Overall, what was the cumulative
remission rate?
The theoretical cumulative remission rate
after four acute treatment steps was 67%.
Remission was more likely to occur during the
first two levels of treatment than during the
last two. The cumulative remission rates for
the first four steps were:
Level 1—33%
Level 2—57%
Level 3—63%
Level 4—67%.
Patients with a clinically meaningful response
or, preferably, remission at any level could
enter into a 12-month observational follow-
up phase. Those who had required more treat-
ment levels had higher relapse rates during
this phase.
Further, if a patient achieved
Lithium can be
an adjunctive
treatment for
depression, but
its side effects
must be closely
remission rather than just response to treat-
ment, regardless of the treatment level, the
prognosis at follow-up was better, confirming
the importance of remission as the goal of
Results also provided a warning—the
greater the number of treatment levels that a
patient required, the more likely that patient
and physician would settle for response.
Whether the greater relapse rates reflect a
harder-to-treat depression or the naturalistic
design of the follow-up phase (with less con-
trol over dosing) is unclear.
•Measurement-based care is feasible in pri-
mary care. Primary care doctors can ensure
vigorous but tolerable dosing using a self-
report depression scale to monitor response, a
side-effects tool to monitor tolerability, and
medication adjustments at critical decision
points guided by these two measures.
Remission, ie, complete recovery from a
depressive episode, rather than merely sub-
stantial improvement, is associated with a bet-
ter prognosis and is the preferred goal of treat-
Pharmacologic differences between psy-
chotropic medications did not translate into
substantial clinical differences, although
tolerability differed. These findings are con-
sistent with a large-scale systematic evi-
dence review recently completed by the
Agency for Healthcare Research and
Quality that compared the effectiveness of
Given the difficulty in
predicting what medication will be both
efficacious for and tolerated by an individ-
ual patient, familiarity with a broad spec-
trum of antidepressants is prudent.
Remission of depressive episodes will most
likely require repeated trials of sufficiently sus-
tained, vigorously dosed antidepressant med-
ication. From treatment initiation, physicians
should ensure maximal but tolerable doses for
at least 8 weeks before deciding that an inter-
vention has failed.
If a first treatment doesn’t work, either
switching or augmenting it is a reasonable
choice. Augmentation may be preferred if
the patient is tolerating and receiving par-
tial benefit from the initial medication
choice. While bupropion SR and buspirone
were not different as augmenters by the pri-
mary remission outcome measure, secondary
measures (eg, tolerability, depressive symp-
tom change over the course of treatment,
clinician-rated Quick Inventory of Depres-
sive Symptomatology) recommended bupro-
pion-SR over buspirone.
If physicians switch, either a within-class
switch (eg, citalopram to sertraline) or an out-
of-class switch (eg, citalopram to bupropion
SR) is effective, as is a switch to a dual-action
agent (eg, venlafaxine XR).
The likelihood of improvement after two
aggressive medication trials is very low and
likely requires more complicated medication
regimens, and the existing evidence base is
quite thin. These primary care patients should
likely be referred to psychiatrists for more
aggressive and intensive treatment.
For patients who present with major
depressive disorder, STAR*D suggests that
with persistence and aggressive yet feasible
care, there is hope: after one round, approxi-
mately 30% will have a remission; after two
rounds, 50%; after three rounds, 60%; and
after four rounds, 70%.
While STAR*D excluded depressed
patients with bipolar disorder, a depressive
episode in a patient with bipolar disorder can
be difficult to distinguish from a depressive
episode in a patient with major depressive dis-
order. Primary care physicians need to consid-
er bipolar disorder both in patients presenting
with a depressive episode and in those who
fail an adequate trial.
Subsequent STAR*D analyses will compare in
greater depth outcomes in primary care vs psy-
chiatric settings at each level of treatment.
Given the greater risk of depression persis-
tence associated with more successive levels of
treatment, subsequent research will focus on
ways to more successfully treat depression in
the earlier stages, possibly through medication
combinations earlier in treatment (somewhat
analogous to a “broad-spectrum antibiotic”
approach for infections).
persistence and
aggressive yet
feasible care,
there is hope
Dr. Gaynes has received grants and research support from the National
Institute of Mental Health, Agency for Healthcare Research and Quality,
Robert Wood Johnson Foundation, Pfizer, and Ovation Pharmaceuticals. He
has performed as an advisor or consultant for Pfizer; Shire Pharmaceuticals;
and Wyeth-Ayerst. He has also received a speaker’s honorarium from
Dr. Rush has provided scientific consultation to or served on Advisory Boards
for Advanced Neuromodulation Systems;AstraZeneca; Best Practice Project
Management; Bristol-Myers Squibb Company; Cyberonics; Forest
Pharmaceuticals; Gerson Lehman Group; GlaxoSmithKline; Jazz Pharmaceuticals;
Eli Lilly & Company; Magellan Health Services; Merck & Co.; Neuronetics; Ono
Pharmaceutical; Organon USA; PamLab, Personality Disorder Research Corp.;
Pfizer; The Urban Institute; and Wyeth-Ayerst Laboratories. He has received
royalties from Guilford Publications and Healthcare Technology Systems, and
research/grant support from the Robert Wood Johnson Foundation, the National
Institute of Mental Health, and the Stanley Foundation; has been on speaker
bureaus for Cyberonics, Forest Pharmaceuticals, GlaxoSmithKline, and Eli Lilly &
Company; and owns stock in Pfizer.
Dr. Trivedi has received research support from Bristol-Myers Squibb
Company; Cephalon; Corcept Therapeutics; Cyberonics; Eli Lilly &
Company; Forest Pharmaceuticals; GlaxoSmithKline; Janssen
Pharmaceutica; Merck; National Institute of Mental Health; National
Alliance for Research in Schizophrenia and Depression; Novartis; Pfizer;
Pharmacia & Upjohn; Predix Pharmaceuticals; Solvay Pharmaceuticals; and
Wyeth-Ayerst Laboratories. He has served as an advisor or consultant for
Abbott Laboratories; Akzo (Organon Pharmaceuticals); Bayer; Bristol-Myers
Squibb Company; Cephalon; Cyberonics, Inc.; Forest Pharmaceuticals;
GlaxoSmithKline; Janssen Pharmaceutica Products, LP; Johnson & Johnson
PRD; Eli Lilly & Company; Meade Johnson; Parke-Davis Pharmaceuticals;
Pfizer; Pharmacia & Upjohn; Sepracor; Solvay Pharmaceuticals; and Wyeth-
Ayerst Laboratories. He has received speaker honoraria from Akzo
(Organon Pharmaceuticals); Bristol-Myers Squibb Company; Cephalon;
Cyberonics; Forest Pharmaceuticals; Janssen Pharmaceutica Products, LP;
Eli Lilly & Company; Pharmacia & Upjohn; Solvay Pharmaceuticals; and
Wyeth-Ayerst Laboratories.
Dr. Wisniewski has received grants and research support from the
National Institute of Mental Health. He has performed as a consultant for
Cyberonics Inc. and ImaRx Therapeutics.
Dr. Spencer has no disclosures to report.
Dr. Fava has received research support from Abbott Laboratories,
Alkermes, Aspect Medical Systems, Astra-Zeneca, Bristol-Myers Squibb
Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals,
GlaxoSmithKline, J & J Pharmaceuticals, Lichtwer Pharma GmbH, Lorex
Pharmaceuticals, Novartis, Organon Inc., PamLab, LLC, Pfizer, Pharmavite,
Roche, Sanofi/Synthelabo, Solvay Pharmaceuticals, and Wyeth-Ayerst
Laboratories. He has served on Advisory Boards and done Consulting for
Aspect Medical Systems, Astra-Zeneca, Bayer AG, Biovail Pharmaceuticals,
BrainCells, Bristol-Myers Squibb Company, Cephalon, Compellis, Cypress
Pharmaceuticals, Dov Pharmaceuticals, Eli Lilly & Company, EPIX
Pharmaceuticals, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals,
GlaxoSmithKline, Grunenthal GmBH, Janssen Pharmaceutica, Jazz
Pharmaceuticals, J & J Pharmaceuticals, Knoll Pharmaceutical Company,
Lundbeck, MedAvante, Neuronetics, Novartis, Nutrition 21, Organon,
PamLab, LLC, Pfizer, PharmaStar, Pharmavite, Roche, Sanofi/Synthelabo,
Sepracor, Solvay Pharmaceuticals, Somaxon, Somerset Pharmaceuticals, and
Wyeth-Ayerst Laboratories. Dr. Fava has served on the speaker’s bureau for
Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Company,
Cephalon, Eli Lilly & Company, Forest Pharmaceuticals, GlaxoSmithKline,
Novartis, Organon, Pfizer, PharmaStar, and Wyeth-Ayerst Laboratories. He
has equity in Compellis and MedAvante.
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ADDRESS: Bradley N. Gaynes, MD, MPH, Department of Psychiatry,
University of North Carolina at Chapel Hill, First Floor, Neurosciences
Hospital, Room 10306, CB#7160, Chapel Hill, NC 27599; e-mail
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... TMS therapy may restore neuronal circuit activity in patients with depression and has been shown to provide statistically and clinically significant improvement of depressive symptoms [61][62][63][64][65][66][67]. Symptom improvement in mood, reduced days of experiencing depressive symptoms and increased engagement in socializing have been reported as early as two weeks following the completion of the TMS therapy protocol [68]. Approximately 83% of patients treated with TMS therapy showed significant improvements in depressive symptoms, and 62% of patients reported symptom relief lasting through 12 months [66][67]69]. ...
... Major depressive disorder (MDD) is the most common mental disorder, with prevalence rates ranging from 7.2% to 10.8% in the general population [1]. It is a highly recurrent disorder [2], with approximately 50% of patients experiencing a relapse after a first episode, 70% after a second episode, and 90% after a third one [3]. ...
Full-text available
This study aims to assess the efficacy of a psychoeducational family intervention (PFI) to reduce the severity of depressive symptoms and to improve psychosocial functioning and to increase social contacts in a sample of patients with major depressive disorder (MDD). The degree to which PFI will reduce patients’ relapses, hospitalizations, and self-stigmatization and will improve their quality of life will also be assessed. Other secondary outcomes include the improvement of relatives’ coping strategies, family burden, expressed emotions and quality of life. This non-profit, unfunded, national, multicentric randomized controlled trial with blinded outcome assessments will be carried out in 24 Italian university outpatient units. Families will be assessed at baseline and at 6, 12, and 24 months post-randomization. Our working hypothesis is that the PFIs will reduce the patients’ severity of depressive symptoms, their relapses, and their hospitalizations, and that they will improve their psychosocial functioning and quality of life. We expect these results to be maintained after 12 and 24 months, albeit with a reduction in magnitude. The sample will consist of 384 patients randomized at a 1:1 ratio and stratified according to center, age, gender, and educational level.
... The general population has shown that in order to achieve remission, aggressive phased care that is based on measurement methods, including several pharmaceutical trials lasting a number of months each, together with psychotherapy, may be necessary [14]. Depressive disorders in PD can be successfully treated with medication, somatic therapies, psychotherapies, rehabilitative therapies, or a combination of these therapies when they are actively and diligently pursued [15]. ...
Full-text available
Parkinson's disease has a high prevalence of depression, which is frequently undiagnosed and untreated and has a tight relationship to health-related quality of life. In order to study the latest findings in this field, This article summarizes the research related to PD depression from 2010 to 2022, respectively, from the pathogenesis research, including the influence of genes, nutritional factors, and proteins, and it also summarizes the current treatment methods for PD depression, including drug therapy, behavioral therapy, and psychotherapy. It also summarizes recent clinical trials, including new drugs and cognitive therapies. Finally, the future development direction of Parkinson's depression has been prospected. This paper finds that new genes and nutritional factors have been found in the pathological study of Parkinson's depression, and new combinations of drug therapy have been added to the treatment of Parkinson's depression, as well as new methods of using behavioral therapy and psychological intervention to assist the treatment.
... Mientras que en el hipotiroidismo subclínico, definido como una concentración elevada de niveles de TSH y niveles circulantes normales de T4L y T3, 7,8 no se ha evidenciado una asociación clara entre la condición y la presencia de síntomas neuropsiquiátricos 4 . La presentación clínica de un trastorno depresivo debido a hipotiroidismo tiende a remitir con la administración de hormonas tiroideas, hallazgo que llevó a la consideración de la administración de estos compuestos para el aumento de la respuesta y potenciación terapéutica de los antidepresivos en depresión primaria 6,9 . Los primeros ensayos clínicos de combinación de hormonas tiroideas y antidepresivos tricíclicos (ATC) se hicieron hace más de 35 años en pacientes eutiroideos con depresión y esta estrategia continúa vigente dentro de la aproximación algorítmica en depresión monopolar refractaria 10,[27][28][29][30] . ...
... Due to the lack of reliable biomarkers, the diagnosis of MDD mainly relies on the symptoms of patients and depression rating scales, resulting in a high rate of misdiagnosis [5]. Although a wide variety of antidepressants are available, 30-50% of patients with MDD do not achieve complete remission [6], reflecting that the conventional therapies do not address the important biological processes involved in MDD pathology. Therefore, a better understanding of the underlying pathophysiological mechanisms of MDD is necessary to identify possible treatment targets for the development of biomarkers that help provide a more accurate and early diagnosis. ...
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Background Major depressive disorder (MDD) is a life-threatening and debilitating mental health condition. Mitophagy, a form of selective autophagy that eliminates dysfunctional mitochondria, is associated with depression. However, studies on the relationship between mitophagy-related genes (MRGs) and MDD are scarce. This study aimed to identify potential mitophagy-related biomarkers for MDD and characterize the underlying molecular mechanisms. Methods The gene expression profiles of 144 MDD samples and 72 normal controls were retrieved from the Gene Expression Omnibus database, and the MRGs were extracted from the GeneCards database. Consensus clustering was used to determine MDD clusters. Immune cell infiltration was evaluated using CIBERSORT. Functional enrichment analyses were performed to determine the biological significance of mitophagy-related differentially expressed genes (MR-DEGs). Weighted gene co-expression network analysis, along with a network of protein–protein interactions (PPI), was used to identify key modules and hub genes. Based on the least absolute shrinkage and selection operator analysis and univariate Cox regression analysis, a diagnostic model was constructed and evaluated using receiver operating characteristic curves and validated with training data and external validation data. We reclassified MDD into two molecular subtypes according to biomarkers and evaluated their expression levels. Results In total, 315 MDD-related MR-DEGs were identified. Functional enrichment analyses revealed that MR-DEGs were mainly enriched in mitophagy-related biological processes and multiple neurodegenerative disease pathways. Two distinct clusters with diverse immune infiltration characteristics were identified in the 144 MDD samples. MATR3, ACTL6A, FUS, BIRC2, and RIPK1 have been identified as potential biomarkers of MDD. All biomarkers showed varying degrees of correlation with immune cells. In addition, two molecular subtypes with distinct mitophagy gene signatures were identified. Conclusions We identified a novel five-MRG gene signature that has excellent diagnostic performance and identified an association between MRGs and the immune microenvironment in MDD.
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Objective: To meta-analyze clinical efficacy and safety of ketamine compared with other anesthetic agents in the course of electroconvulsive therapy (ECT) in major depressive episode (MDE). Methods: PubMed/MEDLINE, Cochrane Library, Embase, GoogleScholar, and US and European trial registries were searched from inception through May 23, 2023, with no language limits. We included RCTs with (1) a diagnosis of MDE; (2) ECT intervention with ketamine and/or other anesthetic agents; and (3) measures included: depressive symptoms, cognitive performance, remission or response rates, and serious adverse events. Network meta-analysis (NMA) was performed to compare ketamine and 7 other anesthetic agents. Hedges’ g standardized mean differences (SMDs) were used for continuous measures, and relative risks (RRs) were used for other binary outcomes using random-effects models. Results: Twenty-two studies were included in the systematic review. A total of 2,322 patients from 17 RCTs were included in the NMA. The overall pooled SMD of ketamine, as compared with a propofol reference group, was -2.21 (95% confidence interval [CI], -3.79 to -0.64) in depressive symptoms, indicating that ketamine had better antidepressant efficacy than propofol. In a sensitivity analysis, however, ketamine-treated patients had a worse outcome in cognitive performance than propofol-treated patients (SMD, -0.18; 95% CI, -0.28 to -0.09). No other statistically significant differences were found. Conclusions: Ketamine-assisted ECT is tolerable and may be efficacious in improving depressive symptoms, but a relative adverse impact on cognition may be an important clinical consideration. Anesthetic agents should be considered based on patient profiles and/or preferences to improve effectiveness and safety of ECT use.
Introduction: Mental health disorders, especially depressive and anxiety disorders, are associated with substantial health-related burden. While the second-generation antidepressants are widely accepted as first-line pharmacological treatment for major depressive disorder (MDD), patient response to such treatment is variable, with more than half failing to achieve complete remission, and residual symptoms are frequently present. Areas covered: Here, the pharmacodynamics of venlafaxine XR are reviewed in relation to its role as both a selective serotonin reuptake inhibitor (SSRI) and a serotonin-norepinephrine-reuptake inhibitor (SNRI), and we look at how these pharmacodynamic properties can be harnessed to guide clinical practice, asking the question 'is it possible to develop a symptom-cluster-based approach to the treatment of MDD with comorbid anxiety utilizing venlafaxine XR?.' Additionally, three illustrative clinical cases provide practical examples of the utility of venlafaxine-XR in real-world clinical practice. The place of venlafaxine XR in managing fatigue/low energy, a frequent residual symptom in MDD, is explored using pooled data from clinical trials of venlafaxine XR. Expert opinion: Venlafaxine XR should be considered as a first-line treatment for MDD with or without comorbid anxiety, and there are clear pharmacodynamic signals supporting a symptom cluster-based treatment paradigm for venlafaxine XR.
Full-text available
We undertook a study to confirm and extend preliminary findings that participants with major depressive disorder (MDD) in primary care and specialty care settings have with equivalent degrees of depression severity and an indistinguishable constellation of symptoms. Baseline data were collected for a distinct validation cohort of 2,541 participants (42% primary care) from 14 US regional centers comprised of 41 clinic sites (18 primary care, 23 specialty care). Participants met broadly inclusive eligibility criteria requiring a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of MDD and a minimum depressive symptom score on the 17-item Hamilton Rating Scale for Depression. The main outcome measures were the 30-item Inventory of Depressive Symptomatology--Clinician Rated and the Psychiatric Diagnostic Screening Questionnaire. Primary care and specialty care participants had identical levels of moderately severe depression and identical distributions of depressive severity scores. Both primary care and specialty care participants showed considerable suicide risk, with specialty care participants even more likely to report prior suicide attempts. Core depressive symptoms or concurrent psychiatric disorders were not substantially different between settings. One half of participants in each setting had an anxiety disorder (48.6% primary care vs 51.6% specialty care, P = .143), with social phobia being the most common (25.3% primary care vs 32.1% specialty care, P = .002). For outpatients with nonpsychotic MDD, depressive symptoms and severity vary little between primary care and specialty care settings. In this large, broadly inclusive US sample, the risk factors for chronic and recurrent depressive illness were frequently present, highlighting a clear risk for treatment resistance and the need for aggressive management strategies in both settings.
Major depressive disorder is expected to become the second leading cause of disability worldwide by the year 2020. A large proportion of this disability can be attributed to the large number of patients (>70%) who do not achieve sustained remission following initial treatment. Presently, the evidence available to guide management for treatment-resistant depression (TRD) is quite limited. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study has been designed to evaluate treatment options to improve clinical outcomes for depressed outpatients who do not achieve a satisfactory outcome after one or more treatment attempts. STAR*D helps to define the best "next-step" treatments for patients with TRD, and it will provide descriptive information on the longer-term benefits of successful treatments, as well as the side-effect burden and economic costs associated with different treatments. The study has enrolled over 4,000 patients recruited from primary care and psychiatric settings in the public and private sectors. Preliminary baseline findings are currently being reported. Final results regarding preferred treatment options are expected by May 2006.
Context.— Psychotropic medications are widely prescribed, but how new classes of psychotropic medications have affected prescribing patterns has not been well documented.Objective.— To examine changes between 1985 and 1994 (data from 1993 and 1994 were combined) in the prescribing patterns of psychotropic medications by office-based primary care physicians, psychiatrists, and other medical specialists.Design.— National estimates for the number of visits during which a physician prescribed a psychotropic medication based on the National Ambulatory Medical Care Surveys conducted in 1985, 1993, and 1994.Setting.— Office-based physician practices in the United States.Participants.— A systematically sampled group of office-based physicians.Main Outcome Measures.— National estimates of visits that included a psychotropic medication.Results.— The number of visits during which a psychotropic medication was prescribed increased from 32.73 million to 45.64 million; the proportion of such visits, as a proportion of all visits, increased from 5.1% to 6.5% (P≤.01). Antianxiety or hypnotic drug visits, previously the largest category, decreased as a proportion of psychotropic drug visits (P≤.01) and are now surpassed by antidepressant visits. Visits for depression increased from 10.99 million in 1988 to 20.43 million in 1993 and 1994 (P≤.01). Stimulant drug visits increased from 0.57 million to 2.86 million (P≤.01). Although visits for depression doubled for both primary care physicians and psychiatrists, the proportion of visits for depression during which an antidepressant was prescribed increased for psychiatrists but not for primary care physicians.Conclusions.— The patterns of psychotropic medication use in outpatient medical practice changed dramatically during the study period, especially in psychiatric practice.
Depressive disorders can affect all aspects of a person's functioning and are often associated with significant psychosocial impairment. Such psychosocial problems promote studies of the efficacy of short-term psychotherapy for depressive disorders. This report summarizes the literature on acute-phase, short-term psychotherapy for adult outpatients with major depressive disorder and is an updated component of a larger review commissioned by the United States Public Health Services Agency for Health Care Policy and Research (AHCPR review on "Short-term Psychotherapy for Depression," Jarrett and Maguire [1991]; Jarrett and Down [in press] during the preparation of the Clinical Practice Guidelines in primary care (Depression Guideline Panel 1993). The short-term psychotherapies reviewed here and studied most often include behavior therapy, cognitive therapy, interpersonal psychotherapy, and brief dynamic psychotherapy, which all aim to reduce depressive symptoms. We comment on the state of the literature and raise some of the questions which await data.